For Reference NOT TO BE TAKEN FROM THIS ROOM Frontispiece. Pl.ATE I 5 ( 9 E 2 ) F G 1 2 ,■'■•*■ . . ... >V MB 3 •-1 • . 4- 5 6 7 £ B 9 10 WfiBw: Solar spectrum with Fraunhofer lines. 2. Absorption spectrum of a concentrated solution of oxyhse globin; all the light is absorbed except in the red and orange. "•. Absorption spectrum of a les> concentri solution of oxyhemoglobin, i. Absorption spectrum of a dilute solution of oxyhemoglobin, showing tin characteristic bands. •">. Absorption spectrum of a very dilute solution of oxyhsemoglobin, showing only 6 Absorption spectrum of a dilute solution of reduced haemoglobin, showing the characteristic .-' ed with spectrum 4). 7. Absorption Bpectrum of a dilute solution of carbon-monoi haemoglobin (to be compared with spectrum I). 8. Absorption spectrum of metheemoglobin. 9. Absoi H spectrum of acid h tlcoholic solution). 10. Absorption spectrum of alkaline haematin (alcoholic - odifled from MacMunn, Thi Specb-oscopt in Medicine). AN AMERICAN TEXT-BOOK OF PHYSIOLOGY LM Angeles, CaJ, HENRY P. BOWDITCH, M. D. WARREN P. LOMBARD, M. D. JOHN G. CURTIS, M.D. GRAHAM LUSK, Ph.D., F.R.S. (EDIN.) HENRY H. DONALDSON, Ph. D. W. T. PORTER, M.D. W. H. HOWELL, Ph.D., M.D. EDWARD T. REICHERT, M.D. FREDERIC S. LEE, Ph.D. HENRY SEW ALL, Ph.D., M.D. EDITED BY WILLIAM H. HOWELL, Ph.D., M.D. Professor of Physiology in the Johns Hopkins University, Baltimore, Md. SECOND EDITION, REVISED Vol. I. BLOOD, LYMPH, AND CIRCULATION; SECRETION, DIGESTION AND NUTRITION; RESPIRATION AND ANIMAL HEAT; CHEMISTRY OF THE BODY PHILADELPHIA AND LONDON W. B. SAUNDERS & COMPANY 1901 I 4 Copyright, 1900. By W. B. SAUNDERS & COMPANY. ELECTROTYPED BY PRESS OF WESTCOTT * THOMSON PHILAOA. W - B - SAUNDERS & COMPA CONTRIBUTORS TO VOL. L JOHN G. CURTIS, M.D., Professor of Physiology in Columbia University (College of Physicians and Surgeons). W. H. HOWELL, Ph. D., M. D., Professor of Physiology in the Johns Hopkins University. GRAHAM LUSK, Ph.D., F. R. S. (Edin.), Professor of Physiology in the University and Belle vue Hospital Medical College, New York. W. T. PORTER, M.D., Associate Professor of Physiology in the Harvard Medical School. EDWARD T. REICHERT, M. D., Professor of Physiology in the University of Pennsylvania. PREFACE TO THE SECOND EDITION. Advantage has been taken of the necessity of issuing a second edition of the American Text-Book of Physiology to alter somewhat its general arrangement. The book has proved to be successful, and for the most part has met only with kindly and encouraging criticisms from those who have made use of it. Many teachers, however, have suggested that the size of the book, when issued in a single volume, has constituted to some extent an inconvenience when regarded from the standpoint of a student's text- book that may be needed daily for consultation in the lecture-room or the labora- tory. It has been thought best, therefore, to issue the present edition in two volumes, with the hope that the book may thereby be made more serviceable to those for whose aid it was especially written. This change in the appearance of the book has necessitated also some alteration in the arrangement of the sections, the part upon the Physiology of Nerve and Muscle being transferred to the second volume, so as to bring it into its natural relations with the Physiology of the Central Nervous System. The actual amount of material in the book remains substantially the same as in the first edition, although, naturally, very many changes have been made. Even in the short time that has elapsed since the appearance of the first edition there has been much progress in physiology, as the result of the constant activity of experimenters in this and the related sciences in all parts of the world, and an effort has been made by the various contributors to keep pace with this progress. Statements and theories that have been shown to be wrong or improbable have been eliminated, and the new facts discovered and the newer points of view have been incorporated so far as possible. Such changes are found scattered throughout the book. The only distinctly new matter that can be referred to specifically is found in the section upon the Central Nervous System, and in a short section upon the modern ideas and nomenclature of physical chemistry, with reference especially to the processes of osmosis and diffusion. The section dealing with the < Vntral Nervous System has been recast in large part, with the intention of making it more suitable to the actual needs of medical students ; while a brief presen- tation of some of the elementary conceptions of physical chemistry seems to he necessary at the present time, owing to the large part that these views are taking in current discussions in physiological and medical literature. The index has been revised thoroughly and considerably amplified, a table of contents has been added to each volume, and numerous new figures have been introduced. August. 1900. PREFACE. The collaboration of several teachers in the preparation of an elementary text-book of physiology is unusual, the almost invariable rule heretofore having been for a single author to write the entire book. It does not seem desirable to attempt a discussion of the relative merits and demerits of the two plans, since the method of collaboration is untried in the teaching of physi- ology, and there is therefore no basis for a satisfactory comparison. It is a fact, however, that many teachers of physiology in this country have not been altogether satisfied with the text-books at their disposal. Some of the more successful older books have not kept pace with the rapid changes in modern physiology, while few, if any, of the newer books have been uniformly satis- factory in their treatment of all parts of this many-sided science. Indeed, the literature of experimental physiology is so great that it would seem to be almost impossible for any one teacher to keep thoroughly informed on all topics. This fact undoubtedly accounts for some of the defects of our present text-books, and it is hoped that one of the advantages derived from the col- laboration method is that, owing to the less voluminous literature to be consulted, each author has been enabled to base his elementary account upon a comprehensive knowledge of the part of the subject assigned to him. Those who are acquainted with the difficulty of making a satisfactory elementary presentation of the complex and oftentimes unsettled questions of physiology must agree that authoritative statements and generalizations, such as are fre- quently necessary in text-books if they are to leave any impression at all upon the student, are usually trustworthy in proportion to the fulness of informa- tion possessed by the writer. Perhaps the most important advantage which may be expected to follow the use of the collaboration method is that the student gains thereby the point of view of a number of teachers. In a measure he reaps the same benefit as would be obtained by following courses of instruction under different teachers. The different standpoints assumed, and the differences in emphasis laid upon the various lines of procedure, chemical, physical, and anatomical, should give the student a better insight into the methods of the science as it exists PREFACE. to-day. A similar advantage may be expected to follow the inevitable over- lapping of the topics assigned to the various contributors, since this has led in many cases to a treatment of the same subject by several writers, who have approached the matter under discussion from slightly varying standpoints, and in a few instances have arrived at slightly different conclusions. In this last respect the book reflects more faithfully perhaps than if written by a single author the legitimate differences of opinion which are held by physi- ologists at present with regard to certain questions, and in so far it fulfils more perfectly its object of presenting in an unprejudiced way the existing state of our knowledge. It is hoped, therefore, that the diversity in method of treatment, which at first sight might seem to be disadvantageous, will prove to be the most attractive feature of the book. In the preparation of the book it has been assumed that the student has previously obtained some knowledge of gross and microscopic anatomy, or is taking courses in these subjects concurrently with his physiology. For this reason no systematic attempt has been made to present details of histology or anatomy, but each author has been left free to avail himself of material of this kind according as he felt the necessity for it in developing the physiolog- ical side. In response to a general desire on the part of the contributors, references to literature have been given in the book. Some of the authors have used these freely, even to the point of giving a fairly complete bibliography of the subject, while others have preferred to employ them only occasionally, where the facts cited are recent or are noteworthy because of their importance or historical interest. References of this character are not usually found in ele- mentary text books, so that a brief word of explanation seems desirable. It has not been supposed that the student will necessarily look up the references or commit to memory the names of the authorities quoted, although it is pos- sible, of course, that individual students may be led to refer occasionally to original sources, and thereby acquire a truer knowledge of the subject. The main result hoped for, however, is a healthful pedagogical influence. It is too often the case that the student of medicine, or indeed the graduate in medicine, regards his text-book as a final authority, losing sight of the fad that such books are mainly compilations from the works of various investigators, and that in all matters in dispute in physiology the final decision must be made, so far as possible, upon the evidence furnished by experimental work. To enforce this latter idea and to indicate the character and source of the great literature from which the material of the text-book is obtained have been the main reasons for the adoption of the reference system. It is hoped also that the PREFACE. book will be found useful to many practitioners of medicine who may wish to keep themselves in touch with the development of modern physiology. For this class "I readers references to literature are not only valuable, but frequently essential, since the limits of a text-book forbid an exhaustive discussion of mauv points of interesl concerning which fuller information may be desired. The numerous additions which are constantly being made to the literature of physiology and the closely related sciences make it a matter of difficulty to escape errors of statement in any elementary treatment of the subject. It can- not be hoped that this book will be found entirely free from defects of this character, but an earnest effort has been made to render it a reliable repository of the important facts and principles of physiology, and, moreover, to embody in it, so far as possible, the recent discoveries and tendencies which have so characterized the history of this science within the last few years. CONTENTS OF VOLUME I. INTRODUCTION (By W. H. Howell) 17 Definition of physiology and protoplasm, 17 — Animal and plant physiology, 17 — Vital irritability, 18 — Nutrition, assimilation and disassimilation, auabolism, kataholism, metabolism, 19 — Reproduction, 20,28 — Contractility and conductivity, 20 — Physiologi- cal division of labor, 22 — Pfliiger hypothesis of the structure of the living molecule, 23 — Loew's and Latham's hypothesis of the structure of the living molecule, 23 — The chemical structure of proteids, protamine, 24 — Physical structure of living matter, 24 — Vital force, 25 — Secretion and absorption, 27 — Heredity and consciousness, 28 — Gen- eral and special physiology, 29 — Methods of investigation used in the science of physiology, 30. BLOOD (By W. H. Howell) 33 A. General Properties — Physiology of the Corpuscles 33 Histological structure of blood, 33 — Definition of blood-plasma, blood-serum, and defibrinated blood, 33 — Reaction of blood, 34— Specific gravity of blood, 34 — Histology of red corpuscles, 35 — Condition of the haemoglobin in the red corpuscles, 35 — Laking of blood, 35 — Globulicidal and toxic action of blood-serum, 36 — Isotonic, hypertonic, hypotonic solutions, 36 — Nature and amount of hfemoglobin, 37 — Compounds of haemo- globin with O, CO, NO. and CO2, 38— The iron of the haemoglobin molecule, 39— Haemo- globin crystals, 40 — Absorption spectra of haemoglobin, 40 — Derivative compounds of haemoglobin, 44— Origin and fate of the red corpuscles, 45 — Variations in the number of red corpuscles, 46 — Morphology and physiology of the leucocytes, 47 — Physiology of the blood plates, 49. B Chemical Composition op the Blood — Coagulation — Total Quantity of Blood — Regeneration after Hemorrhage 50 Composition of the plasma and corpuscles, 50 — Proteids of the blood plasma, 51 — Serum albumin, 52 — Paraglobulin, 53 — Fibrinogen, 53 — Coagulation of blood, super- ficial appearances, 54 — Time of clottiug, 55 — Theories of coagulation, 55 — Nature and origin of fibrin ferment, 58 — Intravascular clotting, 60 — Means of hastening or retard- ing clotting, 61 — Total quantity of blood in the body, 63 — Regeneration of the blood after hemorrhage, 63 — Transfusion of blood and salines, 64. C. Diffusion and Osmosis, and Their Importance in the Body 65 Osmotic pressure, 65 — Calculation of, 67 — Electrolysis, 67 — Grammolecular solutions, 67 — Osmotic pressure of proteids, 69 — Diffusion of proteids, 70. LYMPH (By W. H. Howell) 70 Lymph-vascular system, 70 — Formation of lymph, theories of, 70 — The factors con- trolling the flow of lymph, 75, 145 — Pressure in lymph-vessels, 146 — Effect of thoracic aspiration on lymph-flow, 147— Effect of body movements and valves on lymph-flow, 147. CIRCULATION 70 PART I. — The Mechanics of the Circulation of the Blood and of the Move- ment of the Lymph (By John G. Curtis) 76 A. General Considerations 76 General course of the blood-flow, 76 — Causes of the blood-flow, 77 — Working of die pumping mechanism, 78 — Pulmonary circuit, 78. B. Movement of the Blood in the Capillaries, Arteries, \m> Veins .... 79 Anatomical characteristics of the capillaries, 79— The circulation as observed under the microscope, 80 — Behavior of the red corpuscles, 81 Friction, axial stream, and inert layer, 81 — Behavior of the leucocyte-, 82 Emigration of the leucocytes, 83 Velocity of the blood in the small vessels, S3 Capillary blood-pressure. 84 C. The Pressure of the Blood in the Arteries, Capillaries, lnd Veins ... 85 Method of studying bl 1-pressure, manometers, 85— The mercurial manometer and graphic record of blood-pressure upon a kymograph, 88 — The mean pressure in arteries and veins, 90. 9 10 CONTENTS. PAGE D. The Causes of the Pressure in the Arteries, Capillaries, and Veins ... 91 Balance of the factors producing arterial pressure, 92 — The arterial pulse, 93 — The capillary pressure and its cause, 93- Extinction of tile arterial pulse in the capillaries, 94 — Venous pressure and its causes, 94— Subsidiary forces assisting the blood-flow, 95 — Respiratory pulse in the veins, 96 — The dangerous region, entrance of air into veins, 97. E. The Velocity of the Blood in Arteries, Capillaries, and Veins 98 Measurement of velocity in large vessels. Stromuhr, 98 — Measurement of rapid changes in velocity, Kin — Velocity and pressure of blood compared, KM — Relation of velocity to the sectional area of the vascular bed, 102 — Time spent by blood in capillary, 103. F. The Blood-flow through the Linus 103 (}. The Pulse Volume and the Work Done by the Ventricles 104 The cardiac cycle, 104 — The pulse volume, 105 — The work of the ventricles, 106 — Heart's contraction as a source of heat, 108. II. The Mechanism of the Valves of the Heart 108 I'se of the valves. 108 — The auriculoventricular valves, 108 — Use of the tendinous cords, 109 — The papillary muscles and their uses, 110 — The semilunar valves, 110 — Lunuhe and corpora arantii, 111. I. The Changes in Form and Position of the Beating Heart, and the Cardiac Impulse 112 General changes in the heart and arteries, 112 — The heart and vessels in the open chest, 113 — Changes of size and form in the beating ventricles, 113 — Changes of posi- tion of the ventricle, 114 — Changes in the auricle, great veins, and great arteries, 115 — Effects of opening the chest, 115 — Probable changes in heart in the unopened chest, 116 — The cardiac impulse or apex beat, 117. J. The Sounds of the Heart 118 Relations and character of the heart-sounds, 118 — Cause of the second sound, 118 — Causes of the first sound, 119. K. The Frequency of the Cardiac Cycles 121 L. The Relations in Time of the Main Events of the Cardiac Cycle .... 121 The auricular, ventricular, and cardiac cycles, 122 — The variability of each cycle, 123 — Relative lengths of ventricular systole and diastole, 123 — Lengths of auricular systole and heart pause, 124. M. The Pressure Within the Ventricles 125 Range of pressure within ventricles, 125 — Methods of recording ventricular press- ures. 126 — General character of curve of intraventricular pressure, 128 — Effect of auricular systole on the curve of ventricular pressure. 130— The opening and closing of the heart valves in relation to the curve of ventricular pressure, 130— Analysis of the curve of ventricular pressure, 133 — Negative pressure within the ventricles, 134. N. The Functions of the Auricles 135 The auricle as a force pump. 135 — Time relations of auricular systole and diastole, 136 — Statement of functions of auricles, l.;i; Negative pressure within the auricles, 137— Is the auricle emptied by its systole? 138— Question of regurgitation from auri- cles to veins, 138. O. The Arterial Pulse 139 Nature and importance of the arterial pulse, 139— Rate of transmission of the pulse- wave, 1 1(1 Frequency and regularity of the pulse, 141 — Arterial tension as indicated by the pulse, 141— Size and celerity of pulse. 1 II The pulse-trace, or sphygmogram. 142— Analysis of the sphygmogram, 143— The dicrotic wave, 143— The diagnostic use of i lie sphygmogram. 115. Part II.— The [nnervation ok the Heart (By W. T. Porter) 148 The cause of the rhythmic heart-heat. IIS The intracardiac ganglion ells and nerves, 148— The nerve theory of the heart-beat, 149— The muscular theory of the heart-beat, 150 The excitation wave and its passage over the heart, 152 The passage of the excitation wave from auricle to ventricle, 154— The refractory period and com- pensatory pause, 156, A. The Cardiac Nerves 159 Anatomical arrangement of the heart nerves, 159 The inhibitory nerves. 161 — Effect of inhibition on the ventricles 162— Effect of inhibition on the auricle and sinus, L64 Effect of inhibition on the bulbus arteriosus, 165 Effect of inhibition on the irritability of the heart. 165 Relation of inhibition to rate and strength of stim- ulus, 165 -Arrest of the heart in systole, 165— Comparative inhibitory power of the two vagi. 166 Effect of the septal nerves on the inhibition, 166— Theories of the nature of vagus inhibition, L66 Relation of age, temperature, and intracardiac press- are to inhibition, 167 — The augmentor or accelerator nerves of the heart, 167 — Effect of stimulating the augmentor nerves, Kill Simultaneous stimulation of the accelerator and inhibitory fibres, 17<» classification of the inhibitory and augmentor fibres, 171 — The centripetal nerves of the heart. 172 Existence of sensory nerves in the heart, CONTENTS. 11 FAGE 172 — The depressor nerve of the heart, 172 — Analysis of the effect of stimulation of the depressor nerve, 173 — Keflex etTeet of sensory nerves on the heart, 175 — Reflex effects through the sympathetic system on the heart, 175. B. The Centres of the Heart-nerves 170 The inhibitory centre, 176 — Tonus of the inhibitory centre, 176 — Origin of the car- dio-inhibitory fibres, 177 — Position of the augmentor centre, 177 — Action of higher parts of the brain on the cardiac centres, 178— The existence of peripheral reflex centres, 178 — Ligatures of Stan n ins, 17."v Part III.— The Nutrition of the Heart (By W. T. Porter) 179 Spongy structure of frog's heart, 179— The coronary arteries iu the dog, 179 — The terminal nature of coronary arteries, 180— The effect of closure of the coronary arte- ries, 181 — The cause of the arrest of the heart after closure of the coronary arteries, 182— Fibrillary contractions and recovery from, 183— Closure of the coronary veins, 184 — The volume of the coronary circulation, 184— The effect of the heart-eontractious on the coronary circulation, 185 — The vessels of Thebesius and the coronary veins, 186— Blood-supply and heart-beat, 186— Lymphatics of the heart, 186. C. Solutions which Maintain the Beat of the Heart 187 Methods of nourishing the heart with solutions, 187 — The composition and action of nutrient solutions, 189— The effect of CO2, organic substances, and physical character- istics of nutrient solutions, 191— Nourishment of the isolated mammalian heart, 191. Part IV.— The Innervation of the Blood-vessels (By W. T. Porter) 192 Historical account of the discovery of vaso-motor nerves, 192— Methods of demon- strating vaso-motor phenomena, 195— Experimental distinctions between vaso-const ric- tor and vaso-dilator nerve-fibres, 196 — Anatomical course of vaso-motor fibres. 197— Vaso-motor centre in the medulla, 198— Vaso-motor centres in the spinal cord, 199— Sympathetic vaso-motor centres— peripheral tone, 200— Rhythmical changes in vascular tone, 201 — Vaso-motor reflexes, 201, 202— Relation of cerebrum to vaso-motor centres, 202 — Pressor and depressor fibres, 202— Vaso-motor fibres to the brain, 203— Vaso-motor fibres to the head, 204— Vaso-motor fibres to the lungs, 21)5— Vaso-motor fibres to the heart, 206— Vaso-motor fibres to the intestines, 206— Vaso-motor fibres to the liver, 206 — Vaso-motor nerves of the kidney, 207 — Vaso-motor nerves of the spleen, 207 — Vaso- motor nerves of the pancreas, 207 — Vaso-motor nerves of the external generative organs, 207 — Vaso-motor nerves of the internal generative organs, 208 — Vaso-motor nerves of the portal system, 209— Vaso-motor nerves of the limbs, muscles, and tail, 209. SECRETION (By W. H. Howell) >1\\ A. General Considerations 211 Definition of gland and secretion, 211 — Types of glandular structure, 212— Older views of secretion and excretion, 213— General proofs that gland cells take an active part in secretion, 214 — Filtration through living and dead tissues, 215. B. Mucous and Albuminous Glands— Salivary Glands 215 Distinction between mucous and albuminous glands, 215— Goblel cells as unicellular mucous glands, 216— Anatomical relations of salivary glands, 217 Nerve-sapply to salivary glands, 218 — Histology of salivary glands, 219— Composition id" the saliva, 220 — Significance of the potassium sulphocyanide in saliva, 221 — Discovery of secre tory nerve-fibres to the salivary glands, 221— Distinct ion between "chorda" and "sympathetic" saliva, 222— Effect of varying the strength of the stimulus upon the composition of the saliva, 223 — Theory of trophic and secretory fibres, 224 Vacuoles in gland cells during secretion, 226 —Histological changes in glands as a result of func- tional activity, 226 — Action of atropin, pilocarpin, and nicotin on secretory fibres, 229 — The normal mechanism of salivary secretion, 230— Electrical changes in the salivaVy glands during secretion, 231. C The Pancreas — Glands of the Stomach and Intestines 231 Anatomical relations of the pancreas, 231 Histological characters of the pancreas, 231 — Composition of the pancreatic secretion, 232 - Secretory nerves of the pancreas, 232 — Histological changes in pancreatic cells during secretion, '.':;:: Distinction between enzymes and zymogens, 235 The normal mechanism of the pancreatic Becre- tion, 235— The histological characteristics of the gastric glands, 237 Composition of the gastric secretion, 238 -Secretory nerves of the gastric plan ds, 239 The normal mechanism of the gastric secretion, 210 Histological changes in the gastric glands during secretion, 242 — The secretion of the intestinal glands, 243. D. Liver and Kidney 244 Histology of liver in relation to the bile-ducts, -J 1 1 Composition of the bile, 215 — The quantity of bile secreted, 246— Relation of the blood-flow to the secretion of bile, 247 — Secretory nerve-libres to the liver cells, 217 Motor innervation of the bile-ducts and gall-bladder, 248— The normal mechanism of the bile secretion, 248 Effect of occlusion of the bile-ducts, 249— Histological characteristics of the kidney. 249 Com- position of the urine, 250— General theories of the secretion of urine. 251 Secretion of urea and related nitrogenous bodies, 252 Secretion of the water and salts, 253 — The blood-flow through the kidney and its relations to secretion. 255. 12 CONTENTS. PAGE E. Cutaneous Glands — Internal Seceetion 257 Sebaceous secretion, 257— The sweat-glands and the quantity of their secretion, 258 — The composition of sweat. 258 Secretory fibres to the sweat-glands, 25!) — The posi- tion of the sweat-centres in the cord and medulla, 26Q— The structure and phylogeny of the mammary glands, 261 — Composition of the milk, 261? Histological changes in the mammary glands during secretion, 262 — Secretory nerve-fibres to the mammary glands, 263 — Normal mcchauism of the secretion of milk, 264 — Internal secretions, general statements, 265 The internal secretions of the liver, 265 The internal secre- tion of the pancreas, 266 -The anatomical and histological relations of the thyroid body, 267 Accessory thyroids, 268 The anatomical relations of the parathyroids, 268 The functions of the thyroids and parathyroids, 268 Effect of removal of the adrenal bodies, 271 — Action of adrenal extracts on the circulation, 271 — Secretory nerves to the adrenals, 272 The isolation of epinephrin, 272— Anatomical relations of the pituitary body, 272— Physiological effects of extracts of the pituitary body, 272 — The internal secretions of the testis and the ovary, 273. CHEMISTRY OF DIGESTION AND NUTRITION (By W. H. Howell) 275 A. Definition and Composition of Foods Characteristics of Enzymes . . . . 275 General statements regarding foods and food-stuffs, 275 — General nutritive sig- nificance of the food-stuffs, 27I2 The excretion of the COa through the skin, 342, 11. Body-metabolism- Nutritive Value of the Food-stuffs 343 Determination of the total metabolism id" the body, 343 Definition of nitrogen- equilibrium, 344 -Definition of carbon- and general body-equilibrium, 315 — The nutri- tive importance of the proteids, 345 The luxus-consumption idea, 348 The nutritive value of albuminoids, 319 The nutritive value of fats, 350 The formation of fat in the body, 351 — The nutritive value of carbohydrates, 353— The nutritive value of water and salts, 354. CONTENTS. 13 PAGE I. Accessory Articles of Diet— Variations of Body-metabolism under Dif- ferent Conditions — Potential Energy of Food — Dietetics 357 Accessory articles of diet, 357 — Stimulants, 357 — Condiments, flavors, and meat extracts, 359 — Conditions influencing body-metabolism, 359 — The effect of muscular work on metabolism, 359 — Metabolism during sleep, 361— The effect of variations in temperature on body-metabolism, 362 — The effect of starvation on body-metabolism, 362 — The potential energy of food, 364 — The principles of dietetics, 366. MOVEMENTS OF THE ALIMENTARY CANAL, BLADDER, AND URETER (By W. H. Howell) 369 The physiology of plain muscle tissue, 369 — Mastication, 372 — Deglutition, 372— The Kronecker-Meltzer theory of deglutition, 375 — The nervous control of degluti- tion, 376 — Movements of the stomach, 377 — The extrinsic nerves controlling the move- ments of the stomach, 381 — Movements of the intestines, 3S2 — The peristaltic move- ments, 382 — Mechanism of the peristaltic movement, 384 — Pendular movements of the intestines, 3*4— Extrinsic nerves of the intestines, 384 — Effect of various conditions on the intestinal movements, 385 — The mechanism of defecation, 386 -The act of vomiting, 387 — The nervous mechanism of vomiting, 388 — Micturition, 389 — Move- ments of the ureters, 389 — Movements of the bladder, 390 — Nervous control of the bladder movements, 392. RESPIRATION (By Edward T. Reichert) 395 General statements, internal and external respiration, 395. A. The Respiratory Mechanism in Man 395 Physiological anatomy of the lungs and thorax, 395 — Conditions of pressure within the thorax, 396 — Definition of respiration, inspiration, and expiration, 398— Movements of the diaphragm, 398 — Movements of other muscles assisting the diaphragm, 399— Movements of the ribs, 400 — The function of the intercostal muscles, 402 — Summary of the action of the inspiratory muscles, 405 — Movements of expiration, 406 — Summary of the action of the expiratory muscles, 407 — Associated respiratory movements, 408 — Intrapulmonary and intrathoracic pressure, 408 — Respiratory sounds and nasal breathing, 409. B. The Gases in the Lungs, Blood, and Tissues 409 Alterations in the gases in the lungs, 409 — Alterations in the gases in the blood. 411 — The forces concerned in the diffusion of O and CO2 in the lungs, 412 — The interchange of O and CO2 between the alveoli and the blood, 414 — The tension of in the blood and tissues, 415 — The tension of CO2 in the blood and tissues, 416 — The tension of N, 417 — The forces producing the interchange of O and CO2 in the lungs, 417 — The forces producing the interchange of O and CO2 in the tissues, 419 — The extraction of gases from the blood, 420 — Cutaneous respiration, 422 — Internal or tissue respira- tion, 422. C. The Rhythm, Frequency, and Depth of the Respiratory Movements . . 423 The rhythm of the respiratory movements, 423 — The frequency and depth of the respiratory movements, 425. D. The Volumes of Air, Oxygen, and Carbon Dioxide Respired 426 Normal volumes of air respired and capacity of lungs and bronchi. 126 The volumes of O and CO2 respired, 428— Conditions influencing the volumes of () and COa respired, 429— The respiratory quotient, 436— Conditions influencing the respiratory quotient, 437. E. Principles of Ventilation 439 F. The Effects of the Respiration of Various Gases tin G. The Effects of the Gaseous Composition of the Blo< \ the Respi- ratory Movements I pi Eupncea, dyspnoea, apncea, and polypncsa, 440 The causes of apnoea, 441- The effect of muscular activity on the respiratory movements. 442- The conditions producing polypnosa, 443— The conditions producing dyspnoea, 443 -Asphyxia. 145. H. Artificial Respiration na I. The Effects of the Respiratory Movements on the Circulation .... 117 The effects of respiration on blood-pressure, 117 The effects of respiration on blood- flow, 450— The effects of respiration on the pulse, 151 The effects of obstruction of the air-passages and of the respiration of rarefied and compressed aii on the circula- tion, 45l. J. Special Respiratory Movements i;, I The movements in coughing, hawking, sneezing, laughing, crying, sobbing, sighing, etc., 454. K. The NERVOUS Mechanism of the RESPIRATORY Movements 455 The respiratory centres, 155 The rhythmic activity of the respiratory centre, 158— The afferent respiratory nerves, 160 Effects of section and stimulation oftbepneumo- 14 CONTENTS. PAGE gastric nerves, 460 — Effects of stimulation of the superior laryngeal nerve, 462 — Effects of stimulation of the glossopharyngeal nerve, 462 — Effects of stimulation of the tri- geminal nerve, 463 Effects of stimulation of the cutaneous nerves, 463 — The efferent respiratory nerves, 163. L. The Condition of the Respiratory Centre in the Fetus 464 The reasons for the absence of respiratory movements in the fetus, 464. M. The Innervation of the Lings 465 Broncho-constrictor and broncho-dilator fibres, 465 — Vaso-motor fibres to the lungs, 466 Summary of the pulmonary fibres found in the vagus, 466. ANIMAL HEAT (By Edward T. Reichert) 467 A. Body-temperature 467 Eomothermous and poikilothermous animals. 467 — Temperatures of different spe- cies of animals, 467 — The temperature <>f the different regions of the body, 46s — The conditions affecting body-temperature, 469 — Temperature regulation, 473. B. Income and Expenditure of Heat 474 The potential energy as furnished by the food-stuffs, 474 — The income of heat and methods of measuring, 475— The expenditure of heat, 476. C. Beat-production and Heat-dissipation 477 ( alorimetry, 477 — The construction and use of calorimeters, 478 — Conditions affect- ing heat-production, 482 — Conditions affecting heat-dissipation, 485. D. THE Heat-mkchanism . . 489 The mechanism concerned in thermogenesis, 489 — The thermogenic tissues, 490 — The thermogenic nerves and centres, 490 — The mechanism concerned in thermolysis, 494 — Therruotaxis, 495 — Abnormal thermotaxis, 496 — Post-mortem rise of tempera- ture, 497. THE CHEMISTRY OF THE ANIMAL BODY (By Graham Lusk) . 499 A. The Non-metallic Elements 499 The preparation, occurrence, and properties of hydrogen, 499 — The preparation, occurrence, and properties of oxygen, 500 — Ozone, 502 — Traube's theory of oxidations in the body, 502 — Occurrence, properties, and functions of water, 503 — Peroxide of hydrogen, 505 — The preparation, occurrence, and properties of sulphur, sulphuretted hydrogen, sulphurous and sulphuric acids, 505 — Preparation and properties of chlorine, 508 -Bromine and its compounds in the body, 508 — Iodine and its compounds in the body, 509 — Fluorine and its compounds in the body, 510 — Occurrence and properties of nitrogen and its compounds, 510 — Occurrence of phosphorus, 513 — Phosphorus-pois- oning, 513 — Compounds of phosphorus, 514 — Phosphorus in the body, 515 — Occurrence of carbon, 516 — Compounds of carbon, 517— Metabolism of carbon in the body, 518 — Properties and compounds of silicon, 519 — Occurrence and properties of potassium compounds, 519— Potassium in the body, 520 — Occurrence and properties of sodium and its compounds, 521 — Occurrence of ammonium carbonate and its fate in the body, 523 — Occurrence anil properties of calcium and its compounds, 523 — The history of cal- cium in the body, 525 — Occurrence of strontium in the body, 526 — Occurrence and prop- erties of magnesium compounds, 527 — The compounds of iron and its history in the metabolism of the body, 528. B. The Compounds of Carbon 531 The derivatives of methane. 531 — General formula and reactions of the monatomic alcohols, 531 — General formula and reactions of the fatty acids, 532 — The properties and occurrence of methane, 532 -Properties of trichlormethane (chloroform!, 533 — The properties of methyl aldehyde and general properties of aldehydes, 533 — Other methyl compounds and their action in the body, 531 — Properties and occurrence of formic acid, 534 — The properties of ethyl alcohol, 535— The fate of alcohol in the body, 535 -The properties of ethyl ether and chloral hydrate, 535 -The properties of acetic acid. 536— The properties of aceto-acetic acid, 537 — The properties of glycocoll (amido-acetic acid |, 5:;? The properties of Barcosin, 537 — Propyl compounds and their occurrence in the body, 53* Butyl compounds and their occurrence in the body, 539 — Pentyl compounds and their occurrence in the body, 539 Acids containing more than five carbon atoms (leucin, palmitin, etc.), 540 — Amines, their structure and occurrence, 541 — The cyanogen compounds, 541 — The. amines of the olefines [ptomaines, toxines, etc. i, 542 — Occurrence and structure of taurin, 543 — Occurrence and properties of the biliary salts. 513 — The properties and occurrence of lactic acid. 545— -The properties and occurrence of cvstein and cystin, 546— The amido-deri vat i ves of carbonic acid (urea, carbamic acid . 548 The properties and occurrence of urea, 548 — Creatin, creatinin, histidin, arginin, 550 The purin or alloxuric bodies and bases, 552 — Oxalic, succinic, and aspartic acids, 557— The properties and occurrence of glycerin and its compounds, 558 — The properties ami occurrence of lecithin, 559 — The history of fats in the body, 559 — The properties of oleic acid, 560. CONTENTS. 15 PAGE Carbohydrates 561 The structure and classification of carbohydrates, 561 — The glycoses, 562 — The di- saccharides, 564 — The cellulose group (starch), 5. Benzol Derivatives, or Aromatic Compounds 568 The benzol ring, 568— Phenol, its structure and occurrence, 569— Benzoic acid, its structure and occurrence, 569 — Tyrosiu, its structure and occurrence, 570 — Indol. its structure and occurrence, 571 — Epinephrin, its structure and occurrence, 572 — The history of the aromatic bodies in the urine, 572 — The structure and history of inosit, 573. Substances of Unknown Composition 573 The properties and occurrence of haemoglobin aud its compounds, 57:5 — The bile-pig- ments aud the melanius, 574 — The properties and occurrence of cholesterin, 575 — The general structure aud reactions of proteids, 575 — The classification of the proteids, 576 — The protamins and remarks upou the theoretical composition of the proteid molecule, 580. Index 583 CONTENTS OF VOLUME II. THE GENERAL PHYSIOLOGY OF MUSCLE AND NERVE (By Warren P. Lombard). THE CENTRAL NERVOUS SYSTEM (By Henry H. Donaldson). THE SPECIAL SENSES— VISION (By Henry P. Bowditch). HEARING, CUTANEOUS AND MUSCULAR SENSIBILITY, EQUI- LIBRIUM, SMELL, AND TASTE (By Henry Sewall). THE PHYSIOLOGY OF SPECIAL MUSCULAR MECHANISMS. THE ACTION OF LOCOMOTOR MECHANISMS (By War- ren P. Lombard). VOICE AND SPEECH (By Hexry Sewall). REPRODUCTION (By Frederic S. Lee). AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. I. INTRODUCTION. The term "physiology" is, in an etymological sense, synonymous with " natural philosophy," and occasionally the word is used with this significance even at the present day. 1 By common usage, however, the term is restricted to the liviug side of nature, and is meant to include the sum of our know- ledge concerning the properties of living matter. The active substance of which living things are composed is supposed to be fundamentally alike in structure in all cases, and is commonly designated as protoplasm {-oioroz, first, and nXdofxa, anything formed). It is usually stated that this word was first introduced into biological literature by the botanist Von Mold to designate the granular semi-liquid contents of the plant-cell. It seems, however, that priority in the use of the word belongs to the physiologist Purkinje (1840), who employed it to describe the material from which the young animal embryo is constructed. 2 In recent years the term has been applied indif- ferently to the soft material constituting the substance of either animal or plant-cells. The word must not be understood to mean a substance of a definite chemical nature or of an invariable morphological structure ; it is applied to any part of a cell that shows the properties of life, and is therefore only a convenient abbreviation for the phrase " mass of living matter." Living things fall into two great groups, animals and plant's, and corre- sponding to this there is a natural separation of physiology into two sciences, one dealing with the phenomena of animal life, the other with plant life. In what follows in this introductory section the former of these two divisions is chiefly considered, for although the most fundamental laws of physiology are, without doubt, equally applicable to animal and vegetable protoplasm, nevertheless the Structure as well as the properties of the two forms of matter are in some respects noticeably different, particularly in the higher types of organisms in each group. The most striking contrast, perhaps, is found in the fad that plants exhibit a lesser degree of specialization in form and function and 1 See Mineral Physiology ami Physiography, 'I'. Sterry Hunt, L886. 2 O. Hertwig: Die '/Ale and die (,'ewehe, lS. Vol. T.— 2 17 18 I.V AMERICAN TEXT-BOOK OF PHYSIOLOGY. a much greater power of assimilation. Owing to this latter property the plant-cell is able, with the aid of solar energy, to construct its protoplasm from very simple forms of inorganic matter, such as water, carbon dioxide, and inorganic salts. In this way energy is stored within the vegetable cell in the substance of complex organic compounds. Animal protoplasm, on the con- trary, has comparatively feeble synthetic properties ; it is characterized chiefly by its destructive power. In the long run, animals obtain their food from the plant kingdom, and the animal cell is able to dissociate or oxidize the complex material of vegetable protoplasm and thus liberate the potential energy con- tained therein, the energy taking the form mainly of heat and muscular work. We must suppose that there is a general resemblance in the ultimate structure of animal and vegetable living matter to which the fundamental similarity in properties is due, but at the same time there must be also some common dif- ference in internal structure between the two, and it is fair to assume that the divergent properties exhibited by the two great groups of living things are a direct outcome of this structural dissimilarity ; to make use of a figure of speech employed by Bichat, plants and animals are cast in different moulds. It is difficult, if not impossible, to settle upon any one property that absolutely shall distinguish living from dead matter. Nutrition, that is, the power of converting dead food material into living substance, and repro- duction, that is, the power of each organism to perpetuate its kind by the formation of new individuals, are probably the most fundamental charac- teristics of living things; but in some of the specialized tissues of higher animals the power of reproduction, so far as this means mere multiplication li\ cell-division, seems to be lost, as, for example, in the case of the nerve-eel 1- in the central nervous system or of the matured ovum itself before it is fertil- ized by the spermatozoon. Nevertheless these cellular units are indisputably living matter, and continue to exhibit the power of nutrition as well as other properties characteristic of the living state. It is possible also that the power of nutrition may, under certain conditions, be held in abeyance, tempo- rarily at least, although it is certain that a permanent loss of this property is incompatible with the retention of the living condition. It is frequently said that the most general property of living matter is its irritability. The precise meaning of the term vital irritability is hard to define. The word implies the capability of reacting to a stimulus and usually also the assumption that in the reaction some of the inner potential energy of tin- living materia] is liberated, so that the energy of the response is many time- greater, it may be, than the energy of the stimulus. This la-t idea is illustrated by the case of a i trading muscle, in which the stimulus acts as a liberating force causing chemical decompositions of the substance of the muscle with the liberation of a comparatively large amount of energy, chiefly in the form of heat or of heat and work". It may be remarked in passing, however, that we are not justified at present in assuming that a similar liberation of stored energy takes place in all irritable tissues. In the case of nerve-fibres, for instance, we have a typically irritable tissue which responds readily to INTR OD UCTION. 1 9 external stimuli, but as yet it has not been possible to show that the forma- tion or conduction of a nerve impulse is accompanied by or dependent upon a liberation of so-called potential chemical energy. The nature of the response of irritable living matter is found to vary with the character of the tissue or organism on the one hand, and, so far as intensity goes at least, with the nature of the stimulus on the other. Response of a definite character to appropriate external stimulation may be observed frequently enough in dead matter, and in some cases the nature of the reaction simulates closely some of those displayed by living things. For instance, a dead catgut string may be made to shorten after the manner of a muscular contraction by the appropriate application of heat, or a mass of gunpowder may be exploded by the action of a small spark and give rise to a great liberation of energy that had previously existed in potential form within its molecules. As regards any piece of matter we can only say that it exhibits vital irritability when the reaction or response it gives upon stimulation is one characteristic of living matter in general or of the particular kind of living matter under observation ; thus, a muscle-fibre contracts, a nerve-fibre conducts, a gland-cell secretes, an entire organism moves or in some way adjusts itself more perfectly to its environment. Considered from this standpoint, "irritability menus only the exhibition of one or more of the peculiar properties of living matter and can- not be used to designate a property in itself distinctive of living structure ; the term, in fact, comprises nothing more specific or characteristic than is implied in the more general phrase vitality. When an amoeba dies it is no longer irritable, that is, its substance no longer assimilates when stimulated by the presence of appropriate food, its conductivity and contractility disappear so that mechanical irritation no longer causes the protrusion or retraction of pseudopodia — no form of stimulation, in fact, is capable of calling forth any of the recognized properties of living matter. To ascertain, therefore, whether or not a given piece of matter possesses vital irritability we must first become acquainted with the fundamental properties of living matter in order to recog- nize the response, if any, to the form of stimulation \\>c(\. Nutrition or assimilation, in a wide sense of the word, has already been referred to as probably the most universal and characteristic of these prop- erties. By this term we designate that scries of changes through which dead matter is received into the structure of living substance. The term in its broadest sense may be used to cover the subsidiary processes of digestion. respiration, absorption, and excretion through which {'<><><{ material and oxygen are prepared for the activity of the living molecules, and the waste products of activity are removed from the organism, as well as the actual conversion of dead material into living protoplasm. This last act, which is presumably a synthetic process effected under the influence of living matter, is especially designated as anabolisni or as assimilation in a narrower sense of the word as opposed to disassimilat ion. By disassimilation or katabolism we mean those changes leading to the destruction of the complex substance of the living molecules, or of the food material in contact with these molecules. 20 AN AMERICAN TEXT-HOOK OF PHYSIOLOGY. As was said before, animal protoplasm is pre-eminently katabolic, and the evidence of its katabolism is found in the waste products, sucb as C0 2 , II.O, and area, which arc given off from animal organisms. Assimilation and disassimilation, or anabolism and katabolism, go hand in hand, and together constitute an ever-recurring cycle of activity that persists as long as the material retains its living structure, and is designated under the name metabolism. In most forms of living matter metabolism is in some way self-limited, so that gradually it becomes less perfect, old age comes on, and finally death ensues. It has been asserted that originally the metabolic activity of protoplasm was self-perpetuating — that, barring accident, the cycle of changes would go on forever. Resting upon this assumption it has been suggested by Weissmann that the protoplasm of the reproductive elements still retains this primitive and perfect metabolism and thus provides for the continuity of life. The speculations bearing upon this point will be discussed in more detail in the section on Reproduction. Reproduction in some form is also practically a universal property of living matter. The unit of structure among living organisms is the cell. Under proper conditions of nourishment the cell may undergo separation into two daughter cells. In some cases the separation takes place by a simple act of fission, in other cases the division is indirect and involves a number of interesting changes in the structure of the nucleus and the protoplasm of the body of the cell. In the latter case the process is spoken of as karyokinesis or mitosis. This act of division was supposed formerly to be under the con- trol of the nucleus of the cell, hut modern histology has shown that in kary- okinetic division the process, in many cases at least, is initiated by a special structure to which the name centrosome has been given. The many-celled animals arise by successive divisions of a primitive cell, the ovum, and in the higher forms of life the ovum requires to be fertilized by union with a sper- matozoon before cell-division becomes possible. The sperm-cell acts as a stimulus to the egg-cell (see section on Reproduction), and rapid cell-division is the result of their union. It must be noted also that the term reproduc- tion includes the power of hereditary transmission. The daughter-cells are similar in form to the parent-cell, and tl rganism produced from a fertilized ovum is substantially a facsimile of the parent forms. Living matter, there- fore, not only exhibits the power of separating off other units of living matter, but of transmitting to its progeny its own peculiar internal structure and properties. Contractility and conductivity are properties exhibited in one form or another in all animal organisms, and we must concede that they are to be counted among the primitive properties of protoplasm. The power of con- tracting or shortening is, in fact, one of the commonly recognized features of a living thing. It is generally present in the simplest forms of animal as well as vegetable life, although in the more specialized forms it is found most highly developed in animal organisms. The opinion seems to be general among physiologists that wherever this property is exhibited, whether in the INTlt OD UCTIO N. 2 1 formation of the pseudopodia of an amoeba or white blood-corpuscle, or in the vibratile movements of ciliary structures, or in the powerful contractions of voluntary muscle, the underlying mechanism by which the shortening is produced is essentially the same throughout. However general the property may be, it cannot be considered as absolutely characteristic of living struc- ture. As was mentioned before, Engelmann ' has been able to show that a dead catgut string when surrounded by water of a certain temperature and exposed to a sudden additional rise of temperature will contract or shorten in a man- ner closely analogous to the contraction of ordinary muscular tissue, and it is not at all impossible that the molecular processes involved in the shortening of the catgut string and the muscle-fibre may be esseutiallv the same. That conductivity is also a fundamental property of primitive protoplasmic structure seems to be assured by the reactions which the simple motile forms of life exhibit when exposed to external stimulation. An irritation applied to one point of a protoplasmic mass may produce a reaction involving other parts, or indeed the whole extent of the organism. The phenomenon is most clearly exhibited in the more specialized animals possessing a distinct nervous system. In these forms a stimulus applied to one organ, as for instance light acting upon the eve, may be followed by a reaction involving quite distant organs, such as the muscles of the extremities, and we know that in these cases the irritation has been conducted from one organ to the other by means of the nervous tissues. But here also we have a property that is widely exhibited in inanimate nature. The conduction of heat, electricity, and other forms of energy is familiar to every one. While it is quite possible that con- duction through the substance of living protoplasm is something mi generis, and does not find a strict parallel in dead structures, yet it must be admitted that it is conceivable that the molecular processes involved in nerve conduction may be essentially the same as prevail in the conduction of heat through a solid body, or in the conduction of a wave of pressure through a liquid mass. At present we know nothing definite as to the exact nature of vital conduction, and can therefore affirm nothing. The four great properties enumerated, namely, nutrition or assimilation (including digestion, secretion, absorption, excretion, anabolism, and katabolism), reproduction, conduction, and contractility, form the important features which we may recognize in all living things and which we make use of in distin- guishing between dead and living matter. A fifth property perhaps should be added, that of sensibility or sensation, but concerning this property as a general accompaniment of living structure our knowledge is extremely im- perfect; something more as to the difficulties connected with this subject will •be said presently. The four fundamental properties mentioned are all ex- hibited in some degree in the simplest forms of life, sueli as the protozoa. In the more highly organized animals, however, we find thai specialization of function prevails. Hand in hand with the differentiation in form that is displayed in the structure of tin istituent tissues there goes a specialization 1 Ueber dt'n Uraprung der Muskelkraft, Leipzig, 1893. 22 AN AMERICAN TEXT- HOOK OF PHYSIOLOGY. in certain properties with a concomitant suppression of other properties, the outcome of which is that muscular tissue exhibits pre-eminently the power of contractility, the nerve tissues are characterized by a highly developed power of conductivity, and so on. While in the simple unicellular forms of animal life the fundamental properties are all somewhat equally exhibited within the compass of a single unit or cell, in the higher animals we have to deal with a vast < linunity of cells segregated into tissues each of which possesses some distinctive property. This specialization of function is known technically as the physiological division of labor. The beginning of this process may be recognized in the cell itself. The typical cell is already an organism of some complexity as compared with a simple mass of undifferentiated protoplasm. The protoplasm of the nucleus, particularly of that material iu the nucleus which i- designated as chromatin, is differentiated, both histologically aud physiologically, from the protoplasm of the rest of the cell, the so-called cyto- plasm. The chromatin material iu the resting cell is arranged usually in a network, but during the act of division (karyokinesis) it is segmented into a number of rods or filaments known as chromosomes. Iu the ovum there are good reasons for believing that the power of transmitting hereditary charac- teristics is dependent upon the structure of these chromosomes. The nucleus, moreover, controls in some way the metabolism of the entire cell, for it has been shown, iu some cells at least, that a non-nucleated piece of the cytoplasm is not only deprived of the power of reproduction, but has also such limited powers of nutrition that it quickly undergoes disintegration. On the other hand contractility and conductivity, and some of the functions connected with nutrition, such as digestion and excretion, seem often to be specialized iu the cytoplasm. As a further example of differentiation in the cell itself the ex- istence of the centrosome may be referred to. The centrosome is a body of very minute size that has been discovered in numerous kinds of cells. It is considered by many observers to be a permanent structure of the cell, lying either in the cytoplasm, or possibly in some discs within the boundaries of the nucleus. When present it seems to have some special function in connection with the movements of the chromosomes during the act of cell-division. In the many-celled animals the primitive properties of protoplasm become highly developed, in consequence of this subdivision of function among the various tissues, and in many ways the most complex animals are, from a physiological standpoint, the simplest for purposes of study, since in them the various prop-' erties of living matter are not only exhibited more distinctly, but each is, as it were, isolated from the others and can therefore be investigated more directly. We are at liberty to suppose that the various properties so clearly recognizable in the differentiated tissues of higher animals are all actually or potentially contained in the comparatively undifferentiated protoplasm of the simplest uni- cellular forms. That the lilies of variation, or in other words the direction of specialization in form and function, are not infinite, but on the contrary comparatively limited, seems evident when we reflect that in spite of the numerous branches of the phylogenetic stem the properties as well as the poss INTR OD UCTION. 21 1 forms of the differentiated tissues throughout the animal kingdom are strikingly alike. Striated muscle, with the characteristic property of sharp and powerful contraction, is everywhere found; the central nervous system in the inver- tebrates is built upon the same type as in the highest mammals, and the variations met with in different animals are probably but varying degrees of perfection in the development of the innate possibility contained in primitive protoplasm. It is not too much to say, perhaps, that were we acquainted with the structure and chemistry of the ultimate units of living substance, the key to the possibilities of the evolution of form and function would be in our os session. Most interesting suggestions have been made in recent years as to the essentia] molecular structure of living matter. These views are necessarily very incomplete and of a highly speculative character, and their correctness or incorrectness is at present beyond the range of experimental proof; never- theless they are sufficiently interesting to warrant a brief statement of some of them, as they seem to show at least the trend of physiological thought. Pfliiger, 1 in a highly interesting paper upon the nature of the vital pro- cesses, calls attention to the great instability of living matter. He supposes that living substance consists of very complex and very unstable molecules of a proteid nature which, because of the active intra-molecular movement pre- sent, are continually dissociating or falling to pieces with the formation of simpler and more stable bodies such as water, carbon dioxide and urea, the act of dissociation giving rise to a liberation of energy. " The intra-molecular heat (movement) of the cell is its life." He suggests that in this living mole- cule the nitrogen is contained in the form of a cyanogen compound, and that the instability of the molecule depends chiefly upon this particular grouping. Moreover the power of the molecule to assimilate dead proteid and convert it to living proteid like itself he attributes to the existence of the cyanogen group. It is known that cyanogen compounds possess the property of polymerization, that is, of combining with similar molecules to form more complex mole- cules, and we may suppose that the molecules of dead proteid when brought into contact with the living molecules are combined with the latter by a pro- cess analogous to polymerization or condensation. By this means the stable structure of dead proteid is converted to the labile structure of living proteid, and the molecules of the latter increase in size and instability. When living substance dies its molecules undergo alteration and become incapable of ex- hibiting the usual properties of life. Pfliiger suggests that the change may consist essentially in an absorption of water whereby the cyanogen grouping passes over into an ammonia grouping. Loew 2 assumes also that the dif- ference between dead and living or active proteid lies chiefly in the fact thai in the latter we have a very unstable or labile molecule in which the atoms are in active motion. The instability of the molecules he likewise attributes to 1 Archiv fur die gesammte Physiologie, 1ST"), I'd. lo. S. 251. 2 Ibid., 1880, Bd. 22; Loew and Bokorny: Die chemische Kraftquelh in lebenden Protoplasma, Miinchen, 1882; Imperial Institute of Tokyo (College of Agriculture), 1894. 24 AN AMERICA X TEXT-BOOK OF PHYSIOLOGY. the existence of certain groupings of the atoms. Influenced in part by the power of living material to reduce alkaline silver solutions, he supposes that the specially important labile group in the molecule is the aldehyde radical — C ~ it • The nitrogen exists also in a labile amido- combination, — NH 2 , and the active or living form of these two groups may be expressed by the -CH-NH 2 formula Q. 11 this grouping by chemical change became con- = c -c j, f 1TT VII verted to the grouping __ ^ — PHOH' li wou ^ ^ orm a comparatively inert compound such as we have in dead proteid. Latham 1 proposes a theory which combines the ideas of Pfliiger and of Loew. He suggests that the living molecule may be composed of a chain of cyan-alcohols united to a ben- zene nucleus. The cyan-alcohols are obtained by the union of an aldehyde with hydrocyanic acid ; they contain, therefore, the labile-aldehyde grouping as well as the cyanogen nucleus to which Pfliiger attributes such importance. Actual investigation of the chemical structure of living matter can hardly be said to have made a beginning. The first step in this direction has been made in the study of the chemical structure of the group of proteids which have usually been considered as forming the most characteristic constituent of protoplasm. Proteids as we obtain them from the dead tissues and liquids of the body have proved to be very varied in properties and structure, so much so in fact that it is impossible to give a satisfactory definition of the group. Man) of them can be obtained in a pure, even in a crystalline form, and their percentage composition can therefore be determined with ease. But the fundamental chemical structure that may be supposed to characterize the proteid group, and the changes in this structure producing the different varieties of proteids are matters as yet undetermined. Several promising efforts have been made to construct proteids synthetically, but the results obtained are at present incomplete. On the other hand, Kossel 2 has isolated from the spermatozoa of certain fishes a comparatively simple nitrogenous body of basic properties (protamine), which he regards as the simplest form of pndeid and the essential cure or nucleus characterizing the structure of the whole group. It is an interesting thought that in the heads of the sperma- tozoa with their complex possibilities of development and hereditary trans- mission, dependent as these properties must be upon the chemical structure of the germ protoplasm, there may be found the simplest form of proteid. Kossel's work, it may be noted, has not gone so far as to indicate the possible molecular structure of the protamines. It has been assumed by many observers that the properties of living matter, as we recognize them, are not solely an outcome of the inner structure of the hypothetical living molecules. They believe that these latter units are 1 British Medical Journal, 1886, p. 629. Zeitschrift fur physiol. Chem., 1898; xxv. L899, xxvi. INTR OD UCTION. 2 5 fashioned into larger secondary units each of which is a definite aggregate of chemical molecules and possesses certain properties or reactions that depend upon the mode of arrangement. The idea is similar to that advanced by mineralogists to explain the structure of crystals. They suppose that the chemical molecules are arranged in larger or smaller groups to which the name "physical molecules" has been given. So in living protoplasm it may be that the smallest particles capable of exhibiting the essential properties of life are groups of ultimate molecules, in the chemical sense, having a definite arrangement and definite physical properties. These secondary units of structure have been designated by various names such as " physiological molecules," 1 "somacules," 2 micellae, 3 etc. Many facts, especially from the side of plant physiology, teach us that the physical constitution of protoplasm is probably of great importance in understanding its reaction to its environ- ment. Microscopic analysis is insufficient to reveal the existence or character of these " physiological molecules," but it has abundantly shown that proto- plasm has always a certain physical construction and is not merely a struc- tureless fluid or semi-fluid mass. What has been said above may serve at least to indicate the prevalent physiological belief that the phenomena shown by living matter are in the 11 i;i in the result of the action of the known forms of energy through a substance of a complex and unstable structure which possesses, moreover, a physical organization responsible for some of the peculiarities exhibited. In other words, the phenomena of life are referred to the physical and chemical struc- ture of protoplasm and maybe explained under the general physical and chemical laws which control the processes of inanimate nature. Just as in the case of dead organic or inorganic substances we attempt to explain the differences in properties between two substances by reference to the difference in chemical and physical structure between the two, so with regard to living matter the peculiar differences in properties that separate them from dead matter, or for that matter the differences that distinguish one form of living- matter from another, must eventually depend upon the nature of the under- lying physical and chemical structure. In the early part of this century many prominent physiologists were still so overwhelmed with the lnvsteriousness of life that they took refuge in the hypothesis of a vital force or principle of life. By this term was meant a something of an unknown nature that controlled all the phenomena ex- hibited by living things. Even ordinary chemical compounds of a so-called organic nature were supposed to be formed under the influence of this force, and it was thought could not be produced otherwise. The error of this latter view has been demonstrated conclusively within recent years : many of the substances formed by the processes of plant and animal life are now easily produced within the laboratory by comparatively simple synthetic methods. 1 Meltzer : " Ueber die fundamentale Bedeutung der Erechiitterung fur die lebende Ma- terie," Zeitschrift fur Biologie, Bd. xxx., 1894. -Foster: Physiology (Introduction). s NSgeli: Theorieder Oahrung, Miinchen, 1879. 26 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. By the distinguished labors of Kinil Fischer 1 even the structure of carbohy- drate bodies lias been determined, and bodies belonging to this group have been synthetically constructed in the laboratory. Moreover, the work of Schiitzenberger, Grimaux, and Pickering gives promise that before long pro- teid bodies may be produced by similar methods. Physiologists have shown, furthermore, that the digestion that takes place in the stomach or intestine may be effected also in test-tubes, and at the present day probably no one doubts that in the act of digestion we have to deal only with a series of chemical reactions which in time will be understood as clearly as it is possible to comprehend any form of chemical activity. Indeed, the whole history of food in the body follows strictly the great physical law- of the conservation of matter and of energy which prevail outside the body. No one disputes the proposition that the material of growth and of excretion comes entirely from the food. It has been demonstrated that the measureable energy given off from the body is all contained potentially within the food that is eaten. 2 Living things, so far as can be determined, can only transform matter and en- ergy ; they cannot create or destroy them, and in this respect they are like inan- imate objects. But, in spite of the triumphs that have followed the use of the experimental method in physiology, every one recognizes that our knowledge is as yet very incomplete. Many important manifestations of life cannot be explained by reference to any of the known facts or laws of physics and chemistry, and in some cases these phenomena are seemingly removed from the field of experimental investigations. As long as there is this residuum of mystery connected with any of the processes of life, it is but natural that there should be two points of view. Most physiologists believe that as our knowledge and skill increase these mysteries will be explained, or rather will be referred to the same great final mysteries of the action of matter and energy under definite laws, under which we now classify the phenomena of lifeless matter. Others, however, find the difficulties too great, — they perceive that the laws of physics and chemistry are not completely adequate at present to explain all the phenomena of life, and assume that they never will be. They suppose that there is something in activity in living matter which is not present in dead matter, and which for want of a better term may be desig- nated as vital force or vital energy. However this may be, it seems evident that a doctrine of this kind stifles inquiry. Nothing is more certain than the fact that the great advances made in physiology during the last four decades are mainly owing to the abandonment of this idea of an unknown vital force and the determination on the part of experimenters to make the greatest pos- sible use of the known laws of nature in explaining the phenomena of life. There is n<> reason to-day to suppose that we have exhausted the results to be obtained by the application of the methods of physics and chemistry to the study of' living things, and as a matter of fact the great bulk of physiological research is proceeding along these lines. It is interesting, however, to stop 1 Die Chemieder Kohlenhydrale, Berlin, 1S94. 2 Kubner : Tkitschrift fur Biologic, Bd. xxx. 8. 73, 1894. INTRODUCTION. 27 for a moment to examine briefly some of the problems which as yet have escaped satisfactory solution by these methods. The phenomena of secretion and absorption form important parts of the digestive processes in higher animals, and without doubt are exhibited in a minor degree in the unicellular types. In the higher animals the secretions may be collected and analyzed, and their composition may be compared with that of the lymph or blood from which they are derived. It has been found that secretions may contain entirely new substances not found at all in the blood, as for example the mucin of saliva or the ferments and HC1 of gastric juice; or, on the other hand, that they may contain substances which, although pres- ent in the blood, are found in much greater percentage amounts in the secre- tion — as, for instance, is the case with the urea eliminated in the urine. In the latter case we have an instance of the peculiar, almost purposeful, elective action of gland-cells of which many other examples might be given. With regard to the new material present in the secretions, it finds a sufficient general explanation in the theory that it arises from a metabolism of the protoplasmic material of the gland-cell. It offers, therefore, a purely chemical problem which may and probably will be worked out satisfactorily for each secretion. The selective power of gland-cells for particular constituents of the blood is a more difficult question. We find no exact parallel for this kind of action in chemical literature, but there can be no reasonable doubt that the phe- nomenon is essentially a chemical or physical reaction involving the activity of some of the forms of energy with which the study of inanimate objects has already made us partially familiar. We may indulge the hope that the details of the reaction will be discovered by more complete chemical and micro- scopical study of the structure of these cells. If in the meantime the act of selection is spoken of as a vital phenomenon, it is not meant thereby that it is referred to the action of an unknown vital force, but only that it is a kind of action dependent upon the living structure of the cell-substance. The act of absorption of digested products from the alimentary canal was for a time supposed to be explained completely by the laws of imbibition, diffusion, and osmosis. The epithelial lining and its basement membrane form a septum dividing the blood and lymph on the one side from the contents of the alimentary canal on the other. Inasmuch as the two liquids in question ;irc of unequal composition with regard to certain constituents, a diffusion stream should be set up whereby the peptones, sugar, salts, etc. would pass from the liquid in the alimentary canal, where they exist in greater concen- tration, into the blood, where the concentration is less. Careful work of recent years has shown that the laws of diffusion and osmosis are not adequate to explain fully the absorption that actually occurs; a more detailed account of the difficulties met with may be found in the section on Digestion and Nutrition. It has become customary to speak of absorption as caused in part by the physical laws of diffusion and osmosis, and in pari by the vital activity of the epithelial cells. It will be noticed that the vital property in this case is again an elective affinity for certain constituents similar to that which has been 28 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. referred to in discussing the act of secretion. The mere fact that the physical theory has proved so far to be insufficient is in itself no reason for abandoning all hope of a satisfactory explanation. Most physiologists probably believe that further experimental work will bring this phenomenon out of its obscurity and show that it is explicable in terms of known physical and chemical forces exerted through the peculiar substance of the absorptive cell. The facts of heredity and consciousness offer difficulties of a much graver character. The function of reproduction is two-sided. In the first place there is an active multiplication of cells, beginning with the segmentation of the ovum into two blastomeres, and continuing in the larger animals to the formation of an innumerable multitude of cellular units. In the second place there is present in the ovum a form-building power of such a character that the great complex of eel Is arising from it produces not a heterogeneous mass, but a definite organism of the same structure, organ for organ and tissue for tissue, as the parent form. The ovum of a starfish develops into a starfish, the ovum of a dog into a dog, and the ovum of man into a human being. Herein lies the great problem of heredity. The mere multiplication of cells by direct or indirect division is not beyond the range of a conceivable me- chanical explanation. Given the properties of assimilation and contractility it is possible that the act of cell-division may be traced to purely physical and chemical causes, and already cytological work is opening the way to credible hypotheses of this character. But the phenomena of heredity, on the other hand, are too complex and mysterious to justify any immediate expectation that they can be explained in terms of the known properties of matter. The crude theories of earlier times have not stood the test of investigation by modern methods, the microscopic anatomy of both ovum and sperm showing that they are to all appearances simple cells that exhibit no visible signs of the wonderful potentialities contained within them. Histological and experi- mental investigation has, however, cleared away some of the difficulties for- merlv surrounding the subject, for it has shown with a high degree of prob- ability that the power of hereditary transmission resides in a particular sub- stance in the nucleus, namely in the so-called chromatin materal that forms the chromosomes. The fascinating observations J that have led to this con- clusion promise to open up a new field of experimentation and speculation. It seems to be possible to study heredity by accepted scientific methods, and we may therefore hope that in time more light will be thrown upon the con- ditions of its existence and possibly upon the nature of the forces concerned in it> production. In the facts of consciousness, lastly, we are confronted with a problem seemingly more difficult than heredity. In ourselves we recognize different states of consciousness following upon the physiological activity of certain parts of the central nervous system. We know, or think we know, that these so-called psychical state- are correlated with changes in the protoplasmic material of the cortical cells of the cerebral hemispheres. When these cells 'Wilson: Tht Cell in Development and Inheritance, 1896. INTRODUCTION. 29 are stimulated, psychical states result; when they are injured or removed, psychical activity is depressed or destroyed altogether according to the extent of the injury. From the physiological standpoint it would seem to be as justifiable to assert that consciousness is a property of the cortical nerve-cells as it is to define contractility as a property of muscle-tissue. But the short- ening of a muscle is a physical phenomenon that can be observed with the senses — be measured and theoretically explained in terms of the known prop- erties of matter. Psychical states are, however, removed from such methods of study ; they are subjective, and cannot be measured or weighed or otherwise esti- mated with sufficient accuracy and completeness in terms of our units of energy or matter. There must be a causative connection between the objective changes in the brain-cells and the corresponding states of consciousness, but the nature of this connection remains hidden from us ; and so hopeless does the problem seem that some of our profouudest thinkers have not hesitated to assert that it can never be solved. Whether or not consciousness is possessed by all animals it is impossible to say. In ourselves we know that it exists, and we have convincing evidence, from their actions, that it is possessed by many of the higher animals. But as we descend in the scale of animal forms the evidence becomes less impressive. It is true that even the simplest forms of animal life exhibit reactions of an apparently purposeful character which some have explained upon the simple assumption that these animals are endowed with consciousness or a psychical power of some sort. All such reactions, however, may be explained, as in the case of reflex actions from the spinal cord, upon purely mechanical principles, as the necessary response of a definite physical or chemical mechanism to a definite stimulus. To assume that in all cases of this kind conscious processes are involved amounts to making psychical activity one of the universal and primitive properties of protoplasm whether animal or vegetable, and indeed by the same kind of reasoning there would seem to be no logical objection to extending the property to all matter whether living or dead. All such views are of course purely speculative. As a matter of fact we have no means of proving or disproving, in a scientific sense, the exist- ence of consciousness in lower forms of life. To quote an appropriate remark of Huxley's made in discussing this same point with reference to the crayfish, " Nothing short of being a crayfish would give 1 us positive assurance that such an animal possesses consciousness." The study of psychical states in our- selves, for reasons which have been suggested above, does not usually form a part of the science of physiology. The matter has been referred to lure simply because consciousness is a fact that our science cannot :is yet explain. So far, some of the broad principles of physiology have been considered — principles which are applicable with more or less modification to all forms of animal life and which make the basis of what is known as general physiology. It must be borne in mind, however, that each particular organism possesses a special physiology of its own, which consists in part in a study of the properties exhibited by the particular kinds or variations of protoplasm in each individual, and in large part also in a study of the various median- 30 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. isms existing in each animal. In the higher animals, particularly, the com- binations of various tissues and organs into complex mechanisms such as those ol* respiration, circulation, digestion, or vision, differ more or less in each group and to a minor extent in each individual of any one species. It follows, therefore, that each animal has a special physiology of its own, and in this sense we may speak of a special human physiology. It need scarcely be -aid that the special physiology of man is very imperfectly known. Books like the present one, which profess to neat of human physiology, con- tain in reality a large amount of general and special physiology that has been derived from the study of lower animal forms upon which exact experi- mentation is possible. Most of our fundamental knowledge of the physiology of the heart and of muscles and nerves has been derived from experiments upon frogs and similar animals, and much of our information concerning the mechanisms of circulation, digestion, etc. has been obtained from a study of other mammalian forms. We transfer this knowledge to the human being, and in general without serious error, since the connection between man and related mammalia is as close on the physiological as it is on the morphological side, and the fundamental or general physiology of the tissues seems to be every- where the same. Gradually, however, the material for a genuine special human physiology is being acquired. In many directions special investigation upon man is possible; for instance, in the study of the localization of function in the cerebral cortex, or the details of body metabolism as obtained by exam- ination of the excreta, or the peculiarities of vaso-motor regulation as revealed by the use of plethysmography methods, or the physiological optics of the human eye. This special information, as rapidly as it is obtained, is incorpo- rated into the text-books of human physiology, but the fact remains that the greater part of our so-called human physiology is founded upon experiments upon the lower aninals. Physiology as a science is confessedly very imperfect; it cannot compare in exactness with the sciences of physics and chemistry. This condition of affairs need excite no surprise when we remember the very wide field that physiology attempts to cover,a held co-ordinate in extent with the physics as well as the chemistry of dead matter, and the enormous complexity and instability of the form of matter that it seeks to investigate. The progress of physiology is therefore comparatively slow. The present era seems to be one mainly of accumulation of reliable data derived from laborious experiments and observa- tions. The synthesis of these facts into great laws or generalizations is a task l.ir i lie future. Corresponding with the diversity of the problems to be solved we find that the methods employed in physiological research are mani- fold in character. Inasmuch as animal organisms are composed either of single cells or aggregates of cells, it follows that every anatomical detail with regard to the organization of the cell itself or the connection between dif- fered cells, and every advance in our knowledge of the arrangement of the tissues and organs that form the re complicated mechanisms, is of imme- diate value to phvsiology. The microscopic anatomy of the cell (a branch of I ST HO DICTION. 31 histology that is frequently designated by the specific name of cytology), general histology, and gross anatomical dissection arc therefore frequently employed in physiological investigations, and form what may be called the observational side of the science. On the other hand, we have the experimental methods, that seek to discover the properties and functional relationships of the tissues and organs by the use of direct experiments. These experiments may be of a surgical character, involving the extirpation or destruction or alteration of known parts by operations upon the living animal, or they may consist in the application of the accepted methods of physics and chemistry to the living organism. The physical methods include the study of the physical properties of living matter and the interpretation of its activity in terms of known physical laws, and also the use of various kinds of physical apparatus such as manometers, galvanometers, etc. for recording with accuracy the phenomena exhibited by living tissues. The chemical methods imply the application of the synthetic and analytic operations of chemistry to the study of the composition and structure of living matter aud the products of its activity. The study of the subjective phenomena of conscious life — in fact, the whole question of the psychic aspects or properties of living matter — for reasons that have been mentioned is not usually included in the science of physiol- ogy, although strictly speaking it forms an integral part of the subject. This province of physiology has, however, been organized into a separate science, p-ychology, although the boundary line between psychology as it exists at present and the scientific physiology of the nervous system cannot always be sharply drawn. It follows clearly enough from what has been said of the methods used in animal physiology that even an elementary acquaintance with the subject as a science requires some knowledge of general histology and anatomy, human as well as comparative, of physics, and of chemistry. When this preliminary training is. lacking, physiology cannot be taught as a science; it becomes simply a heterogeneous mass of facts, and fails to accomplish its function as a preparation for the scientific study of medicine. The mere facts of physiology arc valuable, indeed indispensable, as a basis for the study of the succeed im.: branches of the medical curriculum, but in addition the subject, properly taught, should impart a scientific discipline and an acquaintance with the possible methods of experimental medicine ; for among the so-called experi- mental branches of medicine physiology is the most developed and the ino.-t exact, and serves as a type, so far as methods are concerned, to which the others must conform. II. BLOOD AND LYMPH. BLOOD. A. General Properties : Physiology op the Corpuscles. The blood of the body is contained in a practically closed system of tubes, the blood-vessels, within which it is kept circulating by the force of the heart- beat. The blood is usually spoken of as the nutritive liquid of the body, but its functions may be stated more explicitly, although still in quite general terms, by saying that it carries to the tissues food-stuffs after they have been properly prepared by the digestive organs; that it transports to the tissues oxygen absorbed from the air in the lungs ; that it carries off from the tissues various waste products formed in the processes of disassimilatioD ; that it i> the medium for the transmission of the internal secretion of certain glands ; and that it aids in equalizing the temperature and water contents of the body. It is quite obvious, from these statements, that a complete consideration of the physiological relations of the blood would involve substantially a treat- ment of the whole subject of physiology. It is proposed, therefore, in this section to treat the blood in a restricted way — to consider it, in fact, as a tissue in itself, and to study its composition and properties without special reference to its nutritive relationship to other parts of the body. Histological Structure. — The blood is composed of a liquid part, the plasma, in which float a vast number of microscopic bodies, the blood-corpus- cles. There are at least three different kinds of corpuscles, known respectively as the red corpuscles; the white corpuscles or leucocytes, of which in turn there are a number of different kinds; and the blood-plate*. As the details of structure, size, and number of these corpuscles belong properly to text- books on histology, they will be mentioned only incidentally in this section when treating of the physiological properties of the corpuscles. Blood-plasma, when obtained free from corpuscles, is perfectly colorless in thin layers — for example, in microscopic preparations; when seen in large quantities it shows a slightly yellowish tint, the depth of color varying with dillerent animals. This color is due to the presence in small quantities of a special pigment, the nature of which is not definitely known. The ml color of blood is not due, there- fore, to coloration of the blood-plasma, but is caused by the mass of red cor- puscles held in suspension in this liquid. The proportion by bulk of plasma to corpuscles is usually given, roughly, as two to one. Illood-xcrum and I )f a preliminary definition, that blood-serum is the liquid part of blood after coagulation has taken place, as blood-plasma is the liquid part of blood before coagulation has taken place. If shed blood is whipped vigorously with a rod or some similar object while it is clotting, the essential part of the clot — namely, the fibrin — forms differently from what it docs when the blood i- allowed to coagulate quietly; it is deposited in shreds on the whipper. Blood thai has been treated in this way is known as defibrinated blood. It consists of blood-serum plus the red and white corpuscles, and as far as appearance- go it resembles exactly normal blood ; it has lost, however, the power of clot- ting. A more complete definition of these terms will be given after the sub- ject of coagulation has been treated. Reaction. — The reaction of blood is alkaline, owing mainly to the alka- line salts, especially the carbonates of soda, dissolved in the plasma. The degree of alkalinity varies with different animals: reckoned as Xa,C0 3 , the alkalinity of dog's blood corresponds to 0.2 per cent, of this salt; of human blood, 0.35 per cent. The alkaline reaction of blood is very easily demon- sl rated upon clear plasma free from corpuscles, but with normal blood the red color prevents the direct application of the litmus test. \ number of simple devices have been suggested to overcome this difficulty. For example, the method employed by Zuutz is to soak a strip of litmus-paper in a concentrated solution of NaCl, to place on this paper a drop of blood, and, after a few seconds, to remove the drop with a stream of water or with a piece of filter- paper. The alkaline reaction becomes rapidly less marked after the blood has been shed; it varies also slightly under different conditions of normal life and in certain pathological conditions. After meals, for instance, during the act of digestion, it is said to be increased, while, on the contrary, exercise causes a diminution. In no case, however, does the reaction become acid. For details of the methods used for quantitative determinations of the alka- linitv of human blood, reference must be made to original sources. 1 Specific Gravity. — The specific gravity of human blood in the adult male may vary from 1041 to 1067, the average being about 1055. Jones 2 made a careful study of the variations in specific gravity of human blood under different conditions of health and disease, making use of a simple method which requires only a few drops of blood for each determination. He found that the specific gravity varies with age and sex, that it is diminished after eating and is increased by exercise, that it falls slowly during the day and rises gradually during the night, and that it varies greatly in individuals, "so much so that a specific gravity which is normal for one may be a sign of dis- ease in another." The specific gravity of the corpuscles is slightly greater 1 Wright: The Lancet, 1897, p. 8; Winternitz: Zeitschrifl furphysiol. Chemie, 1891, Bd. 15, s. 505. 2 Journal o) PhysiiAofjy, 1891, vol. xii., p. 299. BLOOD. 35 than that of the plasma. For this reason the corpuscles in shed blood, when its coagulation is prevented or retarded, tend to settle to the bottom of the containing utensil, leaving a more or less clear layer of supernatant plasma. Among themselves, also, the corpuscles differ slightly in specific gravity, the red corpuscles being heaviest and the blood-plates being lightest. Red Corpuscles. — The red corpuscles in man and in all the mammalia, with the exception of the camel and other members of the group Camelidae, are biconcave circular disks without nuclei; in the Camelidae they have an elliptical form. Their average diameter in man is given as 7.7 ft (1// = 0.001 of a mm.); their number, which is usually reckoned as so many in a cubic millimeter, varies greatly under different conditions of health and disease. The average number is given as 5,000,000 per cubic mm. for males and 4,500,000 for females. The red color of the corpuscles is due to the presence in them of a pigment known as " haemoglobin." Owing to the minute size of the corpuscles, their color when seen singly under the microscope is a faint yellowish-red, but when seen in mass they exhibit the well-known blood-red color, which varies from scarlet in arterial blood to purplish-red in venous blood, this variation in color being dependent upon the amount of oxygen contained in the blood in combination with the haemoglobin. Speaking generally, the function of the red corpuscles is to carry oxygen from the lungs to the tissues. This function is entirely dependent upon the presence of haemoglobin, which has the power of combining easily with oxygen gas. The physiology of the red corpuscles, therefore, is largely contained in a description of the properties of haemoglobin. Condition of the Haemoglobin in the Corpuscle. — The finer structure of the red corpuscle is not completely known. It is commonly believed that the corpuscle consists of two substances — a delicate, extensible, colorless pro- toplasmic material, which gives to the corpuscle its shape and which is known as the stroma, and the haemoglobin. The latter constitutes the bulk of the cor- puscle, forming as much as 95 per cent, of the solid matter. It was formerly thought that haemoglobin is disseminated as such in the interstices of the porous spongy stroma, but there seem to be reasons now for believing that it is present in the corpuscles in some combination the nature of which is not fully known. This belief is based upon the fact that Hoppe-Seyler ' has shown that haemoglobin while in the corpuscles exhibits certain minor differ- ences in properties as compared with haemoglobin outside the corpuscles. In various ways the compound of haemoglobin in the corpuscles may be destroyed, the haemoglobin being set iri'v and passing into solution in the plasma. Blood in which this change has occurred is altered in color and is known as " laky blood." In thin layers it is transparent, whereas normal blood with the haemoglobin still in the corpuscles is quite opaque even in very thin strata. Blood may be made laky by the addition of ether, of chloroform, of bile or the bile acids, of the serum of other animals, by an excess of water, by alternately freezing and thawing, and by a number of other methods. In connection with two of these methods of discharging haemoglobin from the 1 ZeUschrifi fur physiologische Chemie, Bd, xiii., 1889, S. 177. 3b' AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. corpuscles there have come into use in current medical and physiological literature two technical terms which it may be well to attempt to define. Globulicidal Action of Serum. — It was shown first by Landois that the serum of one animal may have the property of destroying the red corpuscles in the blood of another animal, thus making the blood laky. This fact, which ha- since been investigated more fully, is now designated under the term of " globulicidal " action of the serum. Jt has been found that different kinds of serum show different degrees of globulicidal activity, and that white as well as red corpuscles may be destroyed. Dog's serum or human serum is strongly globulicidal to rabbit's blood. Tt would seem that this action is not due to mere variations in the amounts of inorganic salts in the different kinds of serum, since the remarkable tact has been discovered that heating serum to 55° or 60° C. for a few minutes destroys its globulicidal action, although such treatment causes no coagulation of the proteids nor any visible change in the liquid. Moreover, it is known that foreign scrum injected into the veins of a living animal may exert a marked toxic effect that cannot be explained solely by its globulicidal action — for instance, 7 to 14 c.c. of fresh dog's serum will suffice to kill a rabbit — and lastly, serum is known to exert a similar destructive effect on bacteria, its so-called bactericidal action. These three effects of serum, globulicidal, bactericidal and toxic, seem all to be destroyed I >y heating to 50°-60° C, and it is possible that they arc all traceable to the existence in the blood of some proteid substance, an alexine, which is present in -mall quantity and is different for each species of animal, the material in the blood of one species being more or less globulicidal and toxic, as a rule, to the tissues of another species. 1 Tsoto i iii- Solutions. — When blood or defibrinated blood is diluted with water, a point is soon reached at which haemoglobin begins to pass out of the corpuscles into the plasma or the serum, and the blood begins to appear laky. It appears that the liquid surrounding the corpuscles must have a certain concentration as regards salts or other soluble substances, such as sugar, in order to prevent the entrance of water into the substance of the corpuscle. Normally the substance of the red corpuscle possesses a certain osmotic pressure which may be supposed to be equal to that of the plasma by which it is surrounded, so that the interchange of water between them is at an equilibrium. If the concentration of the outside Liquid is diminished, this equilibrium is destroyed and water passes into the corpuscle ; if the dilution has been sufficient, enough water passes into the corpuscle to make it swell and eventually to force out the haemoglobin. Liquids containing inorganic salt-, or other soluble substances that possess an osmotic pressure sufficient to pre- vent the imbibition of water by the corpuscles, are -aid to be "isotonic to the corpuscles." Red corpuscles suspended in such liquids do not change in shape nor lose their haemoglobin. When solutions of different substances are com- pared from this standpoint, it is found that the concentration necessary varies with the substance used. Tim-, a solution ofNaClofO.64 per cent, is isotonic 1 For :i recenl paper .-mil the literature see Friedenthal and Lewandowsky, Arehiv fiir Phys~ - 531. BLOOD. 37 with a solution of sugar of 5.5 per cent, or a solution of KX0 3 of 1.09 per cent. When placed in any of these three solutions red corpuscles <1<» not take up water — at least not in quantities sufficient to discharge the haemo- globin. For a more complete account of these relations the reader is referred to original sources (Hamburger 1 ). A solution whose osmotic pressure is lower than that of blood-plasma is said to be hypo-isotonic <>r hypotonic to blood. Such solutions may cause the blood to lake. Solutions of a higher osmotic pressure than that of the plasma are spoken of as hvper-isotonic or hypertonic. Whenever it is necessary to dilute shed blood or to inject any quantity of a neutral liquid into the circulation care must be taken to have the solution isotonic with the blood. (See p. 65 for an explanation of the term osmotic pressure.) Nature and Amount of Haemoglobin. — Haemoglobin is a very complex substance belonging to the group of combined proteids. (For the definition and classification of proteids, as well as for the purely chemical properties of haemoglobin and its derivatives, reference must be made to the section on "The Chemistry of the Body.") When decomposed in various ways haemoglobin breaks up into a proteid (globin, 86 to 96 per cent.), a simpler pigment (haemal- tin, 4 per cent.), and an unknown residue. 2 When the decomposition takes place in the absence of oxygen, the products formed are globin and haemo- chromogen, instead of globin and luematin. Haemochromogen in the presence of oxygen quickly undergoes oxidation to the more stable luematin. Hoppe- Seyler has shown that haemochromogen possesses the chemical grouping which gives to haemoglobin its power of combining readily with oxygen and its distinctive absorption spectrum. On the basis of facts such as these, haemo- globin may be defined as a compound of a proteid body with haemochromogen. It seems, then, that although the haemochromogen portion is the essential tiling, giving to the molecule of haemoglobin its valuable physiological prop- erties as a respiratory pigment, yet in the blood-corpuscles this substance is incorporated into the much larger and more unstable molecule of haemoglobin, whose behavior toward oxygen is different from that of the haemochromogen itself, the difference being mainly in the fact that the haemoglobin as it exists in the corpuscles forms with oxygen a comparatively feeble combination that may be broken up readily with liberation of the gas. Haemoglobin is widely distributed throughout the animal kingdom, being found in the blood-corpuscles of mammalia, birds, reptiles, amphibia, and fishes, and in the; blood or blood-corpuscles of many of the invertebrates. The compositi >f its molecule is found to vary somewhat in different animals, so that, strictly speaking, there are probably a number of different (onus of haemoglobin — all, however, closely related in chemical and physiological properties. Elementary analysis of dog's haemoglobin shows the following percentage composition (Jaquet) : C 53.91, H 6.62, N 15.98, S 0.542, Fe 0.333, O 22.62. Its molecular formula is given as < \J I ,..,,, N,,,S,Fe< ), ls , which would make the molecular weight 16. <>(!!». Other estimates are given of 1 Du Bois-Keyniond's Arehivfur Physiologic, L886, 8. 176; 1887, 8. 31. 1 See Scbnlz, Zeitschrift fur physiol. Chemie, Bd. 24; also Lauraw, ibid., Bd. 26. 38 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. the molecular formula, but they agree at least iu showing that the molecule is of enormous size. The molecular formula for haemochromogen is much sim- pler; one estimate makes it C 31 H.j 6 X 4 Fe0 5 . The exact amount of heemoglobin in human blood varies naturally with the individual and with different condi- tions of life. According to Preyer, 1 the average amount for the adult male is 14 grams of haemoglobin to each 100 grams of blood. It is estimated that in the blood of a man weighing 68 kilos, there are contained about 750 grams of haemoglobin, which is distributed among some twenty-five trillions of corpuscles, giving a total superficial area of about 3200 square meters. Practically all of t 1 1 i — large surface of haemoglobin is available for the absorption of oxygen from the air in the lungs, for, owing to the great number and the minute size of the capillaries, the blood, in passing through a capillary area, becomes subdivided to such an extent that the red corpuscles stream through the capil- laries, one may say, in single file. In circulating through the lungs, therefore, each corpuscle becomes exposed more or less completely to the action of the air, and the utilization of the entire quantity of haemoglobin must be nearly perfect. It may be worth while to call attention to the fact that the biconcave form of the red corpuscle increases the superficies of the corpuscle and tends to make the surface exposure of the haemoglobin more complete. Compounds with Oxygen and other Gases. — Haemoglobin has the property of uniting with oxygen gas in certain definite proportions, forming a true chemical compound. This compound is known as oxyhoemoglobin ; it is formed whenever blood or haemoglobin solutions are exposed to air or otherwise brought into contact with oxygen. Each molecule of haemoglobin is supposed to combine with one molecule of oxygen, and it is usually estimated that 1 gram of dried haemoglobin (dog) can take up 1.59 c.c. of oxygen measured at 0° C. and TOO mm. of barometric pressure, although according to a later determination by Hufneiy the ()-capacity of the lib of ox's blood is only 1.34 c.c. () to each gram of III). Oxyhemoglobin is not a very firm compound. If placed iu an atmosphere containing no oxvgen, it will be dissociated, giving off free oxygen and leaving behind haemoglobin, or, :is it is often called by way of distinction, "reduced haemoglobin." This power of combining with oxygen to form a loose chemical compound, which in turn can be dissociated easily wdien the oxygen-pressure is lowered, makes possible the function of haemoglobin in the blood as the carrier of oxygen from the lungs to the tissues. The details of this process are described in the section on Respiration. Haemoglobin forms with carbon- monoxide gas (CO) a compound, similar to oxyhemoglobin, which is known as carbon-monoxide heemoglobin. In this compound also the union takes place in tin' proportion of one molecule of haemoglobin to one molecule of the gas. The compound formed differs, however, from oxy- haemoglobin in being much more stable, and it is for this reason that the breathing of carbon monoxide gas is liable to prove fatal. The CO unites with the haemoglobin, forming a firm compound; the tissues of the bod v are 1 Die Blutkrystalle, Jena, 1871. 2 Archir Oh- Physiologie, 1894, 8. 130. BLOOD. 39 thereby prevented from obtaining their necessary oxygen, and death results from suffocation or asphyxia. Carbon monoxide forms one of the constituents of coal-gas. The well-known fatal effect of breathing coal-gas for some time, as in the case of individuals sleeping in a room where gas is escaping, is trace- able directly to the carbon monoxide. Nitric oxide (NO) forms also with haemoglobin a definite compound that is even more stable than the CO- haemoglobin ; if, therefore, this gas were brought into contact with the blood, it would cause death in the same way as the CO. Oxyhemoglobin, carbon-monoxide haemoglobin, and nitric-oxide haemoglo- bin are similar compounds. Each is formed, apparently, by a definite combina- tion of the gas with the haemochromogen portion of the haemoglobin molecule. and a given weight of haemoglobin unites presumably with an equal volume of each gas. In marked contrast tothese facts, Bohr x has shown that haemoglobin forms a compound with carbon-dioxide gas, carbo-hcemoglobin, in which the quantitative relationship of the gas to the haemoglobin differs from that shown by oxygen. In a mixture of O and C0 2 each gas is absorbed by haemoglobin solutions independently of the other, so that a solution of haemoglobin nearly saturated with oxygen can unite with as much C0 2 as though it held no oxygen in combination. Bohr suggests, therefore, that the O and the CO L> must unite with different portions of the haemoglobin — the oxygen with the pigment portion, the haemochromogen, and the C0 2 possibly with the proteid portion. It seems probable that haemoglobin plays a part in the transportion of the earl ion dioxide as well as the oxygen of the blood, but its exact value in this respect as compared with the blood-plasma, which also acts as a carrier of CO a , has not been definitely determined (see Respiration). Presence of Iron in the Molecule. — It is probable that iron is quite generally present in the animal tissues in connection with nuclein compounds, but its existence in haemoglobin is noteworthy because it has long been known and because the important property of combining with oxygen seems to be connected with the presence of this element. According to the analyses made, the proportion of iron in haemoglobin varies somewhat in different animals: the figures given arc from 0.335 to 0.47 per cent. The amount of haemoglobin in blood may he determined, therefore, by making a quantitative determination of the iron. The amount of oxygen with which haemoglobin will combine may he expressed by saying that one molecule of oxygen will be fixed for each atom of iron in the haemoglobin molecule. In the decom- position of haemoglobin into globulin and haematin, which has been spoken of above, the iron is retained in the haematin. Crystals. — Haemoglobin maybe obtained readily in the form of crystals (Fig. 1). As usually prepared, these crystals are really oxyhaemoglobin, but it has been shown that reduced haemoglobin also crystallizes, although with more difficulty. Haemoglobin from the blood of different animals varies to a marked degree in resped to the power of crystallization. From the blood of the rat, do^, cat, guinea-pig, and horse, crystals arc readily obtained, while haemoglobin from the blood of man and of most of the vertebrates crystallizes 1 Skandivavisches Archivf&r Physiologie, 1892, Bd. '■'<. S. -17. 40 AN AMERICAN 7 1: XT-BOOK OF PHYSIOLOGY. much less easily. Methods tor preparing and purifying these crystals will be found in works on Physiological Chemistry. To obtain specimens quickly for examination under the microscope, one of the most certain methods is to take some blood from one of the animals whose haemoglobin ervstallizes easily, plaee it in a test-tube, add to it a few- drops of ether, shake the tube thoroughly until the blood becomes laky — that is, until the haemoglobin is discharged into the plasma — and then place the tube on ice until the crystals are deposited. Small portions of the crystalline sedi- Cment may then be removed to a glass I slide for examination. Haemoglobin from different animals varies not only as to the ease with which it crystal- lizes, but in some cases also as to the form that the crystals take. In man and in most of the mammalia haemoglo- bin is deposited in the form of rhom- bic prisms; in the guinea-pig it crys- tallizes in tetrahedra (d, Fig. 1), and in the squirrel in hexagonal plates. The crystals are readily soluble in water, and by repeated crystallizations the haemo- globin may be obtained perfectly pure. Fig. 1. -Crystallized hemoglobin fafter Frey): ^ s j„ tne case of Other Soluble proteid- a, b, crystals from venous blood of man ; r, from t . , the blood of a cat; d, from the blood of a like bodies, solutions of haemoglobin are gninea-pig; .from the blood of a hamster; /, prec ipi t ated by alcohol, by mineral acids, from the blood of a squirrel. l L J » J by salts of the heavy metals, by boiling, etc. Notwithstanding the fact that haemoglobin crystallizes so readily, it is not easily dialyzable, behaving in this respect like proteids and other colloidal bodies. The compounds which haemoglobin forms with carbon monoxide (CO) and nitric oxide (XO) are also crystallizable, the crystals being isomor- phous with those of oxyhemoglobin. Absorption Spectra. — Solutions of haemoglobin and its derivative com- pounds, when examined with a spectroscope, give distinctive absorption bands. A brief account of the principle and arrangement of the spectroscope, although 1 1 n necessary for those familiar with the elements of Physics, is given by way of introduction to the description of these absorption bands. Light, when made to pass through a glass prism, is broken up into its constituent rays, giving the play of rainbow colors known as the spectrum. A spectroscope is an apparatus for producing and observing a spectrum. A simple form, which illus- trates sufficiently well the construction of the apparatus, is shown in Figure 2, P being the glass prism giving the spectrum. Light falls upon this prism through the tube (a) to the left, known as the "collimator tube." A slit at the end of this tube (s) admits a narrow slice of light — lamplight or sunlight — which then, by means of a convex lens at the other end of the tube, is made to fall upon the prism BLOOD. 41 (p) with its rays parallel. In passing through the prism the rays are dispersed by unequal refraction, giving a spectrum. The spectrum thus produced is examined by the observer with the aid of the telescope (b). When the telescope is properly focussed for the rays entering it from the prism (p), a clear picture of the spectrum is seen. The length of the spectrum will depend upon the nature and the number of prisms through which the light is made to pass. For ordinary purposes a short spectrum is preferable for hemoglobin bands, and a spectroscope with one prism is generally used. If the source of light is a lamp-flame of some kind, the spectrum is continuous, the colors gradually merging one into another from red to violet. If sunlight is used, the spectrum will be crossed by a number of narrow dark lines known as the " Frauuhofer lines" p IG o — Spectroscope : p, the glass prism ; a, the collimator tube, showing the slit (s) through which the light is admitted ; b, the telescope for observing the spectrum. (see PL I. , Frontispiece, for an illustration in colors of the solar spectrum). The position of these lines in the solar spectrum is fixed, and the more distinct ones are designated by letters of the alphabet, A, b, c, d, e, etc., as shown in the charts below. If while using solar light or an artificial light a solution of any substance which gives absorption bands is so placed in front of the slit that the light is obliged to traverse it, the spectrum as observed through the telescope will show one or more narrow or broad black bands, that are characteristic of the substance used and constitute its absorption spectrum. The positions of these bands may be designated by describing their relations to the Frauu- hofer lines, or more directly by stating the wave-lengths of the portions of the spectrum between which absorption takes place. Some spectroscopes are provided with a scale of wave-lengths superposed on the spectrum, and when properly adjusted this scale enables one to read off directly the wave-lengths of any part of the spectrum. When very dilute solutions of oxyhemoglobin are examined with the spectroscope, two absorption hands appear, both occurring in the portion of the spectrum included between the Frauuhofer lines i> and E. The band nearer the red end of the spectrum is known as the "a-band ;" it is narrower, darker, and more clearly defined than the other, the "/3-band " (Ki^ - . 3, and also PI. I. spectrum 4). With a solution containing 0.0!' per cent, of oxy- hemoglobin, and examined in layers one centimeter thick, the a-band extends over the part of the spectrum included between the wave-lengths I oS.'i 42 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. (583 millionths of a millimeter) and / 571, and the ,9-band between X 550 and / 532 (Gamgee). The width and distinctness of the bands vary naturally with the concentration of the solution used (see PI. I. spectra 2, .'>, 4, and 5), 70 65 55 B C It E b F G Fig. 3.— Diagrammatic representation of the absorption spectrum of oxyhemoglobin (after Rollett). The numerals give the wave-lengths in hundred-thousandths of a millimeter; the letters Bhow the positions of the more prominent Fraunhofer lines of the solar spectrum. The red end of the spectrum is to the left. The a-band is to the right of d, the /3-band to the left of e. or, if the concentration remains the same, with the width of the stratum of liquid through which the light passes. With a certain minimal percentage of oxyhemoglobin (less than 0.01 per cent.) the /3-band is lost and the a- band is very faint in layers one cen- timeter thick. With stronger solu- tions the bands become darker and wider and finally fuse, while some of the extreme red end and a great deal of the violet end of the spec- trum is also absorbed. The varia- tions in theabsorption spectrum with differences in concentration are clear- ly shown in the accompanying illus- tration from Rollett 1 (Fig. 4) ; the thickness of the layer of liquid is supposed to be one centimeter. The numbers on the right indicate the percentage strength of the oxy- hemoglobin solutions. It \vill be noticed that the absorption which takes place as the concentration of the solution increases affects the fed- orange end of the spectrum last of all. Solutions of reduced haemo- globin examined with the spectro- scope show only one absorption band, known sometimes as the "y-band." This band lies also in the portion of the spectrum included between the lines i> and K; its relations to these lines and the bands of oxyhemoglobin are shown in Figure 5 and in PI. I. spectrum 6. The 1 Hermann's Handbuchder Pkysiologie, Bd. iv., 1880. Fig. 4. — Diagram to show the variations in the ab- sorption spectrum of oxyhemoglobin with varying concentrations of the solution (after Rollett). The numbers to the right give the strength "f the oxy- globin solution in percentages; the lettersgive th<> positions of the Fraunhofer lines. To ascertain tin- amounl of absorption for any given concentration up to l per cent., draw a horizontal line across tin' diagram at the level corresponding to the concentra- tion. Where this line passes through the shaded part of the diagram absorption takes place, and the width of the absorption bands i- seen al once. The diagram .-how- clearly that the amount of absorption increases a- the solutions become m<>rc ncentrated, especially the absorption of the blue end of the spectrum. It will he noticed that with concentrations between or, and 0.7 per cent, the two bands between Dandi fuse into ' BLOOD. IS y-band is much more diffuse than the oxyhemoglobin bands, and its limits therefore, especially in weak solutions, are not well defined; in solutions of blood diluted 100 times with water, which would give a haemoglobin solution of about 0.14 per cent., the absorption band lies in the part of the spectrum included between the wave-lengths X 572 and X 542. The width 70 65 B C E b Fig. 5.— Diagrammatic representation of the absorption spectrum of haemoglobin (reduced haemoglo- bin) (after Rollett). The numerals give the wave-lengths in hundred-thousandths of a millimeter ; the letters show the positions of the more prominent Fraunhofer lines of the solar spectrum. The red end of the spectrum is to the left. The single diffuse absorption band lies between d and e. and distinctness of this band vary also with the concentration of the solution. This variation is sufficiently well shown in the accompanying illustration (Fig. 6), which is a companion figure to the one just given for oxyhemoglobin (Fig. 4). It will be noticed that the last light to be absorbed in this case is partly in the red end and partly in the blue, thus explaining the purplish color of hemoglobin solutions and of venous blood. Oxyhemoglobin so- lutions can be converted to hemo- globin solutions, with a correspond- ing change in the spectrum bands, by placing the former in a vacuum or, more conveniently, by adding reducing solutions. The solutions most commonly used for this pur- pose are ammonium sulphide and Stokes's reagent. 1 If a solution of reduced hemoglobin is shaken with air, it quickly changes to oxyhemo- globin and gives two bands instead of one when examined through the spectroscope. Any given solution may be changed in this way from oxyhemoglobin to hemoglobin, and the reverse, a great number of times, thus demonstrating the facility with which haemoglobin takes up and surrenders oxygen. 1 Stokes's reagent is an ammoniacal solution of a ferrous salt. It is made by dissolving 2 parts i by weighl ) of ferrous sulphate, adding ."> parts of tartaric acid, and then ammonia to dis- tinct alkaline reaction. A permanent precipitate should not be obtained. Fig. (i.— Diagram to show the variations In the ab- sorption spectrum of reduced haemoglobin with vary- ing concentrations of the solution (after Rollett). The numbers to the right give the strength <>t' the haemo- globin solution in percentages ; the Letters give the posi- tions of the Fraunhofer Lines. For further directions as in the use of the diagram, see the description of Figure 1. 44 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Solutions of carbon-monoxide haemoglobin also give a spectrum with two absorption bands closely resembling in position and appearance those of oxy- hemoglobin (see PI. I. spectrum 7). They are distinguished from the oxy- hemoglobin bands by being slightly nearer the blue end of the spectrum, as may be demonstrated by observing the wave-lengths or, more conveniently, by superposing the two spectra. Moreover, solutions of carbon-monoxide haemoglobin are not reduced to haemoglobin by adding Stokes's liquid, two bands being still seen after such treatment. A solution of carbon-monoxide haemoglobin suitable for spectroscopic examination may be prepared easily by passing ordinary coal-gas through a dilute oxyhemoglobin solution for a few minutes and then filtering. Derivative Compounds of Haemoglobin. — A number of compounds directly related to haemoglobin have been described, some of them being found normally in the body. Brief mention is made of the best known of these substances, but for the details of their preparation and chemical proper- ties reference must be made to the section on " The Chemistry of the Body." Methcemoglobin is a compound obtained by the action of oxidizing agents on haemoglobin ; it is frequently found, therefore, in blood stains or patho- logical liquids containing blood that have been exposed to the air for some time. It is now supposed to be identical in composition with oxyhemoglobin, with the exception that the oxygen is held in more stable combination. Methemoglobin crystallizes in the same form as oxyhemoglobin, and has a characteristic spectrum (PI. I. spectrum 8). //" mochromogen is the substance obtained when haemoglobin is decomposed by acids or by alkalies in the absence of oxygen. It crystallizes and has a characteristic spectrum. Hit matin (C 3 2H 30 N 4 FeO 3 ) is obtained when oxyhemoglobin is decomposed by acids or by alkalies in the presence of oxygen. It is amorphous and has a characteristic spectrum (PI. I. spectra 9 and 10). lln mill ((\ 32 II ; ,„X 1 Fe0 3 HCl) is a compound of haematin and HC1, and is readily obtained in crystalline form. It is much used in the detection of blood in medico-legal cases, as the crystals are very characteristic and are easily obtained from blood-clots or blood-stains, no matter how old these may be. Hcematoporphyrin (C 16 H I8 N 2 3 ) is a compound characterized by the absence of iron. It is frequently spoken of as "iron-free haematin." It is obtained by the action of strong sulphuric acid on haematin. Hcematoidin (C 16 H 18 N 2 3 ) is the name given to a crystalline substance found in old blood-clots, and formed undoubtedly from the haemoglobin of the clotted blood. It has been shown to be identical with one of the bile- pigments, bilirubin. Its occurrence is interesting in that it demonstrates the relationship between haemoglobin and the bile-pigments. Histohcematins are a group of pigments .-aid to be present in many of the tissues — for example, the muscles. They are supposed to be respiratory pig- ment-, and are related physiologically, and possibly chemically, to hemoglobin. They have not been isolated, but their spectra have been described. BLOOD. 45 ] HI c-pigments and Urinary Pigments — Haemoglobin is regarded as the parent-substance of the bile-pigments and the urinary pigments. Origin and Fate of the Red Corpuscles. — The mammalian red corpuscle is a cell that has lost its nucleus. It is not probable, therefore, that any given corpuscle lives for a great while in the circulation. This is made more certain by the fact that hemoglobin is the mother-substance from which the bile- pigments are made, and, as these pigments are being excreted continually, it is fair to suppose that red corpuscles are as steadily undergoing disintegration in the blood-stream. Just how long the average life of the corpuscles is has not been determined, nor is it certain where and how they go to pieces. It has been suggested that their destruction takes place in the spleen, but the observa- tions advanced in support of this hypothesis are not very numerous or con- clusive. Among the reasons given for assuming that the spleen is especially concerned in the destruction of red corpuscles, the most weighty is the histo- logical fact that one can sometimes find in teased preparations of spleen-tissue certain large cells which contain red corpuscles in their cell-substance in various stages of disintegration. It has been supposed that the large cells actually ingest the red corpuscles, selecting those, presumably, that are in a state of physiological decline. Against this idea a number of objections may be raised. Large leucocytes with red corpuscles in their interior are not found so frequently nor so constantly in the spleen as we would expect should be the case if the act of ingestion were constantly going on. There is some reason for believing, indeed, that the whole act of ingestion may be a post- mortem phenomenon ; that is, after the cessation of the blood-stream the amoeboid movements of the large leucocytes continue, while the red corpuscles lie at rest — conditions that are favorable to the act of ingestion. It may be added also that the blood of the splenic vein contains no haemoglobin in solu- tion, indicating that no considerable dissolution of red corpuscles is taking place in the spleen. Moreover, complete extirpation of the spleen does not seem to lessen materially the normal destruction of red corpuscles, if we may measure the extent of that normal destruction by the quantity of bile-pigment formed in the liver, remembering that haemoglobin is the mother-substance from which the bile-pigments are derived. It is more probable that there is no special organ or tissue charged with the function of destroying red corpus- cles, and that they undergo disintegration and dissolution while in the blood- stream and in anv part of the circulation, the liberated haemoglobin being carried to the liver and excreted in part as bile-pigment. The continual destruction of red corpuscles implies, of course, a continual formation of new- ones. It has been shown satisfactorily that in the adult the organ for the reproduction of red corpuscles is the red marrow of bones. In this tissue /in inatopoiesis, as the process of formation of red corpuscles is termed, goes on continually, the process being much increased after hemorrhages and in certain pathological conditions. The details of the histological changes will be found in the text-books of histology. It is sufficient here to state simply that a group of nucleated colorless cells, erythroblasts, i> found in the red marrow. 46 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. These cells multiply by karyokinesis, and the daughter-cells eventually pro- duce haemoglobin in their cytoplasm, thus forming nucleated red corpuscles. The nuclei arc subsequently lost, either by disintegration or, more likely, by extrusion, and the newly-formed non-nucleated red corpuscles are forced into the blood-stream, owing to a gradual change in their position during develop- ment caused by the growing haematopoietic tissue. When the process has been greatly accelerated, as after severe hemorrhages or in certain pathological conditions, red corpuscles still retaining their nuclei may be found in the circu- lating blood, having been forced out prematurely as it were. Such corpuscles may subsequently lose their nuclei while in the blood-stream. In the em- bryo, haematopoietic tissue is found in parts of the body other than the mar- row, notably in the liver and spleen, which at that time serve as organs for the production of new red corpuscles. In the blood of the young embryo nucleated red corpuscles are at first abundant, but they become less numerous as the fetus grows older. 1 Variations in the Number of Red. Corpuscles. — The average number of red corpuscles for the adult male, as has been stated already, is usually given as 5,000,000 per cubic mm. The number is found to vary greatly, however. Outside of pathological conditions, in which the diminution in number may be extreme, differences have been observed in human beings under such conditions as the following: The number is less in females (4,500,000); it varies in individuals with the constitution, nutrition, and manner of life; it varies with age, being greatest in the fetus and in the new- born child ; it varies with the time of the day, showing a distinct diminution after meals; in the female it varies somewhat in menstruation and in preg- nancv, being slightly increased in the former and diminished in the latter condition. Perhaps the most interesting example of variation in the number of red corpuscles is that which occurs with changes in altitude. Residence in high altitudes is quickly followed by a marked increase in the number of red corpuscles. Viault 2 has shown that living in the mountains for two weeks at an altitude of 4.°>!)2 meters caused an increase in the corpuscles from 5,000,000 to over 7,000,000 per cubic mm., and in the third week the number reached 8,000,000. The accuracy of this observation has been demonstrated since by many investigators. Some very careful work done under the direction of Miescher 3 has shown that a comparatively small increase in altitude, 700 meters, causes a marked increase in the number of red corpuscles and in the amount of haemoglobin, while return to a lower altitude quickly brings the blood back to its normal condition. From these observations it would seem that a diminished pressure of oxygen in the atmosphere stimulates the hema- topoietic organs to greater activity, and it is interesting to compare this result with the effect of an actual loss of blood. In the latter case the production of red corpuscles in the red marrow is increased, because, apparently, the anaemic condition causes a diminution in the oxygen-supply to the haematopoietic tissue, 1 Howell : "Life History of the Blood-corpuscles," etc., Journal of Morphology, 1890, vol. iv. 2 La s, maine m&dicale, 1890, p. 4G4. s Archiv fib- erp. Pathol, u. Pharmakol., 1897, Bd. 39, S. 426-464. BLOOD. 47 and thereby stimulates the erythroblastic cells to more rapid multiplication. Iu the case of a diminution in oxygen-pressure, as happens when the altitude is markedly increased, we may suppose that one result is again a slight dimi- nution in the oxygen-supply to the tissues, including the red marrow, and in consequence the erythroblasts are again stimulated to greater activity. This variation in haemoglobin with the altitude is an interesting adaptation which ensures always a normal oxygen-capacity for the blood. Physiolog-y of the Blood-leucocytes. — The function of the blood-leuco- cytes has been the subject of numerous investigations, particularly in connection with the pathology of blood diseases. Although many hypotheses have been made as the result of this work, it cannot be said that we possess any positive information as to the normal function of these cells in the body. It must be borne in mind in the first place that the blood-leucocytes are not all the same histologically, and it may be that their functions are as diverse as is their mor- phology. Various classifications have been made, based upon one or another difference in microscopic structure and reaction. Thus, Ehrlich groups the leuco- b Fig. 7.— Blood stained with Ehrlich's "triple stain" of acid-fuchsin, methyl-green, and orange G. (drawn with the camera lucida from normal blood) (after Osier): a, red corpuscles; b, lymphocytes; c, large mononuclear leucocytes; , neutrophilic leucocytes with polymorphous nuclei (polynuclear neutrophiles) ; /, eosinophilic leucocytes. cytes according to the size, the solubility, and the staining of the granules (contained in the cytoplasm, making in the latter respect three main groups; oxyphiles or eo&inophiles, those whose granules stain only with acid aniline dyes — that is, with dyes in which the acid part of the dye acts as the stain ; basophiles, those which stain only with basic- dyes; and neutrophiles, those which stain only with neutral dyes 1 (Fig. 7). This classification is fre- quently used, especially in pathological literature, but it is not altogether satisfactory, since no definite functional relationship of the granules has been established ; and, moreover, it is undecided whether or not the granules arc permanent or temporary structures in the cells. A simpler classification 1 Ehrlich : Die Ancemie, Vienna, 1S98; Kanthack and Hardy, Journal of Physiology, vol., xvii., 1894, p. 81. 48 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. based on morphological characteristics is the following: 1. Lymphocytes, which arc small corpuscles with a round vesicular nucleus and very scanty cytoplasm ; they are not capable of amoeboid movements. These corpuscles are so called because they resemble the leucocytes found in the lymph-glands, and are supposed in fact to be brought into the blood through the lymph. According to Ehrlich, they form from 22 to 25 per cent, of the total number of leucocytes. 2. Mononuclear leucocytes, which are large corpuscles with a vesicular nucleus and abundant cytoplasm : they have the power of making amoeboid movements and arc present in only small numbers, 1 per cent. 3. Polymorphous or polynucleated leucocytes, which are large corpuscles with the nucleus divided into lobes that are either entirely separated or are con- nected by line protoplasmic threads. This form shows active amoeboid move- ments and constitutes the largest proportion of the blood leucocytes, 70 to 72 per cent. 4. The eosinophile cells, similar in general to the last, except that the cytoplasm contains numerous coarse granules that take acid stains (eosin) readily. They are present in small numbers, 2 to 4 per cent. It is impossible to say whether these varieties of blood-leucocytes are distinct histological units that have independent origins and more or less dissimilar functions, or whether, as seems more probable to the writer, they represent different stages in the development of a single type of cell, the lymphocytes forming the youngest and the polymorphic or polynucleated leucocytes the oldest stage. Perhaps the most striking property of the leuco- cytes as a class is their pow r er of making amoeboid movements — a charac- teristic which has gained for them the sobriquet of " wandering " cells. By virtue of this property some of them are able to migrate through the walls of blood-capillaries into the surrounding tissues. This process of migration takes place normally, but is vastly accelerated under pathological conditions. As to the function or functions fulfilled by the leucocytes, numerous sugges- tions have been made, some of which may be stated in brief form as follows: (1) They protect the body from pathogenic bacteria. In explanation of this action it has been suggested that they may either ingest the bacteria, and thus destroy them directly, or they may form certain substances, defensive proteids, that destroy the bacteria. Leucocytes that act by ingesting the bacteria are spoken of as "phagocytes" {ipaystv, to eat; xvrot;, cell). This theory of their function is usually designated as the "phagocytosis theory of Metschni- kotf ;" it is founded upon the fact that the amoeboid leucocytes are known to ingest foreign particles with which they come in contact. The theory of the protective action of leucocytes has been used largely in pathology to explain immunity from infectious diseases, and for details of experiments in support of it reference must be made to pathological text-books. (2) They aid in the absorption of fats from the intestine. (3) They aid in the absorption of peptones from the inte-tine. It maybe noticed here that these theories apply to the leucocytes found SO abundantly in the lymphoid tissue of the aliment- ary canal, rather than to those contained in the blood itself. (4) They take pari in the process of blood-coagulation. A complete statement with refer- ence to this function must be reserved until the phenomenon of coagulation is BLOOD. 49 described. (5) They help to maintain the normal composition of the blood- plasma as to its proteids. It may be said for this view that there is considerable evidence to show that the leucocytes normally undergo disintegration and dis- solution in the circulating blood, to some extent at least. The blood-proteids are peculiar, and they are not formed directly from the digested food. It is possible that the leucocytes, which are the only typical cells in the blood, aid in keeping up the normal supply of proteids. From this standpoint they might be regarded in fact as unicellular glands, the products of their metab- olism serving to maintain the normal composition of the blood-plasma. The formation of granules within the substance of the eosinophiles offers a suggestive analogy to the accumulation of zymogen granules in glandular cells. As to the origin of the leucocytes, it is known that they increase in number while in the circulation, undergoing multiplication by karyokinesis ; but the greater number are probably produced in the lymph-glands and in the lymphoid tissue of the body, whence they get into the lymph-stream and eventually are brought into the blood. Physiology of the Blood-plates. — The blood-plates are small circular or elliptical bodies, nearly homogeneous in structure and variable in size (0.5 to 5.5//), but they are always smaller than the red corpuscles (see Histology). Less is known of their origin, fate, and functions than in the case of the leucocytes. It is certain that they are not independent cells, and it is altogether probable, therefore, that they soon disintegrate and dissolve in the plasma. When removed from the circulating blood they are known to disintegrate very rapidly. This peculiarity, in fact, prevented them from being discovered for a long time after the blood had been studied microscopically. Recent work has shown that they are formed elements, and not simply precipitates from the plasma, as was suggested at one time. The theory of Hayem, their real discoverer, that they develop into red corpuscles may also be considered as erroneous. There is considerable evidence to show that in shed blood they take part in the process of coagulation. The nature of this evidence will be described later. Lilienfeld 1 has claimed that chemically the blood-plates contain a nucleo- albumin (see section on Chemistry of the Body), to which he gives the specific name of "nucleohiston." The same substance is contained in the nuclei of leucocytes. This latter fact may be taken as additional evidence for a view which has already been supported on morphological grounds — that the blood- plates are derived from the nuclei of the leucocytes. According to this theory when the polynuclear leucocytes go to pieces in the blood the frag- ments of nuclei contained in them persist for a longer or shorter time as blood-plates, that in time eventually dissolve in the plasma. If this last statement is correct, then it follows that the substance contained in the blood- plates either goes to form one of the normal constituents of the plasma, useful in nutrition or otherwise, or that it forms a waste product that is eliminated from the body. 1 Da Bois-lleymond's Archiv fiir Physiologic, 1893, S. 5G0. Vol. I.— 4 oO AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. B. Chemical Composition of the Blood ; Coagulation; Total Quantity of Blood ; Regeneration after Hemorrhage. Composition of the Plasma and Corpuscles. — Blood (plasma and cor- puscle-) contains a great variety of substances, as may be inferred from its double relation- to tin 4 tissues as a source of food-supply and as a means of removing the waste products of their functional activity. The constituents existing in quantities sufficiently large for recognition by chemical means are as follows: (lj Water j (2) proteids, of which three varieties at least are known to exist in the plasma — namely, fibrinogen, paraglobulin (serum- globulin), and serum-albumin; (3) combined proteids (haemoglobin, nucleo- albumins) j (I) extractives, including such substances as fats, sugar, urea, lecithin, cholesterin, etc.; and (5) inorganic salts. The proportions of these substances found in the blood of various mammals differ somewhat, although the qualitative composition is practically the same in all. 'I lie following tables, taken from different sources, summarize the general result- of the quantitative analyses made by several observer-: Analysis of the Whole Blood, Human (C. Schmidt). Water Solids Proteids and extractives Fibrin (derived from the fibrinogen) I lamatin (and iron) Salts Man Woman (25 years). (30 years.) 788.71 824.55 211.29 175.45 191.78 157.93 3.93 1.91 7.7(1 6.99 7.88 8.62 Inorganic Sails of Human Blood, 1000 parts (C. Schmidt). Blood-corpnscles. CI 1.75 i< i > 3.091 Na 2 0.470 S0 3 0.061 P 2 6 5 1.355 CaO MgO Blood-plasma. CI 3.536 K 2 0.314 Na 2 3.410 so 0.129 I '.<>., 0.145 CaO MgO ■ . These acids and bases exist, of course, in the plasma and the corpuscles as salts. It is not possible to determine exactly how they are combined as salts, but Schmidt suggests the following probable combinations: Probable Salts in the Corpuscles. Potassium sulphate 0.132 Potassium chloride 3.679 Potassium phosphate 'J..".!:; Sodium phosphate 0.633 ira carbonate 0.3 tl < 'alcium phosphate 0.09 I Magnesium phosphate .... 0.060 Probable salt- in the Plasma. Potassium sulphate 0.281 Potassium chloride 0.359 Sodium chloride 5.5 16 Sodium phosphate 0.271 Sodium carbonate 1.532 < alcium phosphate 0.298 Magnesium phosphate .... 0.218 BLOOD. 51 One interesting fact brought out in the above table is the peculiarity in distribution of the potassium and sodium salts between the plasma and the corpuscles. The plasma contains an excess of the total sodium salts, and the corpuscles contain an excess of the potassium salts. Composition of Blood-plasma (1000 parts). Water Solids . Total proteids Fibrin (derived from the fibrinogen Paraglobidin Serum-albumin Extractives and salts Horse. 917.6 82.4 69.5 6.5 38.4 24.6 12.9 Composition of Blood-serum (1000 parts). 1 Horse. 85.97 72.57 45.65 26.92 13.40 Man. 92.07 76.20 31.04 45.16 15.88 Ox. 89.65 74.99 41.69 33.30 14.66 Bed Corpuscles, Human Blood (Hoppe-Seyler). I. II. Oxyhemoglobin 86.8 94.3 per cent. Proteid (and nuclein ?) 12.2 5.1 Lecithin 0.7 0.4 " Cbolesterin 0.3 0.3 " Leucocytes, Thymus of Calf (Lilienfeld). In the 'total dry substance of the corpuscles, which was equal to 11.49 per cent., there were contained — Proteid 1.76 per cent. Leuco-nuclein 68.78 " Histon 8.67 Lecithin 7.51 " Fat 4.02 " Cholesterin 4.40 " Glycogen 0.S0 " The extractives present in the blood vary in amount under different conditions. Average estimates of some of them, given in percentages of the entire blood, have been reported as follows : Dextrose (grape-sugar) 0.117 percent. Urea 0.016 Lecithin 0.0844 " Cholesterin 0.041 " Proteids of the Blood-plasma. — The properties and reactions of proteids and the related compounds, as well as a classification of those occurring in t lie animal body, are described in the section on the Chemistry of the Body. This description should be read before attempting to study the proteids of the plasma and the part they take in coagulation. Three proteids are usually described as existing in the plasma of circulating blood — namely, fibrinogen, paraglobulih, or, as it is sometimes called, "serum-globulin," and serum-albu- min. The first two of these proteids, fibrinogen and paraglobidin, belong to the group of globulins, and hence have many properties in common. Serum- albumin belongs to the group of so-called ''native albumins" of which egg- albumin constitutes another member. 1 Haramarsten : .1 Text-book of Physiological Chemistry, 1898 [translated by Mandel). 52 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Serum-albumin. — This substance is a typical proteid. It can be obtained readily in crystalline form. Its percentage composition, according to Hara- marsten, is as follows : C 53.06, H 6.85, N 16.04, S 1.80, O 22.26. Its molecular composition, according to Schmiedeberg, 1 may be represented by C'.J 1 ,.,,\ ,,,S( ), ( or some multiple of this formula. Serum-albumin shows the general reactions of the native albumins. One of its most useful reactions is its behavior toward magnesium sulphate. Serum-albumin usually occurs in liquids together with the globulins, as is the case in blood. If such a liquid is thoroughly saturated with solid MgS0 4 , the globulins are precipitated com- pletely, while the albumin is not affected. So far as the blood and similar liquids are concerned, a definition of serum-albumin might be given by saying that it comprises all the proteids not precipitated by MgS0 4 . When its solutions have a neutral or an acid reaction, serum-albumin is precipitated in an insoluble form by heating the solution above a certain degree. Precipi- tates produced in this way by heating solutions of proteids are spoken of as coagulations — heat coagulations — and the exact temperature at which coagulation occurs is to a certain extent characteristic for each proteid. The temperature of coagulation of serum-albumin is usually given at from 70° to 75° C, but it varies . greatly with the conditions. It has been asserted, in fact, that careful heating under proper conditions gives separate coagula- tions at three different temperatures — namely, 73°, 77°, and 84° C. — indi- cating the possibility that what is called " serum-albumin " may be a mixture of three proteids. Serum-albumin occurs in blood-plasma and blood-serum, in lymph, and in the different normal and pathological exudations found in the body, such as pericardial liquid, hydrocele fluid, etc. The amount of serum- albumin in the blood varies in different animals, ranging among the mam- malia from 2.67 per cent, in the horse to 4.52 per cent, in man. In some of the cold-blooded animals it occurs in surprisingly small quantities — 0.36 to 0.69 per cent. As to the source or origin of serum-albumin, it is frequently stated that it comes from the digested proteids of the food. It is known that proteid material in the food is not changed at once to serum- albumin during the act of digestion ; indeed, it is known that the final product of digestion is a proteid or group of proteids of an entirely different character — namely, peptones and proteoses ; but during the act of absorption into the blood these latter bodies are supposed to undergo transformation into serum- albumin. From a physiological standpoint serum-albumin is considered to be the main source of proteid nourishment for the tissues generally. As will be explained in the section on Nutrition, one of the most important requisites in the nutrition of the cells of the body is an adequate supply of proteid material to replace that used up in the chemical changes, the metabolism, of the tissues. Serum-albumin is supposed to furnish a part, at least, of this supply, although as a matter of fact there is no substantial proof that this view is correct. As long as the serum-albumin is in the blood-vessels it is, of course, cut off from the tissues. The cells, however, are bathed directly in lymph, 1 Archivjur exper. Pathol, u. PhannakoL, 1897, Bd. 39, S. 1. BLOOD. 53 and this in turn is formed from the plasma of the blood which is transuded, or, according to some physiologists, secreted, through the vessel-walls. Paraglobulin, which belongs to the group of globulins, exhibits the general reactions characteristic of the group. As stated above, it is completely pre- cipitated from its solutions by saturation with MgS0 4 . It is incompletely pre- cipitated by saturation with common salt (NaCl). In neutral or feebly acid solutions it coagulates upon heating to 75° C. Hammarsten gives its percentage composition as— C 52.71, H7.01, N 15.85, S 1.11, O 23.24. Schmiedeberg gives it a molecular composition corresponding to the formula 0,^11, ^N^SO^ + ^H 2 0. According to Faust, 1 the precipitate of paraglobulin usually obtained with MgS0 4 contains a certain amount of an albuminoid body, glutolin, which he believes to be a constant constituent of blood-plasma. Paraglobulin occurs in blood, in lymph, and in the normal and pathological exudations. The amount of paraglobulin present in blood varies in different animals. Among the mam- malia the amount ranges from 1.78 per cent, in rabbits to 4.56 per cent, in the horse. In human blood it is given at 3.10 per cent., being less in amount, therefore, than the serum-albumin. It will be seen, upon examining the tables of composition of the blood-plasma and blood-serum of the horse (p. 51), that more of this proteid is" found in the serum than in the plasma. This result, which is usually considered as being true, is explained by supposing that during coagulation some of the leucocytes disintegrate and part of their substance passes into solution as a globulin identical with or closely resembling paraglobulin. The figures given above show that a considerable amount of paraglobulin is normally present in blood. It is reasonable to suppose that, like serum-albumin, this proteid is valuable as a source of nitrogenous food to the tissues. It is uncertain, however, whether it is used by the tissues directly as paraglobulin or is first converted into some other form of proteid. It is entirely unknown, also, whether its value as a proteid supply is in any way different from that of serum-albumin. The origin of paraglobulin remains undetermined. It may arise from the digested proteids absorbed from the alimentary canal, but there is no evidence to support such a view. Another suggestion is that it comes from the disintegration of the leucocytes (and other formed elements) of the blood. These bodies are known to contain a small quantity of a globulin resembling paraglobulin, and it is possible that this globulin may be liberated after the dissolution of the leucocytes in the plasma, and thus go to make up the normal supply <>i* paraglobulin. The fact remains, however, that at present the origin and the special use of the paraglobulin are entirely unknown. Fibrinogen is a proteid belonging to the globulin class and exhibiting all the general reactions of this group. It is distinguished from paraglobulin by a number of special reactions; for example, its temperature of heat coagula- tion is much lower (50° to 60° C), and it is completely thrown down from its solutions by saturation with NaCl as well as with MgS0 4 . It- most impor- tant and distinctive reaction is, however, that under proper conditions it gives 'Faust, Inaugural Dissertation, Leipzig, L898, 54 AN AMERICAN TEXT-HOOK OE PHYSIOLOGY. rise to an insoluble proteid, fibrin, whose formation is the essential phenom- enon in the coagulation of blood. Fibrinogen has a percentage composition, according to Eammarsten, of— C 52.93, H 6.90, N 16.66, S 1.25, () 22.26; while its molecular composition, according to Schmiedeberg, is indicated by the formula C^gH^gN^SO^. Fibrinogen is found in blood-plasma, lymph, and in some cases, though not always, in the normal and pathological exudations. It is absent from blood- serum, being used up during the process of clotting. It occurs in very small quantities in blood, compared with the other proteids. There is no good method of determining quantitatively the amount of fibrinogen, but estimates of the amount of fibrin, which cannot differ very much from the fibrinogen, show that in human blood it varies from 0.22 to 0.4 per cent. In horse's blood it may be more abundant — 0.65 per cent. As to the origin and the special physiological value of this proteid we are, if possible, more in the dark than in the case of paraglobulin, with the exception that fibrinogen is known to be the source of the fibrin of the blood. But clotting is an occasional phe- nomenon only. What nutritive function, if any, is possessed by fibrinogen under normal conditions is unknown. No satisfactory account has been given of its origin. It has been suggested by different investigators that it may come from the nuclei of disintegrating leucocytes (and blood-plates) or from the dissolution of the extruded nuclei of newly-made red corpuscles, but here again we have only speculations, that cannot be accepted until some experi- mental proof is advanced to support them. Coagulation of Blood. — One of the most striking properties of blood is its power of clotting or coagulating shortly after it escapes from the blood- vessels. The general changes in the blood during this process are easily fol- lowed. At first shed blood is perfectly fluid, but in a few minutes it becomes viscous and then sets into a soft jelly which quickly becomes firmer, so that the vessel containing it can be inverted without spilling the blood. The clot continues to grow more compact and gradually shrinks in volume, pressing out a smaller or larger quantity of a clear, faintly yellow liquid to which the name blood-serum has been given. The essential part of the clot is the fibrin. Fibrin is an insoluble proteid that is absent from normal blood. In shed blood, and under certain conditions in blood while still in the blood-vessels, this fibrin is formed from the soluble fibrinogen. The deposition of the fibrin is peculiar. It i- precipitated, if the word maybe used, in the form of an exceedingly fine network of delicate threads that permeate the whole mass of the blood and give the clot its jelly-like character. The shrinking of the threads causes the subsequent contraction of the clot. If the blood has not been shaken during the act of clotting, almost all the red corpuscles are caught in the line fibrin meshwork, and as the clot shrinks these corpuscles are held more firmly, only the clear liquid of the blood being squeezed out, so that it is possible to get specimens of serum containing few or no red corpuscles. The leucocytes, on the contrary, although they arc also caught at first in .the forming mesh- work of fibrin, may readily pass out into the serum in the later stages of clot- BLOOD. 55 ting, on account of their power of making amoeboid movements. It' the blood has been agitated during the process of clotting, the delicate network will be broken in places and the scrum will be more or less bloody — that is, it will contain numerous red corpuscles. If during the time of clotting the blood is vigorously whipped with a bundle of fine rods, all the fibrin will be deposited as a stringy mass upon the whip, and the remaining liquid part will consist of serum plus the blood-corpuseles. Blood that has been whipped in this way is known as " defibrinated blood." It resembles normal blood in appearance, but is different in its composition: it cannot clot again. The way in which the fibrin is normally deposited may be demonstrated most beautifully under the microscope by placing a good-sized drop of blood on a slide, covering it with a cover-slip, and allowing it to stand for several minutes until coagu- lation is completed. If the drop is now examined, it is possible by careful focussing to discover in the spaces between the masses of corpuscles many examples of the delicate fibrin network. The physiological value of clotting is that it stops hemorrhages by closing the openings of the wounded blood- vessels. Time of Clotting. — The time necessary for the clot to form varies slightly in different individuals, or in the blood of the same individual varies with the conditions. It may.be said in general that under normal conditions the blood passes into the jelly stage in from three to ten minutes. The separation of clot and serum takes [dace gradually, but is usually completed in from ten to forty-eight hours. The time of clotting shows marked variations in different animals; the process is especially slow in the horse and the terrapin, so that coagulation of shed blood is more easily prevented in these animals. In the human being also the time of clotting may be much prolonged under certain conditions — in fevers, for example. This fact was noticed in the days when bloodletting was a common practice. The slow clotting of the blood permitted the red corpuscles to sink somewhat, so that the upper part of the clot in such cases was of a lighter color, forming what was called the " buffy coat." The time of clotting may be shortened or be prolonged, or the clotting may be pre- vented altogether, in various ways, and much use has been made of this fact in studying the composition and the coagulation of blood as well as in con- trolling hemorrhages. It will be advantageous to postpone an account of these methods for hastening or retarding coagulation until the theories of coagulation have been considered. Theories of Coagulation. — The clotting of blood is such a prominent phe- nomenon that it has attracted attention at all times, and as a result numerous theories to account for it have been advanced. Most of these theories possess simply an historical interest, and need not be discussed in a work of this charac- ter, but some reference to older views is unavoidable for a proper presentation of the subject. To prevent misunderstanding it may he stated explicitly in the beginning that there is at present no perfectly satisfactory theory. Indeed, the subject is a difficult one, as it is intimately connected with the chemistry of the proteids of the blood, and it may lie said that a complete understanding 56 AN AMERICAN TENT-BOOK OF PHYSIOLOGY. of clotting waits upon a better knowledge of the nature of these proteids. It is possible that at any moment new facts may be discovered that will alter present ideas of the nature of the process. In considering the different theories that have been proposed there are two general facts that should always be kept in mind : first, that the main phenomenon that a theory of coagulation has to explain is the formation of fibrin ; second, that all theories unite in the common belief that the fibrin is derived, in part, at least, from the fibrinogen of the plasma. Schmidt's Older Theory of < 'oagulation. — The first theory that gained general acceptance in recent times was that of Alexander Schmidt. It was proposed in 1861, and it has served as the basis for all subsequent theories. Schmidt held that the fibrin of the clot is formed by a reaction between para- globulin (he called it " fibrinoplastin ") and fibrinogen, and that this reaction is brought about by a third body, to which he gave the name of fibrin ferment. Fibrin ferment was believed to be absent from normal blood, but to be formed after the blood was shed. Further reference will presently be made to the nature of this substance. Schmidt was not able to determine its nature — whether it was a proteid or not — but he discovered a method of preparing it from blood-serum, and demonstrated that it cannot be obtained from blood immediately after it leaves the blood-vessels, and that consequently it does not exist in circulating blood, in any appreciable quantity at least. Finally, Schmidt believed that a certain quantity of soluble salts is necessary as a fourth " fibrin factor." Uammarsten's Theory of Coagulation. — Hammarsten, who repeated Schmidt's experiments, demonstrated that paraglobulin is unnecessary for the formation of fibrin. He showed that if a solution of pure fibrinogen is prepared, and if there is added to it a solution of fibrin ferment entirely free from paraglobulin, a typical clot is formed. This experiment has since been confirmed by others, so that at present it is generally accepted that paraglob- ulin takes no direct part in the formation of fibrin. Hammarsten's theory was that there are two fibrin factors, fibrin ferment and fibrinogen, and that fibrin results from a reaction between these two bodies. The nature of this reaction could not be determined, but Hammarsten showed that the entire fibrinogen molecule is not changed to fibrin. In place of the fibrinogen there is present after clotting, on the one hand, fibrin representing most of the weight of fibrinogen (60-90 per cent.), and, on the other hand, a newly- formed globulin-like proteid retained in solution in the serum, to which pro- teid the name fibrin-globulin has been given. Hammarsten supposed that although paraglobulin took no direct part in the process, it acted as a favor- ing condition, a greater quantity of fibrin being formed when it was present. Later experiments 1 indicated that this supposition was incorrect, and that paraglobulin may be eliminated entirely trom the theory. The theory of Hammarsten, which is perhaps generally accepted at the present time, is incomplete, however, in that it have.- undetermined the nature of the ferment 1 Frederikse: Zeitschrift fur physioloyische Chemie, lid. 19, 1814, S. 143. BLOOD. 57 and of the reaction between it and fibrinogen. The aim of the newer theories has been to supply this deficiency. Schmidt's Theory of Coagulation. — In a volume 1 containing the re- sults of a lifetime of work devoted to the study of blood-coagulation, Schmidt has modified his well-known theory. His present ideas of the direct and indirect connection of the proteids of the plasma with the formation of fibrin are too complex to be stated clearly in brief compass. He classifies the conditions necessary for coagulation as follows : (1) Certain soluble proteids — namely, the two globulins of the blood — as the material from which fibrin is made. Schmidt does not believe, however, that paraglobulin and fibrinogen react to make fibrin, but believes that fibrinogen is formed from paraglobulin, and that fibrinogen in turn is changed to fibrin. (2) A specific ferment, fibrin ferment, to eifect the changes in the proteids just stated. He proposes for fibrin ferment the distinctive name of thrombin. (3) A certain quantity of neutral salts is necessary for the precipitation of the fibrin in an insoluble form. The Relation of Calcium Salts to Coagulation. — It has been shown by a number of observers that calcium salts take an important part in the pro- cess of clotting. This fact was first clearly demonstrated by Arthus and Pages, who found that if oxalate of potash or soda is added to freshly-drawn blood in quantities sufficient to precipitate the calcium salts, clotting will be prevented. If, however, a soluble calcium salt is again added, clotting occurs promptly. This fact has been demonstrated not only for the blood, but also for pure solutions of fibrinogen, and we are justified in saying that without the presence of calcium salts fibrin cannot be formed from fibrinogen. This is one of the most significant facts recently brought out in connection with coagulation. We know that fibrinogen when acted upon by fibrin ferment produces fibrin, but we now know also that calcium salts must be present. What is the relation of these salts to the so-called "ferment"? The most explicit theory proposed in answer to this question we owe to Pekelharing. Pekelha ring's Theory of Coagulation. — Pekelharing- succeeded in sepa- rating from blood-plasma a proteid body that has the properties of a nucleo- albumin. He finds that if this substance is brought into solution together with fibrinogen and calcium salts, a typical clot will form, while nueleo- albumin alone, or calcium salts alone, added to fibrinogen solutions, cause no clotting. His theory of coagulation is that what has been called "fibrin ferment" is a compound of nucleo-albumin and calcium, and that when this compound is brought into contact with fibrinogen a reaction occurs, the calcium passing over to the fibrinogen and forming an insoluble calcium compound, fibrin. According to this theory, fibrin is a calcium compound with fibrinogen or with a part of the fibrinogen molecule. This idea is strengthened by the unusually large percentage of calcium found in fibrin ash. The theory supposes also that the fibrin ferment is not present in blood- plasma — that is, in sufficient quantity to set up coagulation — but that it is formed 1 Zwr Blutlehre, Leipzig 1893. 2 l T nttrsiirliu)it/rn iibcr (lax Fibriiifcnnrnt, Amsterdam, 1S<)'J. 58 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. after the blood is shed. The nucleo-albumio part is derived faom the cor- puscles of the blood (leucocytes, blood-plates), which break down and go into solution. This nucleo-albumin then unites with the calcium salts present in the blood to form fibrin ferment, an organic compound of calcium capable of reacting with fibrinogen. The theory is a simple one ; it accounts tor the importance of calcium salts in coagulation, and reduces the interchange be- tween fibrinogen and fibrin ferment to the nature of an ordinary chemical reaction; but it cannot be accepted without reservation at present, since the experimental evidence is not entirely in its favor. Hammarsten, for instance, in some careful experiments seems to have obtained facts that are at variance with a part at least of this theory. Hammarsten 1 states that blood-plasma or fibrinogen solutions to which an excess of potsssium oxalate had been added, and which therefore was free presumably from precipitable calcium salts, underwent typical coagulation when mixed with blood-serum to which an excess of oxalate had also been added. In other words, a solution of fibrinogen free from calcium reacted with a solution of fibrin ferment (blood-serum) also apparently free from calcium. It might be urged against this experiment, however, that in the blood-serum used the combination of calcium and nucleo- proteid to form ferment had already taken place, and that in this combination the calcium is not acted upon by the oxalate. Hammarsten indeed admits that something of this kind may occur, for he is convinced, like others, that calcium in some way is essential to coagulation, his suggestion being that it plays an un- known part in the formation of the ferment. He supposes that in the plasma of shed blood a material is present which he designates as prothrombin, and the calcium in some way converts this into the active ferment, the thrombin. According to the more explicit hypothesis of Pekelharing, the prothrombin is a form of nucleo-proteid and the thrombin a calcium compound of this pro- teid. The second part of IVkelharing's theory, namely, that the reaction between the ferment and the fibrinogen consists in a transfer of the calcium from the former to the latter, is directly contradicted by Ilammarsten's experi- ments. Quantitative analysis of fibrinogen and fibrin showed that the latter docs not contain any larger amount of calcium than the former. This author is inclined to consider the ( a contained in fibrin of the nature of an impurity, and not as an essential constituent of the fibrin molecule. By the use of special methods he has succeeded in obtaining typical fibrin containing as little as 0.005 per cent, of ('a. We must be content to say that in the clot- ting of blood three factors are necessary — namely, the fibrinogen and the calcium salts of plasma, which are present in the circulating blood, and the fibrin ferment, which is formed after the blood is shed. Nature and Origin of Fibrin Ferment (Thrombin). — Recent views as to the nature of fibrin ferment have been referred to incidentally in the description of the theories of coagulation just given. The relation of these newei' views to the older idea- can be presented most easily by giving a brief description of the development of our know ledge concerning this body. 1 Zeitschriftfiir physiologische Chemie, Bd. -:-2. S. 333, and 1899, Bd. 28, S. 98.' BLOOD. 59 Schmidt prepared solutions of fibrin ferment originally by adding a large excess of alcohol to blood-serum and allowing the proteids thus precipitated to stand under strong alcohol for a long time until they were thoroughly coagu- lated and rendered nearly insoluble in water. At the end of the proper period the coagulated proteids were extracted with water, and there was obtained a solution which contained only small quantities of protcid. It was found that solutions prepared in this way had a marked effect in inducing coagulation when added to liquids, such as hydrocele liquid, that contained fibrinogen, but did not clot spontaneously or else clotted very slowly. It was after- ward shown that similar solutions of fibrin ferment are capable of setting up coagulation very readily in so-called salted plasma — that is, in blood-plasma prevented from clotting by the addition of a certain quantity of neutral salts. It was not possible to say whether the coagulating power of these solutions was due to the small traces of proteid contained in them, or whether the pro- teid was merely an impurity. The general belief for a time, however, was that the proteids present were not the active agent, and that there was in solu- tion something of an unknown chemical nature which acted upon the fibrinogen after the manner of unorganized ferments. This belief was founded mainly upon three facts : first, that the substance seemed to be able to act powerfully upon fibrinogen, although present in such minute quantities that it could not be isolated satisfactorily ; second, it was destroyed by heating its solutions for a few minutes at 60° C. ; and, third, it did not seem to be destroyed in the reaction of coagulation which it set up, since it was always present in the serum squeezed out of the clot. Schmidt proved that fibrin ferment could not be obtained from blood by the method described above if the blood was made to flow im- mediately from the cut artery into the alcohol. On the other hand, if the shed blood was allowed to stand, the quantity of fibrin ferment increased up to the time of coagulation, and was present in quantity in the serum. Schmidt believed that the ferment was formed in shed blood from the disintegration of the leucocytes, and this belief was corroborated by subsequent histological work. It was shown in microscopic preparations of coagulated blond that the fibrin threads often radiated from broken-down leucocytes — an appearance that seemed to indicate that the leucocytes served as points of origin for the deposition of the fibrin. When the blood-plates were discovered a great deal of microscopic work was done tending to show that these bodies also are con- nected with coagulation in the same way as the leucocytes, and serve probably as sources of fibrin ferment. In microscopic preparations the fibrin threads were found to radiate from masses of partially disintegrated plates ; and, more- over, it was discovered that conditions which retard or prevent coagulation of blood often serve to preserve the delicate plate- from disintegration. At the present time it is generally believed that there is derived from the disintegra- tion of the leucocytes and blood-plates something that is necessary to the coagulation of blood, but there is sonic difference of opinion as to the nature of this substance and whether it is identical with Schmidt's fibrin ferment. Pekelharing thinks that the substance sel free from the corpuscles and plates 60 AN AMERICA* Til XT-BOOK OF PHYSIOLOGY. is a nucleo-proteid, but that this nucleo-proteid is not capable of acting upon fibrinogen until it has combined with the calcium salts of the blood. According to his view, therefore, fibrin ferment, in Schmidt's sense, is a compound of cal- cium and nucleo-proteid. Lilienfeld has shown by chemical reactions that blood-plates and nuclei of leucocytes contain nucleo-proteid material which in all probability is liberated in the blood-plasma by the disintegration of these elements after the blood is shed. Lilienfeld contends, however, that solu- tions of fibrin ferment prepared by Schmidt's method do not contain any nucleo-proteid material, and that, although the liberation of nucleo-proteid material is what starts normal coagulation of blood, nevertheless so-called fibrin ferment is something entirely different from nucleo-proteid. In this point, however, his results are contradicted by the experiments of Pekelhar- ing and of Halliburton, who both find that solutions of fibrin ferment pre- pared by Schmidt's method give distinct evidence of containing nucleo-pro- teid material. We may conclude, therefore, that the essential element of Schmidt's fibrin ferment is a nucleo-proteid compound. The nature of the action of the ferment on fibrinogen is quite undetermined. As was mentioned before, only a portion, and apparently a variable portion, of this fibrinogen appears as fibrin after clotting is completed. Along with the fibrin a new proteid fibrin globulin makes its appearance in the serum. This fact has suggested the view that perhaps the fibrin ferment acts after the manner of the digestive ferments by causing hydrolytic cleavage of the fibrinogen, that is, causes the fibrinogen molecule to take up water and then dissociate into two parts, fibrin and fibrin globulin. Hammarsten, however, is inclined to believe that the reaction is of a different nature, resembling more the change that occurs in the heat coagulation of proteids. According to this suggestion, the ferment causes a molecular rearrangement of the fibrinogen, resulting in the formation of fibrin, most of which is deposited in an insoluble form, while a smaller part, after suffering a still further alteration, appears as fibrin globulin. Intravascular Clotting-. — Clotting may be induced within the blood- vessels by the introduction of foreign particles, either solid or gaseous — for example, air — or by injuring the inner coat of the blood-vessels, as in ligat- ing. In the latter case the area injured by the ligature acts as a foreign surface and probably causes the disintegration of a number of corpuscles. The clot in this case is confined at first to the injured area, and is known a- a " thrombus." Intravascular clotting more or less general in occurrence may be produced by injecting into the circulation such substances as leucocytes obtained by macerating lymph-glands, extracts of fibrin ferment, solutions of nucleo-albumins of different kinds, etc. According to the theory of coagu- lation adopted above, injections of these latter substances ought to cause coagu- lation very readily, since the blood already contains fibrinogen, and needs only the presence of ferment to set up coagulation. As a matter of fact, however, intravascular clotting is produced with some difficulty by these methods, show- ing that the body can protect itself within certain limits from an excess of BLOOD. 61 ferment in the circulating blood. Just how this is done is not positively known, but there is evidence that it may be due mainly to a defensive action of the liver. Delezenne 1 states that when blood-serum is circulated through a liver it loses its power of inducing coagulation in a coagulablc liquid, that is, probably its contained fibrin ferment is altered or destroyed. It seems prob- able that this action of the liver may be of importance in the normal circula- tion in maintaining the non-coagulability of the blood in the living animal. Moreover, injection of leucocytes sometimes diminishes instead of increasing the coagulability of blood, making the so-called " negative phase " of the injection. To explain this latter fact, it may be said that leucocytes give rise on disintegration to a complex nucleo-proteid known as nucleo-histon. Nucleo-histon in turn is said to be broken up in the circulation, with the formation of a second nucleo-proteid, leuconuclein, that favors coagulation, and a proteid body, histon, that has a retarding influence on coagulation. The predominance of the latter substance may account for the " negative phase " under the conditions described. Why Blood does not Clot within the Blood-vessels. — The reason that blood remains fluid while in the living blood-vessels, but clots quickly after being shed or after being brought into contact with a foreign substance in any way, has already been stated in describing the theories of coagulation, but will be restated here in more categorical form. Briefly, then, blood does not clot within the blood-vessels because fibrin-ferment is not present in sufficient quantities at any one time. Leucocytes and blood-plates probably disintegrate here and there within the circulation, but the small amount of ferment thus formed is insufficient to act upon the blood, and the ferment is quickly destroyed or changed, probably by an action of the liver as stated above. When blood is shed, however, the formed elements break down in mass, as it were, liberating a relatively large amount of nucleo-proteids, which, together with the calcium salts, produce fibrin from the fibrinogen. Means of Hastening" or of Retarding - Coagulation. — Blood coagulates normally within a few minutes, but the process may be hastened by increasing the extent of foreign surface with which it comes in contact. Tims, moving the liquid when in quantity, or the application of a sponge or a handkerchief to a wound, will hasten the onset of clotting. This is easily understood when it is remembered that nucleo-proteids arise from the breaking down of leucocytes and blood-plates, and that these corpuscles go to pieces more rapidly when in contact with a dead surface. It has been proposed also to hasten clotting in case of hemorrhage by the use of ferment solutions. Plot sponges or cloths applied to a wound will hasten clotting, probably by accelerating the formation of ferment and the chemical changes of clotting. Coagulation may be retarded or be prevented altogether by a variety of means, of which the following are the most important : 1. By Cooling. — This method succeeds well only in blood that clots slowly — for example, the blood of the horse or the terrapin. Blood from 1 Travaux rd to ex- plain the action of peptone may possibly apply also to these cases. 5. By the Action of Oxalate Solutions. — If blood as it flows from the vessels is mixed with solutions of potassium or sodium oxalate in proportion sufficient to make a total strength of 0.1 per cent, or more of these salts, coagulation will be prevented entirely. Addition of an excess of water will not produce clotting in this case, but solutions of some soluble calcium salt will quickly start the process. The explanation of the action of the oxalate solutions is simple : they are supposed to precipitate the calcium as insoluble calcium oxalate. Total Quantity of Blood in the Body. — The total quantity of blood in the body has been determined approximately for man and a number of the lower animals. The method used in such determinations consists essentially in first bleeding the animal as thoroughly as possible and weighing the quan- tity of blood thus obtained, and afterward washing out the blood-vessels with water aud estimating the amount of haemoglobin in the washings. The results are as follows: Man, 7.7 per ceut. (y 1 ^) of the body-weight; that is, a man weighing 68 kilos, has about 5236 grams, or 4965 c.c, of blood in his body; dog, 7.7 per cent.; rabbit and cat, 5 percent.; new-born human being, 5.26 per cent. ; and birds, 10 per cent. Moreover, the distribution of this blood in the tissues of the body at any one time has been estimated by Ranke, 1 from experiments on freshly-killed rabbits, as follows : Spleen 0.23 per cent. Brain and cord 1.24 " " Kidneys 1.63 u Skin 2.10 " " Intestines 6.30 ' Bones 8.24 " " Heart, lungs, and great blood-vessels 22.76 " " Resting muscles ' 29.20 " " Liver 29.30 " « It will be seen from inspection of this table that in the rabbit the blood of the body is distributed at any one time about as follows: one-fourth to the heart, lungs, and great blood-vessels; one-fourth to the liver; one-fourth to the resting muscles; and one-fourth to the remaining organs. Regeneration of the Blood after Hemorrhage. — A large portion of the entire quantity of blood in the body may be lost suddenly by hemorrhage without producing a fatal result. The extent of hemorrhage thai can be recovered from safely has been investigated upon a number of animals. Although the results show more or less individual variation, it can be said thai in dogs a hemorrhage of from 2 to 3 per cent, of the body-weight 8 is recovered from easily, while a loss of 1.5 per cent., more than half the entire bl 1, will probably prove fatal. In eats a hemorrhage of from 'J i<> •"» per 'Taken from Vieronlt's Anatoimsche, physiologische >ni. .".IT. 70 AN AMERICAN TEXT- HOOK OF PHYSIOLOGY. to the tissues of various glands in amounts greater than could be explained if we sup- posed that the lymph of these tissues was derived solely by filtration from the blood- plasma. (See p. ~'l for an illustration.) Another important conception in this con- nection is the possibility that the capillary walls may be permeable in different degrees to the various soluble constituents of the blood, and furthermore the possibility that the permeability of the capillary walls may vary in different organs. With regard to the first possibility it has been shown by Roth ' that the blood-capillaries are more per- meable to the urea molecules than to sugar or NaCl. With the aid of these facts it is possible to explain in Large measure the transportation of material from the blood to the tissues, and vice versa. For example, to follow a line of reasoning used by Roth, we may suppose that the functional activity of the tissue-elements is attended by a con- sumption of material which in turn is made good by the dissolved molecules in the tissue-lymph. The concentration of the latter is thereby lowered, and in consequence a diffusion stream of these substance- is set up with the more concentrated blood. In this way, by diffusion, a constant supply of dissolved material is kept in motion from the blood to the tissue-elements. On the other hand, the functional activity of the tissue- elements is accompanied by a breaking down of the complex proteid molecule with the formation of simpler, more stable molecules of crystalloid character, such as the sul- phates, phosphates, and urea or some precursor of urea. As these bodies pass into the tissue-lymph they tend to increase its molecular concentration, and thus by the greater osmotic pressure which they exert serve to attract water from the blood to the lymph, forming one efficient factor in the production of lymph. On the other hand, as these substances accumulate in the lymph to a concentration greater than that possessed by the same substances in the blood, they will diffuse toward the blood. By this means the waste-products of activity are drawn off to the blood, from which in turn they are removed by the action of the excretory organs. Diffusion of Proteids. — This simple explanation on purely physical grounds of the flow of material between the blood and the tissues can only be applied, however, at present to the diffusible crystalloids, such as the salts, urea, and sugar. The proteids of the blood, which are supposed to be so important for the nutrition of the tissues, are prac- tically indiffusible, so far as we know. It is difficult to explain their passage from the blood through the capillary walls into the lymph. Provisionally it may be assumed that this passage is due to filtration. The blood-plasma in the capillaries is under a slightly higher pressure than the lymph of the tissues, and this higher pressure tends t" Mpieeze the blood-constituents, including the proteid, through the capillary walls. Tin- explanation, however, cannot be said to be satisfactory, and in this respect the purely physical theory of lymph-formation waits upon a clearer knowledge of the nature of the nutritive proteids and their relations to the capillary walls. LYMPH. LYMPH is a colorless liquid found in the lymph-vessels as well as in the extravascular spaces of the body. All the tissue-elements, in fact, may be regarded as being bathed in lymph. To understand its occurrence in the body one has only to hear in mind its method of origin from the blood. Throughout the entire body there is a rich supply of blood-vessels penetrating every tissue with the exception of the epidermis and some epidermal structures, as the nails and the hair. The plasma of the blood, by the action of physical or chemical processes, the details <- logical Anatomy, translated by A. Bruce, L896, vol. i. \>. 344. 84 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. oscillate, conie to a standstill, and then reverse the direction of their move- ment, and return to the capillary whence they had started. Naturally, no such reversal will ever be seen in a capillary which springs directly from an artery or which directly joins a vein. It will be remembered, however, that any apparent speed of a corpuscle is much magnified by the microscope, aud thai therefore the variations referred to are comparatively unimportant. We may, in fact, without material error, treat the speed of the blood in the capil- laries which intervene between the arteries and veins of a region as approxi- mately uniform for an ordinary period of observation, as the minute varia- tions will tend to compensate for one another. This speed is sluggish, as alreadv noted. In the capillaries of the web of the frog's foot it has beeu found to be about 0.5 millimeter per second. The causes of this sluggishness will be set forth later. That the very short distance between artery and vein is traversed slowly, deserves to be insisted on, as thus time is afforded for the uses of the blood to be fulfilled. Capillary Blood-pressure. — The pressure of the blood against the capil- lary wall is low, though higher than that of the lymph without. This pres- sure is subject to changes, and is readily yielded to by the elastic and deli- cate wall. From these changes of pressure changes of calibre result. The microscope tells us less about the capillary blood-pressure than about the other phenomena of the flow; but the microscope may sometimes show one striking fact. In a capillary district under observation, a capillary not noted before may suddenly start into view as if newly formed under the eye. This is because its calibre has been too small for red corpuscles and leucocytes to enter, until some slight increase of pressure has dilated the transparent tube, hitherto filled with transparent plasma only. This dilatation has admitted corpuscles, and has caused the vessel to appear. That the capillary pressure is low is shown, moreover, by the fact that when one's linger is pricked or slightly cut, the blood simply drips away ; that it does not spring in a jet, as when an artery of any size has been divided. That the capillary pressure is low may also be shown, and more accurately, by the careful scientific application of a familiar fact: If one press with a blunt lead-pencil upon the shin between the base of a finger-nail and the neigh- boring joint, the ruddy surface becomes pale, because the blood is expelled from the capillaries and they are flattened. If delicate weights be used, instead of the pencil, the force can be measured which just suffices to whiten the surface somewhat, that is, to counterbalance the pressure of the distend- ing blood, which pressure thus can be measured approximately. It has been found to be very much lower than the pressure in the large arteries, con- siderably higher than that in the large veins, and thus intermediate between the two; whereas the blood-speed in the capillaries is less than the speed in either the arteries or the veins. The pressure in the capillaries, meas- ured by the method just described, has been found to be equal to that required to sustain against gravity a column of mercury from 24 to 54 milli- CIRCULATION. 85 meters high ; or, in the parlance of the laboratory, has been found equal to from 24 to 54 millimeters of mercury. 1 Summary of the Capillary Flow. — Whether in the Lungs or in the rest of the body, the general characters of the capillary How, as learned from direct inspection and from experiment, may be summed up as follows: The blood moves through the capillaries toward the veins with much friction, contin- uously, slowly, without pulse, and under low pressure. To account for these facts is to deal systematically with the mechanics of the circulation ; and to that task we must now address ourselves. C. The Pressure of the Blood in the Arteries, Capillaries, and Veins. Why does the blood move continuously out of the arteries through the capillaries into the veins? Because there is continuously a high pressure of blood in the arteries and a low pressure in the veins, and from the seat of high to that of low pressure the blood must continuously flow through the capillaries, where pressure is intermediate, as already stated. Method of Studying- Arterial and Venous Pressure, and General Results. — Before stating quantitatively the differences of pressure, we must see how they are ascertained for the arteries and veins. The method of obtain- ing the capillary pressure has been referred to already. If, in the neck of a mammal, the left common carotid artery be clamped in two places, it can, without loss of blood, be divided between the clamps, and a long straight glass tube, open at both ends, and of small calibre, can be tied into that stump of the artery which is still connected with the aorta, and which is called the "proximal" stump. If now the glass tube be held upright, and the clamp be taken off which has hitherto closed the artery between the tube and the aorta, the blood will mount in the tube, which is open at the top, to a consid- erable height, and will remain there. The external jugular vein of the other side should have been treated in the same way, but its tube should have been inserted into the "distal" stump — that is, the stump connected with the veins of the head, and not with the subclavian veins. If the clamp between the tube and the head have been removed at nearly the same time with that upon the artery, the blood may have mounted in the upright venous tube also, but only to a small distance. To cite an actual case in illustration, in a small etherized dog the arterial blood-column has been seen to stand at a height of about loo centimeters above the level of the aorta, the height of the venous column about 18 centimeters above the same level. The heights of the arterial and venous columns of blood measure the pressures obtaining within the aorta and the veins of the head respectively, while at the same time the circulation con- tinues to be free through both the aorta and the venous net work. Therefore, in the dog above referred to, the aortic pressure was between eight and nine 1 N. v. Kries : "Ueberden Druckinden Blutcapillaren der menschlichen Haul." BerichL iiber die Verhnndlungen der k. sachsischen Qeselkchaft der Wwsenschaften zu Leipzig, math.-physische Classe, 1875, S. 149. 86 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. times as great as that in the smaller veins of the head. As, during such an experiment, the blood is free to pass from the aorta through one carotid and both vertebra] arteries to the head, and to return through all the veins of that part, except one external jugular, to the vena cava, it is demonstrated that there must be a continuous flow from the aorta, through the capillaries of the head, into the veins, because the pressure in the aorta is many times as greal as the pressure in the veins. Obviously, such an experiment, although very instructive, gives only roughly qualitative results. Two things will be noted, moreover, in such an experiment. One is that the venous column is steady ; the other is that the arterial column is perpetu- ally fluctuating in a rhythmic manner. The top of the arterial column shows a regular rise and fall of perhaps a few centimeters, the rhythm of which is the same as that of the breathing of the animal ; and, while the surface is thus rising and falling, it is also the seat of frequent flickering fluctuations of smaller extent, the rhythm of which is regular, and agrees with that of the heart's beat. At no time, however, do the respiratory fluctuations of the arte- rial column amount to more than a fraction of its mean height; compared to which last, again, the cardiac fluctuations are still smaller. It is clear, then, that the aortic pressure changes with the movements of the chest, and with the systoles and diastoles of the left ventricle. But stress is laid at present upon the fact that the aortic pressure at its lowest is several times as high as the pressure in the smaller veins of the head. Therefore, the occurrence of incessant fluctuations in the aortic pressure cannot prevent the continuous movement of the blood out of the arteries, through the capillaries, into the veins. The upright tubes employed in the foregoing experiment are called " man- ometers." l They were first applied to the measurement of the arterial and venous blood-pre.-sures by a clergyman of the Church of England, Stephen Hales, rector of Farringdon in Hampshire, who experimented with them upon the horse first, and afterward upon other mammals. He published his method and results in 1 733. 2 The height of the manometric column is a true measure of the pressure which sustains it; for the force derived from gravity with which the bloml in the tube presses downward at its lower open- ing is exactly equal to the force with which the blood in the artery or vein is pressed upward at the same opening. The downward force exerted by the column of blood varies direct ly with the height of the column, but, by the laws of fluid pressure, does not vary with the calibre of the manometer, which cali- bre may therefore be settled on other grounds. It follows also that the arterial and venous manometers need not be of the same calibre. Were, however, another fluid than the blood it-elf used in the manometer to measure a given intravascular pressure, a- is easily possible, the height of the column would differ from that of the column of blood. For a given pressure the height 1 From iKirnr. rare. The Dame was given from such tubes being used to measure the tension of gases. 2 Stephen Hales : Statical Essays : containing Hcema&taticks, etc., London, 1733, vol. ii. p. 1. CIRCULATION. 87 of the column is inverse to the density of the manometric fluid. For example, a given pressure will sustain a far taller column of blood than of mercury. The Mercurial Manometer. — The method of Hales, in its orig- inal simplicity, is valuable from that very simplicity for demonstra- tion, but not for research. The clotting of the blood soon ends the experiment, and, while it continues, the tallness of the tube required for the artery, and the height of the column of blood, are very incon- venient. It is essential to under- stand next the principles of the more exact instruments employed in the modern laboratory. In 1828 the French physician and physiologist J. L. M. Poiseuillc devised means both of keeping the blood from clotting in the tubes, and of using as a measuring fluid the heavy mercury instead of the much lighter blood. He thereby secured a long observation, a low column, and a manageable man- ometer. 1 The " mercurial man- ometer" of to-day is that of Poi- seuille, though modified (see Fig. 15). In an improved form it con- sists of a glass tube open at both ends, and bent upon itself to the shape of the letter U. 'Phis is held upright by an iron frame. If mer- cury be poured into one branch of the U, it will fill both branches to an equal height. If fluid be driven down upon the mercury in one branch or "limb" of the tube, it will drive some of the mercury out of that limb into the other, ami the rest at very unequal levels. The di 1 J. L. M. Poiseuille: Becherches Fig. 15. — Diagram of the recording mercurial man- ometer and the kymograph; the mercury Is indicated in deep black : M, the manometer, connected by the leaden pipe, L, with a glass cannula tied into the proximal stump of the left common carotid artery of a dog; A, the aorta; C, the stop-cock, hy opening which the man- ometer maybe made to communicate through RT, the rubher tube, with ;i pressure bottle of solution of sodium carbonate; F, the float of ivory and hard rubber; R, the lighl Bteel rod, kept perpendicular bj B, the steel bear- ing; /'. the glass capillary pen charged w ith quieklydry- ing ink ; T, a thread which is caused, bj the weight of a light ring of metal suspended from it, to press the pen obliquely and gently agalnsl the paper with which la covered /'. the brass " drum " of the kj mograph, « hicb drum revolves in the direction of the arrow. The Bup ports of the manometer and the body and clock-work of the kymograph are omitted for the sake of simplicity. The aorta and its brandies are draw n disproportionately large for the sake of clearness. two surfaces of the mercury may come to fference of level, expressed in millimeters, sur la force du cceut aortique, Paris, 1828. 88 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. measures the height of the manometric column of mercury the downward pres- sure of which in one limb of the tube is just equal to the downward pressure of the fluid in the other. In order to adapt this " U-tube" to the study of the blood-pressure, that limb of the tube which is to communicate with the artery or vein is capped with a cock which can be closed. Into this same limb, a little way below the cock, opens at right angles a short straight glass tube, which is to communicate with the blood-vessel through a long flexible tube of lead, sup- ported by the iron frame, and a short glass cannula tied into the blood-vessel itself. Two short pieces of india-rubber tube join the lead tube to the manometer and the cannula. Before the blood-vessel is connected with the manometer, the Latter i- tilled with fluid between the surface of the mercury next the blood- vessel and the outer end of the lead tube, which fluid is such that when mixed witli blood it prevents or greatly retards coagulation. With this same fluid the glass cannula in the blood-vessel is also filled, and then this cannula and the lead tube are connected. The cock at the upper end of the " proximal limb" of the manometer is to facilitate this filling, being connected by a rub- ber tube with a "pressure bottle," and is closed when the filling has been accomplished. The fluid introduced by Poiseuille and still generally used is a strong watery solution of sodium carbonate. A solution of magnesium sul- phate is also good. If, in injecting this fluid, the column of mercury in the " distal limb" is brought to about the height which is expected to indicate the blood-pressure, but little blood will escape from the blood-vessel when the clamp is taken from it, and coagulation may not set in for a long time. The Recording Mercurial Manometer and the Graphic Method. — When the arterial pressure is under observation, the combined respiratory and cardiac fluctuations of the mercurial column are so complex and fre- quent that it is very hard to read off their course accurately even with the help of a millimeter-scale placed beside the tube. In 1847 this difficulty led the German physiologist Carl Ludwig to convert the mercurial manometer into a self-registering instrument. This invention marked an epoch not merely in the investigation of the circulation, but in the whole science of physiology, by beginning the present "graphic method" of physiological work, which has led to an immense advance of knowledge in many depart- ments. Ludwig devised the "recording manometer" by placing upon the mercury in the distal air-containing limb of Poiseuille's instrument an ivory float, bearing a light, stiff, vertical rod (see Fig. 15). Any fluctuation of the mercurial column caused float and rod to rise and fall like a piston. The rod projected well above the manometer, at the mouth of which a delicate bear- in- was provided to keep the motion of the rod vertical. A very delicate pen placed horizontally was fastened at right angles to the upper end of the rod. If a firm vertical surface, covered with paper, were now placed lightly in contact with the pen, a rise of the mercury would cause a corresponding vertical line to be marked upon the paper, and a succeeding fall would cause the descending pen to inscribe a second line covering the first. If now the vertical surface were made to move past the pen at a uniform rate, CIBCULA TION. 8 1 » the successive up-and-down movements of the mercury would no longer be marked over and over again in the same place so as to produce a single ver- tical line. The space and time taken up by each fluctuation would be graph- ically recorded in the form of a curve, itself a portion of a continuous trace marked by the successive fluctuations; thus both the respiratory and cardiac fluctuations could be registered throughout an observation by a single complex curviug line. Ludwig stretched his paper around a vertical hollow cylinder of brass, made to revolve at a regular known rate by means <>f clock-work, and the conditions above indicated were satisfied l (see Fig. 1 5). Upon the surface of such a cylinder vertical distance represents space, and a vertical line of measurement is called, by au application of the language of mathematics, an "ordinate;" horizontal distance represents time, and a horizontal line of measurement is called an " abscissa." The curve marked by the events re- corded is always a mixed record of space and time. The instrument itself, the essential part of which is the regularly revolving cylinder, is called the " kymograph." 2 It has undergone many changes, and many varieties of it are in use. Any motor may be used to drive the cylinder, provided that the speed of the latter be uniform and suitable. The curve written by the manometer or other recording instrument may either be marked upou paper with ink, as in Ludwig's earliest work ; or may be marked with a needle or some other fine pointed thing upon paper black- Fig. 16.- The trace of arterial blood-pressure from a dog anaesthetized with morphia and ether. The cannula was in the proximal stump of the common carotid artery. The curve is to he read from left to right. /', the pressure trace written by the recording mercurial manometer ; B L, the base-line or abscissa, representing the pressure of the atmosphere. The distance between the base-line and the pressure-curve varies, in the original trace, between 62 and 77 millimeters/there fore the pressure varies between 124 anil 154 millimeters of mercury, less a small correction for the weight <>f the sodium-carhonate solution ; 7", the time trace, made up of intervals of two seconds each, and written by an electro-mag- netlc chronograph. ened with soot over n flame. The trace written upon Bmoked paper is the more delicate. After the trace has been written, the Bmoked paper is removed from the kymograph and passed through a pan of shellac varnish. This 1 C. Ludwig: "Beitrage zur Kenntnisa dea Einflusaea der Reapirationabewegungen auf den Blutlauf ini Aortenaysteme," Miiller'a Archiv fiir Anatomic, Physiologic, vmd wmenschqflliche Mediem, etc., 1847, S. 242. 2 From KVfta, a wave. 90 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. when dry fixes the trace, which thereafter will not be spoiled by handling. In Figure 16 the uppermost line shows a trace which fairly represents the successive fluctuations of the aortic pressure of the dog. The longer and ampler fluctuations are respiratory, the briefer and slighter are cardiac, in each respiratory curve the lowest point and the succeeding ascent coincide with Inspiration ; the highest point and the succeeding descent with expiration. The horizontal middle line is the base line, representing the pressure of the atmosphere. The base-lirje ha- been shitted upward in the figure simply in order to save room on the page. In the lowermost line the successive spaees from left to right of the read.r represenl successive intervals of time of two seconds each, written by an electro-magnetic chronograph. The pressure-trace taken from a vein may in certain regions near the chest show respiratory fluc- tuations, l>nt nowhere cardiac ones, as the pulse is not transmitted to the veins. The venous pressure i> so small, that for the practical study of it a recording manometer must he used in which some lighter fluid replaces the mercury, which would give a column of insufficient height for working purposes. The values obtained are then reduced by calculation to millimeters of mercury, for comparison with the arterial pressure. The intravascular pressure at a given moment can he measured by measuring a vertical line or "ordinate" drawn from the curve written by the manometer to the horizontal base-line. The latter represents the height of the manometric column when just disconnected from the blood-vessel ; that is, when acted upon only by the weight of the atmosphere and of the solution of sodium carbonate. To ascertain the blood- pressure, the length of the Hue thus measured must be doubled; because the mercury in the proximal limb of the manometer sinks under the blood-pres- sure exactly as much as the float rises in the distal limb. A small correction must also be made for the weight of the solution of sodium carbonate. The Mean Pressure. — The "mean pressure" is the average pressure dur- ing whatever length of time the observer chooses. The mean pressure for the given time is ascertained from the manometric trace by measurements too complicated to be explained here. As the weight and consequent inertia of the mercury cause it to fluctuate according to circumstances more or less than the pressure, the mean pressure is much more accurately obtained from the mercurial manometer than is the true height of each fluctuation, which is very commonly written too small. Therefore, it is especially the mean pressure that is studied by means of the mercurial manometer. The true extent and finer characters of the -ingle fluctuations caused by the heart's beat are better studied with other instruments, as we shall see in dealing with the pulse. It has been seen that the blood (low- continuously through the capillaries because the pressure is continually high in the arteries and low in the veins. The reader is now in position to understand statements of the blood-pressure expressed in millimeters of mercury. The mean aortic pressure in the dog is far from being always the same even in the same animal. W v have found it, in the ease referred to on page 85, to be equivalent to about 121 millimeters of mercury. It will very commonly be found higher than this, and may range CIRCULATION. 91 up to, or above, 200 millimeters. In man it i> probably higher than in the dog. The pressure in the other arteries derived from the aorta which have been studied manoinetricalry is not very greatly lower than in that vessel. In the pulmonary arteries the pressure is probably much lower than in the aortic system. The pressure in the small veins of the head of the dog, the cannula being in the distal stump of the external jugular vein, we have found already in one case to equal about 14 millimeters of mercury. In such a case the presence of valves in the veins and other elements of difficulty make the mean pressure hard to obtain as opposed to the maximum pressure during the period of observation. If a cannula be so inserted as to transmit the pressure obtaining within the great veins of the neck just at the entrance of the chest, without interfer- ing with the movement of the blood through them, and if a manometer be connected with this cannula, the fluid will fall below the zero-point in the distal limb, indicating a slight suction from within the vein, and thus a slightly " negative " pressure. 1 This negative pressure may sometimes become more pronounced during inspiration and regain its former value during ex- piration. Sometimes, again, the pressure during expiration may become posi- tive. The continuous flow from the great arteries through the capillaries to the veins, and through these to the auricle, is therefore shown by careful quantitative methods, no less than by the tube of Hales, to be simply a case of movement of a fluid from seats of high to seats of lower pressure. The Symptoms of Bleeding- in Relation to Blood-pressure. — The dif- ferences of pressure revealed scientifically by the manometer exhibit them- selves in a very important practical way when blood-vessels are wounded and bleeding occurs. If an artery be cleanly cut, the high pressure within drives out the blood in a long jet, the length of which varies rhythmically with the cardiac pulse, but varies only to a moderate degree. From wounded capil- laries, or from a wounded vein, owing to the low pressure, the blood does not spring in a jet, but simply flows out over the surface and drips away without pulsation. At the root of the neck, where the venous pressure may rhythmi- cally fall below and rise above the atmospheric pressure, the bleeding from a wounded vein may be intermittent. D. The Causes of the Pressure in the Arteries, Capillaries, and Veins. The causes of the continuous high pressure in the arteries musl first engage our attention. Resistance. — The great ramification of the arterial system at a distance from the heart culminates in the formation of the countless arterioles mi the confines of the capillary system. We have already seen direct evidence of the friction in the minute vessels which results from this enormous subdivision of the blood-path. The force resulting from this friction i- propagated back- 1 II. Jacobson : " Ueber die Blutbewegung in den Venen," Reicherts •"< having the arterial system, and none is entering it. But before the fall has had time to become pronounced, while the arterial pressure is still high, the cardiac sys- tole recurs, and the pressure rises again, as at the preceding fluctuation. The Arterial Pulse. — The increased arterial pressure and amplitude at the cardiac systole, followed by diminished pressure and amplitude at the cardiac diastole, constitute the main phenomena of the arterial pulse. They are marked in the manoinet rie trace by those lesser rhythmic fluctuations of the mercury which correspond with the heart-beats. The causes of* the arte- rial pulse have just been indicated in dealing with the causes of the arterial pressure. The pulse, in some of its details, will be studied further for itself in a later chapter. For the sake of simplicity, the respiratory fluctuations of the arterial pressure have not been dealt with in the discussion just con- cluded. The causes of these important fluctuations are very complex and are treated of under the head of Respiration. The arterial pressure, then, results from the volume and frequency of the injections of blood made by the heart's contraction ; from the friction in the vessels; and from the elasticity of the arterial wall. The Capillary Pressure and its Causes. — When we studied the move- ment of the blood in the capillaries, we found the pressure in them to be low and free from rhythmic fluctuations. In both of these qualities the capillary pressure is in sharp contrast with the arterial. What is the reason of the differ- ence? The work of driving the blood through as well as into the capillaries Is done during the contraction of the heart's wall by its kinetic energy. During the repose of the heart's wall and the arterial recoil this work is continued by kinetic energy derived, as we have seen, from the preceding cardiac contraction. The work of producing the capillary flow is done in overcoming the resistance of friction. The .capillary walls are elastic. The same three factors, then — the power of the heart, the resistance of friction, the elasticity of the wall — which produce the arterial pressure produce the capillary pressure also. Why is the capillary pressure normally low and pulseless? The answer is not difficult. The friction which must be overcome in order t<> propel the blood out of the capillaries into the wider venous branches is only a part of the total friction which opposes the admission of the blood to the minuter vessels. The resistance is therefore diminished which the blood ha- yet to encounter after it has actually entered the capillaries. The force which propels the blood through the capillaries, although amply sufficient, is greatl} less than the force which propels it into and through the larger arteries. In both cases alike the force is that of the heart'- heat. But, in overcoming the friction which resists the entrance of the blood into the capillaries, a large amount of the kinetic energy derived from the heart has become converted into heat. The power is therefore diminished. As, in producing the high arterial pressure, much power is met by much resistance, and the elastic wall 94 . I X . l MER TCA X TEXT- H K F PHYSIOL OGT. is, therefore, distended with accumulated blood; so, in producing the low capil- lary pressure, diminished power is met by diminished resistance, outflow is relatively easy, accumulation is slight, and the elasticity of the delicate wall is 1 hi t little called upon. The Extinction of the Arterial Pulse. — But why is the capillary pres- sure pulseless, as the microscope shows? To explain this, no new factors need discussion, Imt only the adjustment of the arterial elasticity to the intermittent injections from the heart and to the total friction which opposes the admission of blood to the capillaries. This adjustment is such that the recoil of the arteries displaces blood into the capillaries during the ventricular diastole at exactly the same rate as that produced by the ventricular contraction during the ventricular systole. Thus, through the elasticity of the arteries, the car- diac pulse undergoes extinction ; and this becomes complete at the confines of the capillaries. The respiratory fluctuations become extinguished also, and the movement of the blood in the capillaries exhibits no rhythmic changes. This conversion of an intermittent How into one not merely continuous but approximately constant affords a constant blood-supply to the tissues, at the same time that the cardiac muscle can have its diastolic repose, and the ven- tricular cavities the necessary opportunities to receive from the veins the blood which is to be transferred to the arteries. A simple experiment will illustrate the foregoing. Let a long india-rubber tube be taken, the wall of which is thin and very elastic. Tie into one end of the tube a short bit of glass tubing ending in a fine nozzle, the friction at which will cause great resistance to any outflow through it. Tie into the other end of the rubber tube an ordinary syringe-bulb of india-rubber, with valves. Expel the air, and inject water into the tube from the valved bulb by alternately squeezing the latter and allowing it to expand and be filled from a basin. The rubber tube will swell and pulsate, but if its elasticity have the right relation to the size of the fine glass nozzle and to the amplitude and frequency of the strokes of the syringe, a continuous and uniform jet will be delivered from the nozzle, while the injections of water will, of course, be intermittent. The Venous Pressure and its Causes. — The pressure in the peripheral veins is less than in the capillaries and declines as the blood reaches the larger vein-. Very close to the chest the pressure is below the pressure of the atmosphere, and may sometimes vary from negative to positive, following the rhythm of the breathing. These respiratory fluctuations will be considered later. The low and declining pressures under which the blood moves through the venules and the larger vein- are due to the same causes as those which account for the capillary pressure. It is -till the force generated by the heart's con- tractions, and made uniform by the elastic arteries, which drives the blood into and through the veins back to the very heart itself. As the blood moves through the vein-, what resistance it encounters is still that of the friction ahead. But the friction ahead is progressively less; the conversion of kinetic energy into heat is progressively greater. The venous wall possesses elas- CIRCULATION. 95 ticity, but this is even less called upon than that of the capillaries; and, pres- ently, in the larger veins, the moving blood is found to press no harder from within than the atmosphere from without. Subsidiary Forces which Assist the Flow in the Veins. — There are certain forces which, occasionally or regularly, assisl the heart to return the venous blood into itself. Too much stress is often laid upon these; for it is easy to see by experiment that the heart can maintain the circulation wholly without help. The origins of these subsidiary forces arc first, the contraction of the skeletal muscles in general ; second, the continuous traction of the lungs; third, the contraction of the muscles of inspiration. The Skeletal Muscles and the Venous Valves. — A vein may lie in such relation to a muscle that when the latter contracts the vein is pressed upon, its feeble blood-pressure is overborne, the vein is narrowed, and blood is squeezed out of it. The veins in many parts are rich in valves, competent to prevent regurgitation of the blood while permitting its How in the physio- logical direction. The pressure of a contracting muscle, therefore, can only squeeze blood out of a vein toward the heart, never in the reverse direction. Muscular contraction, then, may, and often does, assist in the return of the venous blood with a force not even indirectly derived from the heart. But such assistance, although it may be vigorous and at times important, is tran- sient and irregular. Indeed, were a given muscle to remain long in contrac- tion, the continued squeezing of the vein would be an obstruction to the flow through it. The Continuous Pull of the Elastic Lungs. — The influence of thoracic aspiration upon the movement of the blood in the veins deserves a fuller dis- cussion. The root of the neck is the region where this influence shows itself most clearly, but it may also he verified in the ascending vena cava of an animal in which the abdomen has been opened. The physiology of respira- tion shows that not only in inspiration, but also in expiration, the elastic til >i< - of the lungs are upon the stretch, and are pulling upon the ribs and intercostal spaces, upon the diaphragm, and upon the heart and the great vessels. This dilating force at all times exerted upon the heart by the lungs is of assistance, as we shall see, in the diastolic expansion of its ventricles. In the same way the elastic pull of the lung- acts upOD the vena- cava' within the chest, and generates within them, as well as within the right auricle, a force of suction. The effects upon the venous flow of this continuous aspiration are besl known in the system of the descending vena cava. This suction from within the chest extends to the great veins just without it in the neck. In these, close t<> the chest, as we have seen, manometric observation reveals :i continuous slight ly negative pressure. A little farther from the chest, however, hut -till within the lower portions of the neck, the intravenous pressure is slightly positive. The elastic pull of the lung, therefore, continuously assists in unloading the terminal part of the venous system, and thus differs markedly from the irreg- ular contractions of the skeletal muscles. The Contraction of the Muscles of Inspiration. — But some skeletal 96 AN AMERICAN TENT-BOOK OF PHYSIOLOGY. muscles, those of inspiration, regularly add their rhythmic contractions to the continuous pull of the lungs, to reinforce the latter. Each time that the chest expands there is an increased tendency for blood to be sucked into it through the veins. At the beginning of each expiration this increase of suction abruptly ceases. The Respiratory Pulse in the Veins near the Chest, and its Limita- tion. — In quiet breathing the movements of the chest-wall produce no very conspicuous effect. W, however, deep and infrequent breaths be taken, the pro-ore within the veins close to the chest becomes at each inspiration much more negative than before; and at each inspiration the area of negative pressure may extend to a greater distance from the chest along the veins of the neck, and perhaps of the axilla. As the venous pressure in these parts now falls as the chest rises, and rises as the chest falls, a visible venous pulse presents itself, coinciding, not with the heart-beats, but with the breathing. At each inspiration the veins diminish in size, as their contents are sucked into the chest faster than they are renewed. At each expiration the veins may be seen to swell under the pressure of the blood coming from the periphery. If the movements of the air in the windpipe be mechanically impeded, these changes in the veins reach their highest pitch; for then the muscles of expiration may actually compress the air within the lungs, and produce a positive pressure within the vena cava and its branches, with resistance to the return of venous blood during expiration, shown by the swelling of the veins. These phenomena are suddenly succeeded by suction, and by collapse and disappearance of the veins, as inspiration suddenly recurs. The respirators venous pulse, when it occurs, diminishes progressively and rapidly as the veins arc observed farther and farther from the root of the neck — a fact which results from the ilaccidity of the venous wall. Were the walls of the veins rigid, like glass, the successive inspirations would produce obvious accelerations of the How throughout the whole venous system, and the con- tractions of the muscles of inspiration would rank higher than they do among the causes of the circulation. In fact, the walls of the veins are very soft and thin. li\ therefore, near the chest, the pressure of the blood within the vein- -inks below that of the atmosphere, the place of the blood sucked into the chest is filled only partly by a heightened flow of blood from the periph- ery, l>nt partly also by the soft venous wall, which promptly sinks under the atmospheric pressure. This is shown by the visible flattening, perhaps disappearance from view, of the vein. This process reduces the visible venous pulse, when' it occur-, to a local phenomenon; for, at each inspira- tion, the promptly resulting shrinkage of all the affected veins together is marly equivalent to the loss of volume due to the sucking of blood into the chest. Therefore the How in the more peripheral veins remains but slightly affected, and the pressure within them continue- to be positive and without a visible pulse. During expiration the swelling of the veins near the chest, the return of positive pressure within them, may be simply from the return of the ordinary balance of forces alter the effects of a deep inspiration have CIRCULA TION. 97 disappeared. But, if expiration be violent and much impeded, the positive pressure may rise much above the normal. Here again, however, regurgita- tion will meet with opposition from the venous valves, though the flow from the periphery may be much impeded. The " Dangerous Reg-ion," and the Entrance of Air into a "Wounded Vein. — Quite close to the chest, then, the normal venous pressure is always slightly negative ; and in deep inspiration it may become more so, and this condition may extend farther from the chest along the neck and axilla, through- out a region known to surgeons as "the dangerous region." It is important to understand the reason for this expression. It has already been mentioned that the wounding of a vein in this region may cause intermittent bleeding. It now will easily be understood that such bleeding will occur onlv when the pressure is positive — that is, during expiration. During deep and difficult breathing, indeed, the venous blood may spring in a jet during expiration instead of merely flowing out, and may wholly cease to flow during inspira- tion. The cessation is due, of course, to the blood being sucked into the chest past the wound rather than pressed out of it. It is not, however, the risks of hemorrhage that have earned the name of "dangerous" for the region where intermittent bleeding may occur. The danger referred to is of the entrance of air into the wounded vein and into the heart, — an accident which is commonly followed by immediate death, for reasons not here to be discussed. Very close to the chest, where the venous pressure is continuously negative and the veins are so bound to the fasciae that they may not collapse, this danger is always present. Throughout the rest of the . dangerous region, the entrance of air into a wounded vein will take place only exceptionally. In quiet breathing the venous pressure is continu- ously positive throughout most of this region; and then a wounded vein will merely bleed. It is only in deep breathing that a venous pulse becomes vis- ible here, and that the venous pressure becomes negative in inspiration. Bu< even in forced breathing it is rare for a wounded vein of the dangerous region to do more than bleed. The cause of this lies in the flaccidity of the venous wall. At each expiration the blood may jet from the wound; but at the fol- lowing deep inspiration the weight of the atmosphere flattens the vein so promptly that the blood is followed down by the wounded wall and no air enters at the opening. It is only when, during deep breathing, the wounded wall for some reason cannot collapse, thai the main part of the "dangerous region " justifies its name. Should the tissues through which the vein runs have been stiffened by disease, or should the wall of the vein adhere to a tumor which a surgeon is lifting as he cuts beneath it, in either case the vein will have become practically a rigid tube. Should it be wounded during a deep inspiration, blood will be sucked past the wound, but the atmospheric pressure will fail to make the wall collapse; air will be drawn into the cut, and blood and air will enter the heart together, probably with deadly effect. Summary. — It appears from what has gone before that the elasticity of the lungs and the contractions of the muscles of inspiration regularly assist in Vol. I.— 7 98 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. unloading the veins in the immediate neighborhood of the heart, and so remove some pan of the resistance to be overcome by the contractions of the cardiac muscle. When we come to the detailed study of the heart it will appear also that a slight force of suction is generated by the heart itself, which force adds it- effects upon the flow of venous blood to those of the elasticity of the lungs and of the contraction of the muscles of inspiration. It must here be repeated, however, that the heart is quite competent to maintain the circulation unaided. This is proven as follows: If in an anaes- thetized mammal a cannula be placed in the windpipe, the chest be widely opened, and artificial respiration be established, the circulation, though modi- fied, continues to be effective. By the opeuing of the chest its aspiration has been ended, and can no longer assist in the venous return. If, further, the animal be drugged in such a manner as completely to paralyze the skeletal muscles throughout the body, their contractions can exert no influence upon the venous return; yet the circulation is still kept up by the heart, unaided either by the elasticity of the lungs, by the contractions of the muscles which produce inspiration, or by those of any other skeletal muscles. E. The Speed of the Blood in the Arteries, Capillaries, and Veins. If we keep as our text, in discussing the circulation, the character of the capillary flow, it will be seen that we have now accounted for the facts that the capillary How is toward the veins; that it shows much friction; that it is continuous, pulseless, and under low pressure. We have not yet accounted for the fact that it is slow. We must now do so, but must first state aud account for the speed of the blood in the arteries and veins. The Measurement of the Blood-speed in Large Vessels; the " Strom- uhr." — The speed of the blood in the larger veins and arteries must be meas- ured indirectly. We can picture to ourselves the volume of blood which moves past a given point in a given blood-vessel in one second, as a cylinder of blood having the same diameter as the interior of the blood-vessel. The length of this cylinder will then be expressed by the same number which will express the velocity with which a particle of the blood would pass the given point in one second, provided that this velocity be uniform and be the same for all the particles. In order, then, to learn the average speed of the blood ;it .1 given point of an artery or vein during a certain number of seconds, we have only to measure the calibre of the blood-vessel and the quantity of blood which passes the selected point during the period of observation. From these two measurements the speed can be obtained by calculation. But these two measurements are not quite easy. The physical properties of the blood-vessels, especially of the veins, make their calibres variable and hard to estimate justly a- affected by the conditions present during an experiment. The menus adopted for measuring the quantity of blood passing a point in a given time necessarily alters the resistance encountered by the How, and so of itself affects both the rate of flow and the blood-pressure; and, with the CIHCCLA TIO.X. 99 Fig. 17.— Diagram of longitudinal sec- tion of Ludwig's "Stromuhr." The ar- rows mark the direction of the blood- stream. For further description see the text. latter, the calibre of the vessel. For these reasons any measurement of the average speed of the blood by the above method is only approximately correct. The best instrument for measuring the quantity of blood driven past a point during an experiment i- the so-called "strom- uhr" or "rheometer" of Ludwig, a longitu- dinal section of which is given diagrammati- cal lv in Figure 17. 1 This is essentially a curved tube shaped like the Greek capital letter £2. Each end of the tube is tied into one of the two stumps (a and 6) of the divided vessel. These ends of the tube are as nearly as possible of the same calibre as the vessel selected. Each limb of the tube is dilated into a bulb, and the upper part of the tube, including the two bulbs, is of glass; the lower part of each limb is of metal. At the top, between the bulbs, is an opening for filling the tubes, which can easily be closed when not in use. Each end of the tube is filled with defibrinated blood before being tied into the blood-vessel. In the limb of the tube (B, (Fig. 17) which is the farther from the heart if an artery be used, or the nearer to the heart if a vein, the defibrinated blood is made to fill the cavity up to the top of the bulb. In the other limb (.1. Fig. 17) the blood fills the tube only up to a mark (e, Fig. 17) near the bottom of the bulb. Through the opening between the bulbs the still vacant space, which includes the whole of the bulb .1, is filled with oil, all air being excluded. The opining i> then closed. If now the clamps lie removed from the blood-vessel, the blood of the animal will enter the tube at a and drive before it the contents of the tube. Thus defibrinated blood from /,' will be driven into the distal -lump of the vessel at b, and will enter the circulation of the animal. Oil will at the same time be driven over from .1 to />. The bulb .1 has upon it two marks, d and e, one near the top of it, the other near the bottom. The instanl when the line between the oil and the advancing blood reaches the mark near the top of A is the instant when a volume of blood equal to that of the displaced oil has entered A, past the mark near the bottom of it. The capacity of the tube between the two marks is accurately known. The time required for this space to be filled with the entering blood is measured by the observer. The calibre of the metal tube at a i- accurately known, and i- ass d i<> lie equal to the calibre of the blood-vessel, from these measurements the average speed of the blood-stream at hy8V6cfo < '/<<*.«■, 1867, S. 200. 100 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. The metallic lower parr of the instrument, which includes both limbs of the tube, is completely divided horizontally at c. The two parts are so built, however, as to be maintained in water-tight apposition. This arrangement permits the whole upper part of the instrument, including the glass bulbs, to be rotated suddenly upon the lower, so that the bulb B may correspond with the entrance for the blood at a, and the bulb ^i with the exit for the blood at b. If this rotation be effected at the instant when the space between the two mark- on A has been tilled with blood, the bulb B, now charged with oil, will be tilled by the blood which enters next, and the first charge of the ani- mal's own blood will make its exit at 6. Oil will now pass over from B to A; when the line between it and the blood which is leaving A has just reached the lower mark on J, the bulbs are turned back to their original position. Thus, by repeated rotations, each of which can be made to record upon the kymograph the instant of its occurrence, a number of charges of blood can be received and transmitted in succession; it is always the same space, between the marks on .1, which is used for measuring the charge; and the time of the experiment can be much prolonged. By this procedure the errors due to a single brief observation can be greatly reduced. Indeed, the time of entrance of a single charge of blood would be quite too short to give a satisfactory result. The use of the stromuhr not only affords necessary data for the calcu- lation of the average speed of the blood, but seeks directly to measure the volume of blood delivered in a given time by an artery to its capillary dis- trict. It is evident that this volume is a quantity of fundamental importance in the physiology of the circulation. Could we ascertain it, by direct meas- urement or by calculation, for the aorta or pulmonary artery, we should know at once the volume of blood delivered to the capillaries in one second, and thus the time taken for the entire blood to enter either those of the lungs or of tin' system at large. By this knowledge, many important problems would be advanced toward solution. The Measurement of Rapid Fluctuations of Speed. — The stromuhr can give only the average speed of the blood during the experiment. To study rapid fluctuations of speed, another method is needed. If, in a large animal, a vessel, best an artery, be laid bare, a needle may be thrust into it at right angles. If the needle be left to itself, the end which projects from the artery will lie deflected toward the heart, because the point will have been deflected toward the capillaries by the blood-stream. The angle of deflection might be read off, could a graduated semicircle be adjusted to the needle. If the stream be arrested, the needle returns to its position at right angles to the artery. The greater the velocity of the stream, the greater is the deflection of the needle. If. later, the same needle be thrust into a tube of rubber through which water flows at known ran- of -peed, the speed corresponding to each angle of deflection of the needle may be determined. If the needle were made to mark upon a kymograph, variations of the speed would be recorded as a curve. CIRCULATION. 101 An instrument based on the principles jus! described is valuable for the study of rapid changes of velocity. 1 In an artery, its needle oscillates rhyth- mically, showing that there the speed of the 1)1 1 varies during each beat of the heart, being greatly accelerated by the systole of the ventricle, and retarded by the cessation of the systole. It will be remembered that the microscope directly shows faint rhythmic accelerations in the minute arteries of the frog. In the veins rhythmic changes of speed do not occur except near the heart from respiratory causes. The Speed of the Blood in the Arteries. — The stromuhr shows that the speed of the blood is liable to great variations. This fact, and the range of speed in the arteries, are fairly exhibited by the results obtained by Dogiel from the common carotid artery of a dog, the experiment upon which lasted 127 seconds. During this time six observations were made which varied in length from 14 to 30 seconds each. For one of these periods the average speed was 243 millimeters in one second ; for another period, 520 millimeters. These were the extremes of speed noted in this case. 2 The speed in the arteries diminishes toward the capillaries. The Speed of the Blood in the Veins. — The speed in a vein tends to be slower than that in an artery of about the same importance, but is not neces- sarily so. 3 It increases from the capillaries toward the heart. The Speed of the Blood in the Capillaries. — The rate of the capillary flow may be measured directly under the microscope. Certain physiologists have also observed the movement of the blood in the retinal capillaries of their own eyes, and have measured its rate there.' Both methods show that in the capillaries the speed is very much less than in the large arteries or large veins. In the capillaries of the web of the frog's foot it is only about 0.5 millimeter in one second. In those of the mesentery of a young dog it has been found to be 0.8 millimeter; in those of the human retina, from 0.6 to 0.9 millimeter. Speed and Pressure of the Blood Compared. — If now we compare the speed with the pressure of the blood in the arteries, in the capillaries, and in the veins, we shall be struck by both similarities ami differences. In the arteries both pressure and speed rhythmically rise and fall together \ and both the mean pressure and the mean speed decline from the heart to the capillaries. In the capillaries both pressure and speed are pulseless and low, — very low compared with the great arteries. In the veins, however, the pressure is everywhere lower than in the capillaries and falls Prom the capillaries to the heart; the speed is everywhere higher than in the capillaries and rises from 1 M. L. Lortet: Recherches sur /" vitesse du coura i' course equal quantities enter and leave it in equal times provided those times are not mere fractions of a beat. In connection with this it is significant that the entrance of blood into the heart takes place during the long auric- ular diastole, while its exit is limited to the shorter ventricular systole. Time Spent by the Blood in a Systemic Capillary. — The width of the path, then, determines the slow movement of the blood in the areas where it is fulfilling its functions; the narrowness of the path, the swiftness of move- ment of the blood in leaving and returning to the heart. We have seen (p. 79) that a particle of blood may make the entire round of a dog's circulation in from fifteen to eighteen seconds. If we assume the systemic capillary flow to be at the rate of 0.8 millimeter in one second, the blood would remain about 0.6 of a second in a systemic capillary half a millimeter long. Slow as is the capillary flow, it thus appears that it is none too slow to give time for the usas of the blood to be fulfilled. F. The Flow of Blood through the Lungs. The blood moves from the right ventricle to the left auricle under the same general laws as from the left ventricle to the right auricle. Certain dif- ferences, however, are apparent, and must he noted. One difference is that the collective friction is less in the pulmonary than in the systemic vessels, and that therefore the resistance to be overcome by each contraction of the right ventricle is less than that opposed to the left ventricle. Accordingly it appears from dissection that the muscular wall of the right ventricle is much thinner than that of the left, No accurate measurements can he made of the normal pressure and speed of the blood in the arteries, capillaries, and veins of the lungs, because they can lie reached only by opening the chest and destroying the mechanism of respiration, and thereby disturbing the normal L04 AN AMERICAN TEXT-BOOK OF PHYSIO LOO V. conditions of the pulmonary blood-stream. In the opened chest these cannot I otirely restored by artificial respiration. The thinness of the wall of the pulmonary artery, however, indicates that it has much less pressure to support than that of the aorta, which fact also is indicated by such roughly approxi- mate results as have been obtained with the manometer after opening the chest. As the pulmonary artery and veins lie wholly within the chest, but outside the lungs, their trunks and larger branches all tend to be dilated continuously by i lie elastic pull of the lungs — a pull which increases at each inspiration. ( )n i lie other hand, tin 1 pulmonary capillaries lie so close to the surface of each lung that they are exposed to the same pressure, practically, as that surface, and the full weight of the atmosphere may act upon them. These conditions all tend to unload the capillaries and the pulmonary veins, but to weaken the unloading of the pulmonary artery. The two eifects can hardly balance one another, however. The wall of the pulmonary artery is so much stiffer than that of the vein, that the actual results should be favorable to the flow. The elasticity of the lungs and the contractions of the muscles of inspiration thus lighten, probably, the work of the right ventricle as well as of the left. The right ventricle, however, like the left, can accomplish its work without assist- ance ; for the entire circulation, including, of course, the flow through the lung-, continues after the chest has been opened, if artificial respiration be maintained. G. The Pulse-volume and the Work done by the Ventricles of the Heart. The Cardiac Cycle. — It is assumed that the anatomy of the heart is known to the reader. The general nature and effects of the heart's beat have been sketched already. Each beat has been seen to comprise a number of phenomena, which occur in regular order, and which recur in the same order during each of the succeeding beats. Each beat is therefore a cycle; and the phrase " cardiac cycle" has become a technical expression for " beat," as it conveys, in a word, the idea of a regular order of events. As each of the four chambers of the heart has its own systole and diastole, there are eight events to be studied in connection with each cycle. The systoles of the two auricles, however, are exactly simultaneous, as are their diastoles ; and the same is true of the sys- toles and of the diastoles of the two ventricles. We may, therefore, without confusion, speak of the auricular systole and diastole, and of the ventric- ular systole and diastole, as of four events, each involving the narrowing or widening of two chambers, a right and a left. The heart of the mammal or bird consists essentially of a pair of pumps, the ventricles, each of which acts alternately as a powerful force-pump and as a very feeble suction- pump. To each ventricle is superadded a contractile appendage, the auricle, through which, and to some extent by the agency of which, blood enters the ventricle. CIRCULATION. 105 The Pulse- volume. — The central fact of the circulation of the blood is the injection, at intervals, by each ventricle, against a strong resistance, of a charge of blood into its artery, which charge the ventricle has just received out of its veins through its auricle. This quantity must be exactly the same for the two ventricles under normal conditions, or the circulation would soon come to an end by the accumulation of the blood in either the pulmonary or the sys- temic vessels. The blood ejected from each vent ride during the systole must also be equal in volume to the blood which enters each set of capillaries, the pulmonary or systemic, during that systole and the succeeding diastole of the ventricles, provided the circulation be proceeding uniformly. The quantity just referred to is called the "contraction volume" or "pulse-volume" of the heart. Were it always the same, and could we measure it, we should possess the key to the quantitative study of the circulation. The pulse-volume may vary in the same heart at different times, as is easily shown by opening the chest, causing the conditions of the circulation to change, and noting that under certain conditions the heart during each beat varies in size more than before. This variation of volume is easily possible because the walls of the heart are of muscle, soft and distensible when relaxed. It is probable that at no systole is the ventricle quite emptied ; that most of its cavity may become obliterated by the coming together of its walls, but that a space remains, just below the valves and above the papillary muscles, which is not cleared of blood. It is also probable that not only the blood which is ejected at the systole may vary in amount, but also the residual blood which remains in the ventricle at the end of the systole. 1 It is therefore clear that it is useless to attempt the measurement of the pulse-volume by measuring the fluid needed to fill the ventricle, even if the heart be freshly excised from the living body and injected under the normal blood-pressure. Rough approx- imations to this measurement may, however, be attempted in at least two ways : In the first place, a modification of the stromuhr has been applied suc- cessfully to the aorta of the rabbit, bet ween the origins of the coronary arteries and of the innominate. This operation requires thai the auricles be clamped temporarily so as to stop the flow of blood into the ventricle.-, and to permit the aorta in its turn to be clamped and divided between the clamp and the ventricle, without serious bleeding. A.fter the circulation lias been re-estab- lished, the volume of the blood which passes through the instrument during the experiment, divided by the number of the heart-beats during the same period, gives the pulse-volume. The average result obtained, for the rabbit, 1 F.Hesse: "Beitriige zur Mechanik der Herzbewegung," Archivfiir Anatomic und Phyaiolo- gie (anatomische Abtheilung), L880, S. 328. C. Sandborg und W. Miiller : " Studien fiber den Mechanismus des fferzens," Pfluger'a Archiv fur die gesammle Physiologic, L880, \\ii. S. 408. C.S. Roy and J. G. Adami: "Contributions to the Physiology and Pathology of the Mammalian Heart," Proceedings <;/' tic l,'<>i/. 435. .1. E. Johansson und R. Tigerstedt : " Ueber die gegenseitigen Beziehungen des Herzens und der Oefasse f "Ueberdie Herzthiitigkeit bei verschieden ascertain the pulse-volume is to measure the swelling and the shrinkage of the heart. This is called the "plethysmography" 2 method. < me application of it is as follows : The chest and pericardium of an animal are opened, and the heart is inserted into a brass ease full of oil. The opening through which the great vessels pass is made water-tight by mechanical means which do not impede the movement of the blood into and out of the heart. The top of the brass case is prolonged into a tube, the oil in which rises as the heart swells and falls as it shrinks. Upon the oil a light piston move- up and down, and records its movements upon the kymograph. The instrument is called a " eardiometer." 3 The average pulse-volume of the human ventricle has been very variously estimated upon the basis of observations of various kinds made upon mam- mals of various species. The figures offered range, in round numbers, from •"><) to 190 cubic centimeters. \{' we assume the human pulse-volume to weigh 100 grams, and the blood of a man who weighs 69 kilograms to weigh 5.308 kilograms, or y 1 ^ of his body-weight, the pulse-volume will be about -^ of the entire blood, and the entire blood will pass through the heart, from the veins to the arteries, in only fifty-three beats — that is, in less than one minute. The speed with which a man may bleed to death if a great artery be severed is therefore not surprising. The Work done by the Contracting - Ventricles. — Uncertain as is this important quantity of the pulse-volume, the estimation of the work done by the heart in maintaining the circulation must be based upon it, and upon the force with which each ventricle ejects the pulse-volume. A small fraction of this force is expended in imparting a certain velocity to the ejected blood ; all the rest serves to overcome a uumber of opposing forces. The force exerted by the muscular contraction is opposed by the weight of the volume ejected, and by the strong arterial pressure, which resists the opening of the semilunar valve and the ejection of the pulse-volume. Moreover, the elasticity of the lung- tend- at all times to dilate the ventricles, with a force which is increased at each recurring contraction of the muscles of inspiration. Probably there is also in the wall of the ventricle itself a slight elasticity which must be over- come by the ventricle's own contraction in orderthat its cavity may be effaced, The -trong arterial pressure, with which the reader is already familiar, is by far the greatest of these resisting forces — in fact, is the only one of them which is not of small importance in the present connection. Are we obliged to measure the force of the systole indirectly ? ('an we not ascertain it by direct experiment ".' Manometers of various kinds have been placed in direct communication with the cavities of the ventricles. The fol- 1 It. Tisjerstedt: " Studien uber die Blutvertheilnng im Korper." Erste Abhandlung. "Bestimmnng der von deni linken Herzen herausgetriebenen Blutmenge," Skandinavisches Arilur fiir Phygiologie, 1891, iii- S. 145. n - From ~?7/th>Gfi6c, enlargement. 3 C S. Roy and J. G. Adami, op. oil. CIRCULATION. L07 lowing method, among others, has been employed : A tube open at both ends is introduced through the external jugular vein of an animal into the right ventricle, or, with greater difficulty, through the carotid artery into the left ventricle. In neither case is the valve, whether tricuspid or aortic, rendered incompetent during this proceeding, nor need the general mechanism of the heart and vessels be gravely disturbed. If the outer end of the tube be connected with a recording mercurial manometer, a tracing of the pressure within the right or left ventricle may be written upon the kymograph. It is found, however, that the pressure within the heart varies so much and so rapidly that the inert mercurial column will not follow the fluctuations, and that the attempt to learu the mean pressure by this method fails. A valve, however, may be intercalated in the tube between the ventricle and the man- ometer — a valve so made as to admit fluid freely to the manometer, but to let none out. The manometer will then record, and record not too incorrectly, the maximum pressure within the right or left ventricle during the experiment; in other words, it will record the greatest force exerted during that time by the ven- tricle in order to do its work. 1 In this way the maximum pressure within the left ventricle of the dog has been found to present such values as 170 and 234 millimeters of mercury, the corresponding maximum pressure in the aorta being 158 and 21 2 millimeters respectively. 2 The maximum pressures obtained from simultaneous observations upon the right and left ventricle of a dog are variously reported. It would perhaps be not far wrong to say that in this animal the pressure in the right ventricle is to that in the left as 1 to 2.6. 3 The work done by each ventricle during its systole is found by multiplying the weight of the pulse-volume ejected into the force put forth in ejecting it. That force is equal to the pressure under which the pulse volume is expelled. If we use as a basis of calculation the pressures observed in the dog's heart with the maximum manometer, we may assume as the measure of a given pressure within the contracting human left ventricle 200 millimeters of mercury, and for the human right ventricle 77 millimeters. If for each column of mercury there be substituted the corresponding column of blood, the heights will be 2.5fi7 meters and 0.988 meter respectively. The force exerted by the right or left ventricle upon the pulse-volume might therefore just equal that put forth in lifting it to a height of 0.988 or 2.507 meters. If we assume 100 grams as the weight of a possible pulse-volume ejected by a human ventricle, the work done at each systole of the left ventricle would be 1<»<> 2.567 25<' ( *aule, op. tit., S. 106. 108 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. 1 1 1 1 1 — , however, they are of moment. When we think of the vast number of beats executed by the heart every day, the great amount of energy rendered manifest in maintaining the circulation becomes apparent, and our interest is heightened in the fact that all of this large sum of energy is liberated in the muscular tissue of the heart itself. Thus, too, the physiological significance nt' the diastole is accentuated as a time of rest for the cardiac muscle, as well as a necessary pause for the admission of blood into the ventricle. To disre- gard minor considerations, the work dune at a systole will evidently depend upon the amount of the pulse-volume, of the arterial pressure overcome, and of the velocity imparted to the ejected blood. All these are variable. The work of the ventricles therefore is eminently variable. The Heart's Contraction as a Source of Heat. — In dealing with the movement of the blood in the vessels we have seen that the energy of visible motion liberated by the cardiac contractions is progressively changed into heat by the friction encountered by the blood ; and that this change is nearly com- plete by the time the blood has returned to the heart, the kinetic energy of each systole sufficing to drive the blood from the heart back to the heart again, but probably not being much more than is required for this purpose. Practi- cally, therefore, all the energy of the heart's contraction becomes heat within the body itself, and leaves the body under this form. As the heart liberates during every day an amount of energy which is always large but very variable, it- contractions evidently make no mean contribution to the heat produced in the body and parted with at its surface. H. The Mechanism of the Valves of the Heart. Use and Importance of the Valves. — The discussion just concluded show- the work of the heart to be the forcible pumping of a variable pulse- volume out of veins where the pressure is low into arteries where the pressure is high. It is owing to the valves that this is possible, and so dependent is the normal movement of the blood upon the valves at the four ventricular apertures that the crippling of a single valve by disease may suffice to destroy life after a longer or -holier period of impaired circulation. The Auriculo-ventricular Valves. — The working of the auriculo-ven- tricular valves (see Fig. 18) is not hard to grasp. When the pressure within the ventricle in its diastole is low, the curtains hang five in the ventricle, although probably never in close contact with its wall. As the blood pours into the ventricle, the pressure within it rises, currents How into the space be- tween the wall and the valve, and probably bring near together the edges of the curtains and also their surfaces for some distance from the edge.-. Thus, upon tin' cessation of the auricular systole, the supervening of a superior pres- sure within the ventricle probably applies the already approximated edges and surfaces of the curtains to one another so promptly that the commencing contraction of the ventricle is not attended by regurgitation into the auricle. The principle of closure is the same for the tricuspid valve as for the mi- tral. A- the force- are exactly equal and opposite which press together the CIBCULA TION. 109 opposed parts of the surfaces of the curtains, those parts undergo no strain, aud hence are enabled to be exquisitely delicate and flexible and therefore easily fitted to oue another. On the other hand, the parts of the valve which intervene between the surfaces of contact aud the auriculo-ventricular ring are tough and much thicker, as they have to bear the brunt of the pressure within the contracting ventricle. As the systole of the ventricle increases, the auric- ulo-ventricular ring probably becomes smaller, aud the curtains of the valve probably become somewhat fluted from base to apex, so that their line of & in- tact is a zig-zag. At the same time their surfaces of contact may increase in extent. Tendinous Cords and their Uses. — The structure so far described is wonderfully effective because it is combined with au arrangement to prevent a reversal of the valve into the auricle, which otherwise would occur at ouce. This arrangement cousists in the disposition of the tendinous cords, which act Fig. is.— 'rile left ventricle and aorta Laid open, t>> show the mitral ami aortic semilunar valves i Efenle). as guy-ropes stretched between the muscular wall of the ventricle aud the valve, whether mitral or tricuspid. These cords are tough and inelastic, and, like the valve, are coated with the slippery lining of the heart. They are stout where they spring from the muscle, but divide and subdivide into branches, strong but sometimes very fine, which proceed fan-wise Prom their IK) AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. stem to their insertions (see Fig. 18). These insertions are both into the free margin of the valve and into the whole extent of that surface of* it which looks toward the wall of the ventricle, quite up to the ring. By means of this arrangement of the cords cadi curtain is held taut from base to apex through- out the systole of the ventricles, the opposed surfaces being kept in apposition, and the parts of the curtains between these surfaces and the ring being kept from bellying unduly toward the auricle. Each curtain is held sufficiently taut from side to side as well, because the tendinous cords inserted into one lateral half of the curtain spring from a widely different part of the wall of the heart from those of the other lateral half of it (see Fig. 18). At all times, therefore, even when the walls of the ventricle are most closely approximated during systole, the cords may pull in slightly divergent directions upon the two lateral halves of each curtain. This arrangement of the cords may also cause them, when taut, to pull in slightly convergent directions upon the contiguous lateral halves of two neighboring curtains and thus to favor the pressing of them together (see Fig. 18). Papillary Muscles and their Uses. — In the left ventricle the tendinous cords arise in two groups, like bouquets, from two teat-like muscular projec- tion- which spring from opposite points of the wall of the heart, and which are called the "papillary muscles " (see Fig. 18). One of these gives origin to the cords for the right half of the anterior and for the right half of the posterior curtain ; the other papillary muscle gives rise to the cords for the left halves of the two curtains. Each papillary muscle is commonly more or less subdivided (see Fig. 18). The same principles are carried out, but less regularlv, for the origins of the tendinous cords of the more complex tricuspid valve. Various opinions have been held as to the use of the papillary muscles. It seems probable that during the change of size and form wrought in the ventricle by its systole, the origins of the tendinous cords and the auriculo- ventricular ring tend to be approximated and the cords to be slackened in consequence. Perhaps this is checked by a compensatory shortening of the papillary muscles, due to their sharing in the systolic contraction of the mus- cular ma>s of which they form a part. Observations have been made which have been interpreted to mean that the papillary muscles begin their con- traction slightly later and end it slightly earlier than the mass of the ven- tricle. 1 Semilunar Valves. — The anatomy and the working of the semilunar valve- are the same in the aorta as in the pulmonary artery, and one account will answer for both valves. Each valve is composed of three entirely sepa- rate segments, set end to end within and around the artery just at its origin from the ventricle. The attachment- of the segment- occupy the entire cir- cumference of the vessel (Fig. 18). Like the tricuspid and mitral valves, each semilunar segment i- composed of a sheet of tissue which is tough, thin, supple, and slippery ; but the semilunar valves differ from the tricuspid and 3. Roy and .1. forcible recoil, without regurgitation having occurred in the process (see Figs. 19, 20). "' Lunulse and their Uses. — Each segment of a semilunar valve, when closed, is in firm contact with its fellows not only at it- Ih'r margin but also over a considerable surface, marked in the anatomy of the segment by the two "lunula?" or little crescents, each of which occupies the surface of the segment from one of its ends to the middle of its {'n^' margin, the shorter a\ II . L891, Bd. xvii. No. 5, S. 360. 112 AN AMERICAN TEXT-HOOK OF PHYSIOLOGY. of the lunula being one-half of the free margin of the segment (see Fig. 18). Over the surface of each lunula each segment is in contact with a different one of ils two fellows (see Fig. 20). The firmness of closure thus secured is shown by Figure li», which represents a longitudinal section of the artery, passing through two of the closed segments. The forces which press together the opposed surfaces are equal and opposite, and the parts of the segments which correspond to these surfaces undergo do strain. The Lunula?, therefore, like the mutually opposed portions of the mitral or tricuspid valve, are very delicate and flexible, while the rest of each semilunar segment is strongly made, to resist of itself the arterial pressure. Corpora Arantii and their Uses. — At the centre of the free margin of each semilunar segment, just between the ends of the two lunula?, there is a small thickening, more pronounced in the aorta than in the pulmonary artery, called the " body of Aranzi " * (corpus Arantii). This thickening both rises above the edge and projects from the surface between the lunula?. When the valve is closed, the three corpora Arantii come together and exactly fill a small triangular chink, which otherwise might be left open just in the centre of the cross section of the artery (see Figs. 18, 20). The foregoing shows that the mechanism of the semilunar valves is no less effective, though far simpler, than that of the mitral and tricuspid. That the latter two should be more complex is natural ; for each of them must give free entrance to and prevent regurgitation from a chamber which nearly empties itself, and hence undergoes a very great relative change of volume ; while the arterial system is at all times distended and undergoes a change of capacity which is relatively small while receiving a pulse-volume and trans- mitting it to the capillaries. I. The Changes in Form and Position of the Beating Heart, and the Cardiac Impulse. General Changes in the Heart and Arteries. — During the brief systole of the auricles these diminish in size while the swelling of the ventricles is completed. During the more protracted systole of the ventricles, which imme- diately follows, these diminish in size while the auricles are swelling and the injected arteries expand and lengthen. During the greater part of the suc- ceeding diastole of the ventricles both these and the auricles are swelling, and all the muscular fibres of the heart are flaccid, up to the moment when a new auricular systole completes the diastolic distention of the ventricles, as above stated. During the ventricular diastole, as the great arteries recoil they shrink and shorten. The changes of size in the beating heart depend entirely upon the changes in the volume of blood contained in it, and not upon changes in the volume of the muscular walls. The muscular fibres of the heart agree with those found elsewhere in not changing their volume appreciably during contraction, but their form only. The cardiac cycle thus runs its course with 1 Named from Julius Ca?sar Aranzi of Bologna, an Italian physician and anatomist, bom in 1530. Clli<:rLATIOX. 113 regularly recurring changes of size in the auricles, the ventricles, and the arteries. These changes of size are accompanied by corresponding changes in the form and position of the heart, which are both interesting in them- selves and important in relation to the diagnosis of disease. The basis of their study consists in opening the chest and pericardium of an animal, and seeing, touching, and otherwise investigating the beating heart. The changes in the beating heart, moreover, underlie the production of the so-called cardiac impulse, or apex-beat, which is of interest in physical diagnosis. Observation of the Heart and Vessels in the Open Chest. — The beat- ing heart may be exposed for observation in a mammal by laying it upon its back, performing tracheotomy, and completely dividing the sternum in the median line, beginning at the ensiform cartilage. Artificial respiration is next established, a tube having been tied into the trachea before the chest was opened. The two sides of the chest are now drawn asunder and the pericar- dium is laid open to expose the heart. If, in any mammal, the ventricles be lightly taken between the thumb and forefinger, the moment of their systole is revealed by the sudden hardening of the heart produced by it, as the muscular fibres contract and press with force upon the liquid within. On the other hand, the ventricular diastole is marked by such flaccidity of the muscular fibres that very light pressure indents the surface, and causes the finger to sink into it, in spite of care being taken to prevent this. Commonly, therefore, at the systole the thumb and finger are palpably and visibly forced apart, no matter where applied, in spite of the fact that the volume of the ventricles is diminishing. This sinking of the finger or of an instrument into the relaxed wall of the heart has given rise to many errors of observation regarding changes during the beat. The time when tin- ventricles are hardened beneath the finger coincides with the up-stroke of the arterial pulse near the heart, and, as shown by Harvey, 1 with the time when an intermittent jet of blood springs from a wound of either ventricle. The hardening is proven thus to mark the systole of the ventricles. Those changes of size, form, and position of the exposed heart which accompany the harden- ing of the ventricles beneath the finger are therefore the changes of the ven- tricular systole; and the converse changes are those of the ventricular diastole. To interpret all the changes correctly by the eye alone, without the aid of tin- finger or of the jet of blood, is a tusk of surpassing difficulty in a rapidly beat- ing heart, as was eloquently set forth by Harvey. 2 Changes of Size and Form in the Beating Ventricles. — In a mam- mal, lying upon its hack, with the heart exposed, the ventricles evidently become smaller during their systole. Their girth is everywhere diminished and their length also, the latter mneh less than the former j indeed the dimi- nution in length is a disputed point. Not merely a change of size, bul a 1 Exercitatio Anatomiea de Motti Cordis et Sanguinis in Animalibus, 1628, p. 23; Willi-' trans- lation, Bowie's edition, 1889, p. 23. 2 Op. tit., 1628, p. 20; Willis' translation, Bowie's edition, p. 20. Vol. I.— 8 114 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. change of form is thus produced ; the heart becomes a smaller and shorter, but a more pointed cone. The narrowing from side to side is very conspicuous. Jn the opened chesi of a mammal lying on its hack this narrowing is accompanied by a change which probably does not occur in the unopened chest, viz., by some increase in the diameter of the heart from breasl to hack, so that the surface of the ventricles toward the observer becomes more convex (see p. 116). Thus the base of the ventricles, which tended to he roughly elliptical during their relaxation, tends to become circular duringtheir contraction ; and the diameter of the circle is greater than the shortest diameter of the ellipse, which latter diameter extends from breast to back. At the same time, the area of the base when circular and contracted is much less than when elliptical and relaxed. 1 Naturally, none of these comparisons to mathematical figures makes any pre- tence to exactness. At the same time that the contracting heart undergoes these changes, the direction of its long axis becomes altered. In animals in which the heart is oblique within the chest, the line from the centre of the base to the apex, that is, the long axis, while it points in general from head to tail, points also toward the breast and to the left. In an animal lying on its back, the ventricles when relaxed in diastole tend to form an oblique cone, the apex having subsided obliquely to the left and toward the tail. As the ventricles harden in their systole, they tend to change from an oblique cone to a right cone ; the long axis tends to lie more nearly at right angles to the base ; and consequently the apex, unfettered by pericardium or chest-wall, makes a slight sweep obliquely toward the head and to the right, and thus rises up bodily for a little way toward the observer. This movement was graphically called by Harvey the erection of the heart. 2 It is accompanied by a slight twisting of the ventricles about their long axis, in such fashion that the left ventricle turns a little toward the breast, the right ventricle toward the back. Changes of Position in the Beating- Ventricles. — The changes in form imply changes in position. The oblique movement of the long axis implies that in systole the mass of the ventricles sweeps over a little toward the median line and also a little toward the head. The shortening of the long axis implies that either the apex recedes from the breast, or the base of the ventricles recedes from the back, or both. Of these last three possible cases, the second is the one that occurs. The oblique movement of the apex is accompanied by no recession of it; but the auriculo-ventricular furrow and the roots of the aorta and pulmonary artery move away from the spinal column :i~ the injected arteries lengthen and expand, and, as the auricles swell, during the c traction of the ventricles. During their diastole the ventricles are soft ; they swell ; and changes of form and position occur which are simply converse to those of the systole and have been indicated already in dealing with the latter. 1 < . Ludwig: " TJVber den Ban nnd die Bewegnngen der Herzventrikel," Zcitschri/t fur L849, vii. 8. 189. 2 Op. rit., 162*. p. 22. Translation, L889, p. 22. CIRCULATIOy. 115 Changes in the Beating- Auricles. — Except in small animals, the walls of both the ventricles are so thick that the color of the two is the same and is unchanging, namely, that of their muscular mass ; but the walls of the auricles are so thin that their color is aiFected by that of the blood within, so that the right auricle looks bluish and dark and the left auricle red and bright. During the brief systole of the auricles they are seen to become smaller and paler as blood is expelled from them, while their serrated edges and auricular appendages shrink rapidly away from the observer. The changes of the auricular systole are seen to precede immediately the changes of the systole of the ventricles and to succeed the repose of the whole heart. During the relatively long diastole of the auricles these are seen to swell, whether the ventricles are shrinking in systole or are swelling during the first and greater part of their diastole. Changes in the Great Veins. — In the venae cava? and pulmonary veins a pulse is visible, more plainly in the former than in the latter, which pulse has the same rhythm as that of the heart's beat. The causes of this pulse are complex. It depends in part upon the rhythmic contraction of muscular fibres in the walls of the veins near the auricles, which must heighten the flow into the latter, and which contraction the auricular systole immediately follows. 1 This venous pulse will be mentioned again in discussing the details of the events of the cycle (see p. 138). Changes in the Great Arteries. — It is interesting to note that even in so large an animal as the calf the pulse of the aorta or of the pulmonary artery can hardly be appreciated by the eye, so far as the increase in girth of either vessel is concerned. The expansion of the artery affects equally all points in its circumference, and being thus distributed, is so slight in propor- tion to the girth of the vessel that the profile of the latter scarcely seems to change its place. The lengthening of the expanding artery can be more readily seen. Effects of Opening the Chest. — Such are the changes observed in the heart and vessels when exposed in the opened chest of a mammal lying on its back. The question at once arises, Can these changes be accepted as iden- tical with those which occur in the unopened chest of a quadruped standing upon its feet, or of a man standing erect? It will be most profitable to deal at once with the case of the human subject. What are the possible, indeed probable, differences between the changes in the heart in the unopened upright chest and in the same when opened and supine '.' When air is freely admitted to both pleural sacs, all those complex effects upon the circulation are at once abolished which we have seen to be caused by the elasticity of the lungs and the movements of respiration. The arti- ficial respiration will have an effect upon the pulmonary transit of the blood and so upon the circulation ; but the details of this effeel are nol the same as those of natural respiration, and, for our present purpose, may lie disregarded. 1 T. Lauder Brunton and 1'". Fayrer: "Note on [ndependent Pulsation of the Pulmonary Veins and Vena Cava," Proceedings of tin- Royal Sociiti/, 1876, vol. \xv. p. 174. 111! AN AMERICAN TEXT- HOOK OF PHYSIOLOGY. "What has been abolished is the continual suction, rhythmically increased in inspiration, exerted by the lungs upon the heart and all the vessels within the chest, which suction at all times favors the expansion and resists the con- traction of the cavities of the heart and of the vessels. On the opening of both pleural sacs the heart and vessels are exposed to the undiminished and unvarying pressure of the atmosphere. Moreover, the heart has ceased to be packed, as it were, between the pleurae and lungs to right and left, the spine, the front of the chest-wall, and the diaphragm. From these considerations it follows that the heart must be freer to change its form and position in the opened than in the unopened chest; and that these changes must be more modified by simple gravity in the former case than in the latter. Even in the open chest we have studied these changes only in an animal lying on its back. But if we turn the creature to either side, or place it upright in imi- tation of the natural human posture, the ventricles of the exposed heart in any case tend to assume, in systole, the same form, which has been com- pared roughly to a right cone with a circular base. This is the form proper to the hardened structure of branching and connected fibres of which the contracting ventricles consist. But if the exposed ventricles be noted in dias- tole, it will appear that their form depends very largely upon the effects of gravity upon the exceedingly soft and yielding mass formed by their relaxed fibres. We have seen them, in diastole, to flatten from breast to back, to spread out from side to side, to gravitate toward the tail and to the left. If the animal is laid on its side, they flatten from side to side, they spread out from breast to back, and gravitate to the right or left, as the case may be. 1 Probable Changes in the Heart's Form and Position in the Unopened Chest. — It is fair to conjecture that the increase of the relaxed ventricles in girth and in length which is seen in the open chest would not be greatly differ- ent in the closed chest of a man in the upright posture. But it is probable that the flattening of the exposed heart from breast to back, which is seen in diastole, would not occur if the chest were closed. It is precisely in this direc- tion that the flaccid heart exposed in the supine chest Mould be flattened un- duly by its own weight, when deprived of many of its anatomical supports and of the dilating influence of the lungs. The flattening from breast to back must cause an exaggerated spreading out from side to side and hence an unduly elliptical form of the base, inasmuch as, at the same time, the girth of the ven- tricles is increasing as they enlarge in their diastole. Conversely, it is prob- able, both a 'priori and from experimental evidence, that in the chest, when closed and upright, the diminution in size of the contracting ventricles pro- ceeds more symmetrically; thai their girth everywhere diminishes through a diminution of the diameter from breast to back as well as of that from side to 1 J. B. Haycraft: "The Movements of the Heart within the (lust cavity, and the < anlio- gram," The Journal of Physiology, vol. xii., Nos. 5 and G, December, 1891, p. 44S ; J. B. Hay- craft and I). K. Paterson : "The Changes in Shape and in Position of the Heart during the Cardiac Cycle," The Journal of Physiology, vol. xix., Nos. 5 and 6, May, 1896, p. 496. CIRCULATION. 117 side, and not through an exaggerated lessening of the latter and an actual increase of the former. In this case, too, the base would tend to become more circular during the systole by means of a less marked change from the diastolic form. 1 It has been said that in systole the ventricles are somewhat shortened in the exposed heart, and probably also in the unopened human chest. In the open chest the apex does not recede at all in virtue of this shorten- ing ; on the contrary, the base of the ventricles is seen to move toward the apex, and away, therefore, from the spine. Experiment has proven that the foregoing is true also of the unopened chest. 2 It has been noted already that this movement of the base, which in the upright chest would be a descent, is accompanied by a lengthening of the aorta aud pulmonary artery as their distention takes place. Very probably it is the thrust of the lengthened arte- ries which largely causes the descent of the base of the contracting ventricles, which descent compensates for the shortening of the ventricles and retains the apex in contact with the chest- wall. The Impulse or Apex-beat. — It must always have been a matter of com- mon knowledge that, in man, a portion of the heart lies so close to the chest- wall that, at each beat, the soft parts of that wall may be seen and felt to pul- sate over a limited area. This is commonly in the fourth or fifth intercostal space, midway between the left margin of the sternum and a vertical line let fall from the left nipple. A similar pulsation maybe observed in other mam- mals. The protrusion of the chest-wall at the site of this " impulse " or "apex- beat " occurs when the arteries expand, and the up-stroke of their pulse is felt ; and the recession of the chest coincides with the shrinking of the arteries away from the finger. The impulse proper, that is the protrusion of the chest-wall, occurs, therefore, at the time of the systole of the ventricles. By far the most important factor of the apex-beat is probably the effort of the hardening ven- tricles to change the direction of their long axis against the resistance of the chest-wall. A heart severed from the body and bloodless, if laid upon a table, lifts its apex as it hardens in systole and assumes its proper form. If a finger be placed near enough to the rising apex to be struck by it, the same sensation is received as from the impulse. It is interesting to note that around the point where the soft parts of the chest are protruded by the impulse, they are found to be very slightly drawn in at the time of its occurrence. This drawing-in is called the "negative impulse," and must be caused by the diminution in size of the contracting ventricles. These are air-tight within the chest, and so their forcibly lessened surface must be followed down, in varying degrees, under the pressure of the atmosphere, by the elastic and yielding lungs and by the far less yield- ing soft parts of the chest-wall. The apex-beat can be brought to bear in various ways upon a recording lever, and thus be made to inscribe upon the kymograph a rhythmically fluc- tuating trace, which is called a cardiogram. Considerable attention has been 1 J. B. Haycraft: he. cit. ~ Haycrafi : lot. cit. 118 AN AMERICAN TEXT- BOOK OF PHYSIOLOGY. given to the elucidation of the curve thus recorded ; but, so far, too little agreement lm< been reached for the subject to be entered upon here. 1 J. The Sounds of the Heart. If the ear be applied to the human chest, at or near the place of the apex- beat, the heart's pulsation will lie heard as well as felt. This fact was known to Harvey. 2 About two hundred years later than Harvey, in 1819, the French physician Laennec, the inventor of auscultation, made known the fact that each heat of the heart is accompanied not by one but by two separate sounds. He also called attention to their great importance in the diagnosis of the diseases of the heart; 1 Relations of the Sounds. — The first sound is heard during the time when the apex-beat is felt ; it therefore coincides with the systole of the ventricles. The second sound is much shorter, and follows the first immediately, or, to speak more strictly, after a scarcely appreciable interval. The second sound, therefore, coincides with the earlier part of the diastole of the ventricles. The second sound is followed in its turn by a period of silence, commonly longer considerably than the second sound, which silence lasts till the begin- ning of the first sound of the next ventricular beat. The period of silence, therefore, coincides with the later, and usually longer, portion of the diastole of the ventricles, and with the systole of the auricles. It is interesting that the great auscultator, Laennec, offered no explanation of the cause of either sound, while he made and reiterated the incorrect and misleading statement that the second sound coincides with the systole of the auricles. When the heart beats oftener than usual, each beat must be accomplished in a shorter time; and it is found that, during a briefer beat, the period of silence is shortened much more than the period during which the two sounds are audi- ble; which latter period may not be altered appreciably. Characters of the Sounds. — The first sound is not only comparatively long, but is low-pitched and muffled. The second sound is comparatively short, and is high and clear. The two sounds, therefore, are sharply con- trasted in duration, pitch, and quality. A rough notion of the contrasted characters of the sound- may lie obtained by pronouncing the meaningless syllables " lubb dup." In other mammals the sounds have substantially the same characters as in man. Cause of the Second Sound. — Since Laennec's time, the cause of the -econd sound has been demonstrated by experiment. The second sound is due to the vibrations caused by the simultaneous closure of the semilunar valves of the pulmonary artery and of the aorta, when the diastole of the ventricles has jusi begun. This cause was first suggested by the French physician 1 M. von Frey : Die Unter&uchung des Pulses, etc., 1892, S. 102; R. Tigerstedt: Lehrbuch der Physiologu d,.< k'nixlmi/,*, Leipzig, 1893, S. 112. '-' Exercilatio Anatomica dt Molv Cordis el Sanguinis in Aiiiiindilni.<, 1028, p. 30; Willis's trans- lation, Bowie's edition, 1889, p. 34. 3 R. T. II. Lai-nnec: De ["auscultation mediate, etc., Paris, 1819. CIRCULATION. 119 Roaa.net in 1832 j 1 not long afterward it was conclusively proven by experi- ment by the English physician C. J. B. Williams. 2 Dr. Williams's experiment was as follows: In a young ass the chest was opened and the heart was exposed. It was ascertained thai tin- second sound was audible through a stethoscope applied to the heart itself. A sharp hook was then passed through the wall of the pulmonary artery, and was so directed as to make the semilunar valve incompetent temporarily. By means of a second hook, the aortic semilunar valve was likewise made incompetent. When both hooks were in position, the heart was auscultated afresh, and the second sound was found to have disappeared, and to be replaced by a hissing murmur. The hooks were withdrawn during auscultation, and at the moment of withdrawal the murmur disappeared and the normal second sound recurred. Subsequent clinical and post-mortem observations have shown that the second sound may be altered by disease which cripples the aortic valves. Causes of the First Sound. — The causes of the first sound have not been proven so clearly by the available evidence, which is partly experimental and partly derived from physical diagnosis followed by post-mortem verifica- tion. The first sound, like the second, was ascribed by Rouanet 3 to vibrations depending upon valvular closure, — the simultaneous closure of the tricuspid and mitral valves ; but the persistence of the sound throughout the whole ventricular systole made this cause less probable than in the case of the second sound. Williams, 4 on the other hand, ascribed the first sound to the con- traction of the muscular tissue of the ventricles, — an explanation consistent with the muffled quality of the first sound, and with its persistence through- out the systole of the ventricles. It is now believed by many that both of the foregoing explanations are correct, and that the first sound is composite in its origin, and due both to closure of the valves and to muscular contraction. The evidence in favor of these causes is, briefly, as follows: In favor of a valvular element in the first sound, it is maintained : Thai if the ventricles of a dead heart be suddenly distended with liquid, the mitral and tricuspid valves produce a sound in closing ; and that clinical and post- mortem observations show that the first sound may lie altered by disease which cripples the auriculo-ventricular valves. In favor of an element in the first sound caused by muscular contraction it is maintained: That in a still living but excised heart, the first sound con tinues to be heard under circumstances which preclude the closure and vibra- tion of the valves, and leave in operation no conceivable cause for ilic first sound except muscular contraction. Experiments upon the first sound of the excised heart were reported in L868 by Ludwig and Dogiel, 8 and were 1 J. Rouanet : Analyse dee bruits du run,-, Paris, L8S2. 2 C. J. B. Williams: Die Pathologie mid Diagnose der Krankheiten der Brust, •<<■. Nach der dritten, sehr vermehrten Auflage aus dem Englischen iibersetzt, Bonn, 1838. The writer baa not seen an English edition.) 3 L<«\ <-i/. ' /.,„■. ril. 3 J. Dogiel und C. Ludwig: "Ein neuer Versuch iiber den ersten FTerzton," Berichte £t&< r die Verhandlungen der k. siichsischen Qesellschafi der Wissensehaften w Leipzig, math.-physisehe < tasse, 1868, S. 89. 120 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. performed upon the dog as follows: The heart was exposed daring arti- ficial respiration, and loose ligatures were placed upon the venae cavae, the pulmonary artery, the pulmonary veins, and the aorta. Next, the loose ligatures were tightened in the order above written, during which process the beating heart necessarily pumped itself as free as possible of blood. The vessels were then divided distally to the ligatures, and the heart was excised and suspended in a conical glass vessel containing freshly drawn defi- brinated blood, in which the hearl was fully immersed without touching the glass at any point. Under these conditions the excised heart might execute as many as thirty beats. The conical glass vessel was supported in a " ring- stand." The narrow bottom of the vessel consisted of a thin sheet of india- rubber, with which last was connected the flexible tube and ear-piece of a stethoscope. By means of the latter any sound produced by the beating heart could be heard through the blood and the sheet of rubber. The second sound was not heard ; but at each contraction of the ventricles the first sound was heard, not of the same length or loudness as normally, but otherwise unal- tered. The conditions of experiment were held to preclude error resulting from adventitious sounds ; moreover, the heart before excision had pumped itself tree from all but a fraction of the amount of blood required to close the valves, and had been so treated that no more could enter. It was therefore believed to be practically impossible that the sound heard could have its origin at the valves; and no origin remained conceivable other than in the muscular contraction of the ventricular systole. Later experiments, in which the auriculo-ventricular valves have been rendered incompetent by mechani- cal means, have seemed to confirm the importance of muscular contraction as a cause of the first sound. 1 By the use of a stethoscope combined with a peculiar resonator, the Ger- man physician Wintrich of Erlangen 2 satisfied himself that he could analyze the first sound upon auscultation, so as to detect in it two components, one higher pitched, which he attributed to the vibration of the auriculo-ventricular valves, and a component of lower pitch, attributed to the muscular contrac- tion df the heart. The other experiments above referred to, however, which sustain muscular contraction as a cause of the first sound, did not reveal a change of pitch following incompetence of the valves, but only a diminution in loudness and duration. Both the closure of the cuspid valves and the contraction of the muscular tissue of the ventricles are rejected by a recent observer as causes of the first sound, which he ascribes to the opening of the semilunar valves. 5 1 L. Krehl: '' Ueber den Herzmuskelton," Archiv fur Anatomie und Physiologic, Physiolo- gische Ahtheilung, 1889, 8. 253 : A Kasem-Bek : " IJeber die Kntstebung des ersten Herztones," /' ger 1 8 Archiv fur die gesammtt Physiologic, L890, Bd. xlvii. 8. 53. 1 Wintrich : " Experimentalstudien iiber Resonanzbewegungen der Membranen," Sitzwngs- phys.-med. Societal eu Erlangen, 1st.!; Wintrich: " Ueber Causation und Analyse der Iler/.etune," Ibid., 1875. ■'■ K. Quain: "On tbe Mechanism by which tbe First Sound of the Heart is Produced," lings of the Royal Society, vol. lxi. p. 331. ( [RCULATION. 121 K. The Frequency op the Cardiac Cycles. 1 In a healthy full-grown man, resting quietly in the sitting posture, the heart beats on the average about 72 times a minute. In the full-grown woman the average is slightly higher, perhaps 80 to the minute. The heart beats less frequently in tall people than in short ones. The difference between men and women largely depends upon this, but careful observation shows that in the case of men and women of the same stature the heart-beats are slightly more frequent in the women. There is, therefore, a real difference as to the pulse between the sexes. Shortly before and after birth the heart-beats are very frequent, from 120 to 140 to the minute. During childhood and youth, the frequency diminishes gradually, the average falling below 100 to the min- ute at about the sixth year, and below 80 to the minute at about the eighteenth year. In extreme old age the pulse becomes slightly increased in frequency. It must, however, be borne in mind that there are very wide differences between individuals as to the average frequency of the heart-beats. Pulses of 40 and even fewer strokes to the minute, or, on the other hand, of more than 400 to the minute, are natural to some healthy people. In every individual the frequency of the pulse varies decidedly, and may vary very greatly, during each twenty-four hours. It is least during sleep, aud less in the lying than in the sitting posture. Standing makes the heart beat oftener, the difference being greater between standing and sitting than between sitting aud lying. During muscular exercise the pulse-rate is much increased, violent exercise carrying it possibly to 150 or even more. Thermal influences have a marked effect, a hot bath, for instance, heightening the fre- quency of the pulse and a cold bath diminishing it. The taking of a meal also commonly puts up the frequency. The influence of emotion upon the heart's contractions is well known. It may act either to heighten the rate or to lower it, Finally, the practising physician soon learns that the heart's rate is more easily affected by comparatively slight causes, emotional or other- wise, in women, and especially in children, than in men — a fact of some importance in diagnosis. The causes of the differences referred to in this section are partly unknown, and partly belong to the subject of the regulation of the circulation. L. The Relations in Time of the Main Events of the Cardiac Cycle. We have now considered the effects produced by the cardiac pump; its general mode of working ; and the actual frequency of its strokes. We mnsl next studv certain important details relating to the individual strokes or beats of the ventricles and of the auricles. For this study the basis has already been laid in the sections headed "Causes of the Blood-flow " (p. 77), " Mode of Working of the Pumping Mechanism" (p. 78), "The Cardiac Cycle" (p. 104), and " Use and Importance of the Valves" (p. 108). These sections 1 Tigerstedt : Lehrbuch der Physiologic dea Kreuloufes, Leipzig, 1898, 8 25 36; Vierordt: Daten und Tabellen zum Gebrauche fur Medieiner, 1888, fci. 105-109, 'J.">9. 122 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. should now l>e read again iu the order just given. Details can best be dealt with if we use, instead of the more familiar word "beat," the more technical one '• cycle." The Auricular Cycle ; the Ventricular Cycle ; the Cardiac Cycle. — Kadi systole and succeeding diastole of" the auricles constitute a regularly recurring pair of events which may truly be spoken of as an "auricular cycle :" and SO also it i- exact to say that the ventricles have their cycle, eon- si-ting of systole and succeeding diastole. As soon, however, as we strive for clearness, we find that the useful phrase "cardiac cycle" is necessarily arbi- trary and imperfect. A perusal of the account given on p. 78 of the "Mode of Working of the Pumping Mechanism " shows at once that each auricular cycle, consisting of systole followed by diastole, must begiu shortly before the corresponding ventricular cycle begins, and must eud shortly before the corresponding ventricular cycle ends. The pumping mechanism is such that the auricular systole is completed just before the ventricular systole begins. The phrase "cardiac cycle" implies a reference to both auricular and ven- tricular events ; if now we assume that the beginning of the auricular sys- tole marks the beginning of the cardiac cycle, this must eud either with the end of the auricular diastole or with the eud of the ventricular diastole. In the former case the cardiac cycle would coincide with the auricular cycle, but would begin before the end of one ventricular diastole and would end before the end of another, thus containing no one complete ventricular diastole. Iu the second case, the cardiac cycle would contain one complete ventricular dias- tole and a fraction of another, and would also contain two auricular sys- toles. The second case is clearly even more objectionable than the first. The cardiac cycle had best be defined as consisting of all the events both auricular and ventricular which occur during one complete auricular cycle. The above discussion deals with a phrase which is a constant stumbling-block to stu- dents; and the question may well be asked, Why should the expression "cardiac cycle" not be abolished? The answer is, that this phrase is indis- pensable in order to accentuate certain important relations of the auricular cycle to the ventricular. During a heart-beat there is a period when the auricles and ventricles are in diastole at the same time. During this period, as we have seen, blood is passing from the veins directly through the auricles into the ventricles, and all the muscular fibres of the heart are resting. This period is therefore called that of "the repose of the whole heart," or the " pause." Whenever the heart is not wholly at rest, either auricles or ven- tricles must be in systole. We see, therefore, that each cardiac cycle must coincide with an auricular systole, the instantly succeeding ventricular systole, and a period of repose of the whole heart; and it Is precisely these two systoles and the succeeding universal rest which most engage the attention when the beating heart is looked at in the opened chest. These three phenomena, it will be noted, exactly coincide with one complete auricular cycle, and so do not confuse the definition of the cardiac cycle which has been given already. We see, therefore, that the phrase which seemed at first so CIU CULA TION. 1 23 misleading has a real value, and will cease to confuse if its limitations be care- fully noted. The Brevity and Variability of Each Cycle. — From the frequency with which the cycles recur, it follows at once that each one, with its complex changes in the walls, chambers, and valves, is very rapidly performed. If, for instance, the heart beat 72 times in one minute, each cycle occupies onlv a little more than 0.83 of a second. The brevity of each cycle is both an im- portant physiological fact and a cause of difficulty in studying details. Each cycle, however, necessarily is capable of completion in much less time if the pulse-rate rise ; for instance, during exercise. If repeated 144 times a minute instead of 72 times, each cycle would occupy only one-half of its previous time of completion. With a pulse of less than 60, again, each cycle would occupy over one second. Relative Lengths of the Ventricular Systole and Diastole. — An im- portant question is whether or no there is any fixed relation between the time required for a systole of the ventricles and the time required for a diastole. When the length of the cycle changes from one second to one-half a second, will the length of the systole be diminished by one-half, and that of the dias- tole also by one-half? Or is a nearly invariable time required for the ventri- cles to do their work of ejection, while the period of rest and of receiving blood can be greatly shortened, for a while at least? The answer is that, while both systole and diastole may vary in length, the length of the systole is much the less variable, while the diastole is greatly shortened or lengthened according as the heart beats often or seldom. These facts have been ascertained as follows: A trained observer 1 auscul- tated the sounds of the human heart during a number of cycles, and, at the instant when he heard the beginning either of the first or of the second sound, made a mark upon the revolving drum of a kymograph by means of a sig- nalling apparatus. Of course, careful account was taken of the time lost between the occurrence of a sound and the recording of it. It was found that the time between the beginning of the first and that of the second sound did not vary to the same degree as the frequency of the beats. Although the interval in question may not be an exact measure of the period of ventricular systole, it is sufficiently near it for the purposes of this observation. A second method 2 depended upon the interpretation of the curve inscribed by a lever pressed upon the skin over a pulsating human artery. Such a curve exhibits two sudden changes of direction, which were taken to indicate approxi- mately the beginning and end of the injection of blood by the ventricle, and, therefore, to afford a rough measure of the duration of its systole. \\ bile the interpretation of the curve in question is not wholly settled, it seems, aeverthe- 1 F. C. Donders: " De Rhytlmuis der Hartetoonen," Nederla/ndsch Archief - t' the Systole of the Heart as Intimated from Sphygrnogrnphic Tracings," Journal of Anatomy and Physiology, ls7t>, vol. x. p. 494. 124 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. less, i" give a fair basis for conclusions as to the present question. The figures resulting from the second method are especially instructive. It was found that, with a pulse of 47 to the minute, the approximate length of the ventricular systole was 0.347 of a second ; of the diastole, 0.930 of a second. With a pulse of 128 to the minute, while the systole was only moderately diminished, viz. to 0.256 of a second, the diastole was reduced to 0.213 of a second — an enormous decline. These results upon the human subject have been confirmed upon animals by experiments in which were registered the movements of a lever laid across the exposed heart; ' or the fluctuations of the pressures within the ventricles. 2 By whatever means investigated, the ventricular systole is found to be shortened with the cycle, and to be lengthened with it; the diastole is short- ened or lengthened much more, however. In fact, if the pulse become very frequent, the diastole may be so shortened that the " pause " nearly disap- pears, and the systole of the auricles follows speedily after the opening of the cuspid valves. This signifies that, for a time, the cardiac muscle can do with very little rest, and that effective means exist for a very rapid "charg- ing" of the ventricular cavity when necessary. For the working period of the ventricle, however, a more uniform time is required. For the average human pulse-rate this time of work is decidedly shorter than the time of rest — viz. about 0.3 of a second for the former as against about 0.5 for the latter. Lengths of Auricular Events and of the Pause. — The systole of the auricles is very brief, being commonly reckoned at about 0.1 of a second, as the result of various observations. 3 At the average pulse-rate, therefore, the auricular systole is only about one-third as long as the ventricular, and the length of the auricular diastole is to that of the ventricular as seven to five. Consequently, a cardiac cycle of 0.8 of a second would comprise an auricular systole of 0.1 of a second ; a ventricular systole of 0.3 of a second ; and a pause, or repose of the whole heart, of 0.4 of a second — one-half of the cycle. Practical Application. — The observations above described upon the inter- val between the beginnings of the sounds have a practical bearing upon physical diagnosis; for they show how faulty are the statements often made which assign regular proportions to the lengths of the sounds and the silences of the heart. The length of the "second silence" must be very fluctuating, as it comprises the longer part of the fluctuating ventricular diastole. The length of the first sound and of the very brief first silence together must be very con- stant, as they nearly coincide with the ventricular systole. 1 N. Baxt: "Die Verkurzun^ der Systolenzeit durch den Nervus accelerans cordis," Archiv fir Anatomie wnd Physiologic, Physiologische Abtheilung, 1878, 8.122. : M. von l'rey and L. Krelil : " Untersuchunffen fiber den Puis," Archiv fiir Anatomie und Physiologie, Physiologische Abtheilung, 1890, S. 31. W.T.Porter: " Researches on the Filling of the Heart," Journal uf Physiology, 1892, vol. xiii. p. ">.">1. II. Vierordl : Daien tmd Tabellen mm Gebrauchefiir Mediciner, 18S8, S. 105 CIRCULATION. 125 M. The Pressures within the Ventricles.' We must now approach the study of further details of the working of the ventricular pumps, which details depend for their elucidation upon the measur- ing and recording of the pressures within the ventricles. Absolute Range of Pressure -within the Ventricles and its Signifi- cance. — In dealing with the work done by the contracting ventricles (p. 106) we have seen that the mercurial manometer, as used for studying the pressure within the arteries, is quite unable to follow the changes of the intra-ventric- ular pressure; but that, by the intercalation of a valve, this instrument can he converted into a useful " maximum manometer" for the measuring: and record- ing of the highest pressure occurring within the ventricle during a given time — that is, during a certain number of cycles. It must now be added that by a simple change of valves this same instrument can at any moment be changed into a "minimum manometer." 2 We can thus, by means of the modified mer- curial manometer, learn with fair correctness the extreme range of pressure within the ventricles. As instances of the extent of this range, two observa- tions may be cited upon the left ventricle of the dog, the chest not having been opened. In one animal the maximum was found to be 234 millimeters of mer- cury, the maximum pressure in the aorta being 212 millimeters; and the min- imum in the left ventricle was —38 millimeters — that is to say, 38 millimeters less than the pressure of the atmosphere, the minimum pressure in the aorta 1 The matters connected witli the ventricular pressure-curve may best be studied in the fol- lowing writings, in which citations of other papers maybe found: K. Hiirthle, in Pfluger's Archiv fiir die gesammte Physiologie, as follows: " Zur Technik der Untersuchung des Blut- druckes," 1888, Bd. 43, S. 399. "Technische Mittheilungen," 1X90, Bd. 47, S. 1. "Ueber den Ursprungsort der sekundiiren Wellen der Pulscurve," Bd. 47, S. 17. "Technische Mit- theilungen," 1891, I'd. 49, S. 29. " Ueber den Zusammenhang zwischen Herzthatigkeit nnd Palsform," Bd. 49, S. 51. " Kritik des Lufttransmissionsverfahrens," 1*92, Bd. 5:>, S. 281. '' Vergleichende Priifung der Tonographen von Frey's nnd Hiirthle's," 1893, Bd. 55, 8. 319. J. A. Tschuewsky : " Vergleichende Bestimmung der Angaben des Quecksilber — nnd des Feder- Manometers in Bezugaufden mittleren Blutdnick," Pfluger's Archiv fiir du gesammte Physiologic, 1898, Bd. Ixxii. S. 585. "Technische Mittheilungen," Ibid., 1898, Bd. lxxii.S.566. K. Hiirthle: " ( >rientirungsversuche iiber die Wirkung des Oxyspartein auf das I [erz, . I rchivfiir experimenteUe Pathologie wnd Pharmakologie, 1892, Bd. xxx. S. 141. \V. I'. Porter: "Researches on the Filling of the Heart." The Journal of Physiology, 1892, vol. xiii. p. 513. "A New Method for the Study of the Intracardiac Pressure Curve," Journal of Experimental Medicine, L896 a vol. i.. No. 2. M. von Frey und L. Krehl : " Untersuchungen iiber den Puis," Archiv fiir Anaiom.it und Physiologie, Physiologische Abtheilung, 1890, S. 31. M. von Frey: "Die Untersuchung des Pulses," Berlin, 1892. "Das Plateau des Kammerpulses," Archiv fiir Anatomie und Phynolagie, Physiologische Abtheilung, L893, S. 1. "Die Ermittlung absoluter Werthe fiir die Leistung von Pulsschreibern," Archiv fiir Anatomie und Physiologie, Physiologische Abtheilung, 1893, S. 17. " Zur Theorie der Lufttonographen," Archiv fiir Anaiomie und Physiologie, Physiologische Abtheilung, 1893, S. 204. " Die Erwarmung der Full in Tonographen," Qmtralblatt fur Ph wlogie vom 30 Juni, 1894, Heft 7. < >. Frank: " Ein experimentelles rlilfsmittel fiir Eine Kritik der Karamerdruckcurven," Zeitschrifi fiir Biologie, 1897, Bd. sxxv 8 178. B. Rub- brecht: "Recherches cardiograph iques chez les Oiseaux," Archives de Biologie, 1898, t. w. p. right. Recorded simultaneously by two clastic man- rs with transmission by liquid, in both curves tin 1 ordinates having the same numbers have the following meaning: l. the in- taut preceding t lie closing of the mitral valve ; ■_', the opening of the semi- lunar valve; '■'•, the beginning of the "dicrotic wave." regarded as marking the instant of closure of the semilunar valve: I. the instant preceding the opening of the mitral valve (Porter). tensive rise of pressure, marked in the curve by a line but slightly inclined from tin; vertical. In the same way the fall of pressure is nearly as sudden and as swift as the rise, and perhaps even more extensive. The systolic rise begins at a pressure a little above that of the atmosphere; the diastolic fall continues, toward its end. perhaps, with diminishing rapidity, till a point is CIRCULATION. 129 reached often below the pressure of the atmosphere. The pressure then rises, perhaps continuing negative for a longer or shorter time, but presently becoming equal to that of the atmosphere. Near this it continues, perhaps with a gentle upward tendency, until, near the end of the ventricular diastole, the rise becomes more rapid to the point at which the succeeding ventricular systole is to begin. It is the course of the pressure between its rapid rise and its rapid fall which has been the most disputed. The observers who employ manometers with liquid transmission, have so far found that the high swift rise at the outset of the systole is soon succeeded by a sudden change. According to them the pressure within the manometer now exhibits fluctuations of greater or less extent which are due, partly at least, to the inertia of the transmitting liquid ; but, with due allowance made for these, the cardiac pressure is seen to maintain itself at a high point throughout most of the systole until the rapid fall begins. During this period of high pressure, the height about which the fluctuations occur may remain nearly the same ; or this height may gradually increase, or gradually decrease, up to the beginning of the rapid fall. As is shown by Figure 23, this course of the systolic pressure causes its curve to bend alternately down- ward and upward between the end of its greatest rise and the beginning of its greatest fall ; but between these two points the general direction of the curve approaches the horizontal, and therefore entitles this portion of it to the name 12 3 4 M ill i meters of mercury. Line of atmospheric pressure. Tenths of " second. Fig. 24.— Magnified curve of the course of pressure within the left ventricle of >li<- dog, the chest being open; to be read from left to right. Recorded by the elastic manometer with transmission by air. The crdinates have the following meaning: l, the closure of the mitral valve; 2, the opening oi the semi- lunar valve ; 3, the closure of the semilunar valve; I, the opening of the mitral valve (von Fr< j i. of the " systolic plateau," a name which becomes more truly descriptive when appropriate means are taken to eliminate the fluctuations due to inertia. The best of the manometers with air transmission yields a curve ot* the pressure within the ventricle which presents a different picture (Figs. 22 and 24). The steeply rising line may diminish its steepness somewhat as it ascends, but its rapid turn at the highest point of the curve is succeeded by no plateau. The line simply describes a single peak, and begins the descent which marks the rapid fall of pressure recognized by all observers. In these peaked curves Vol. I.— 9 130 AN AMERICAN TENT-BOOK OE PHYSIOLOGY. this descent is often steepest in its middle part. Such a peaked curve would indicate, of course, that there is no such thing as the maintenance, daring any large part of the systole of the ventricles, of a varying but high pressure. The experienced observer who is the chief defender of the peaked curve holds the plateau to be a product either of too much friction within the manometer tubes, or of a faulty position of the cannula within the heart, whereby com- munication with the manometer is, for a time, cut off. The able and more numerous adherents of the plateau, on the other hand, attribute the failure to obtain it to the sluggishness of the instrument employed, or to an abnor- mal condition of the heart. Recent comparative tests of elastic manometers, and other studies, would seem to show that the curves obtained by liquid transmission, and which exhibit the plateau, afford a truer picture of the general course of the pressure within the ventricles than the peaked curves written by means of air. The Ventricular Pressure-curve and the Auricular Systole. — It is striking testimony to the smoothness of working of the cardiac mechanism, that the curve of intra-ventricular pressure rarely gives any clear indication of the beginning or end of the auricular systole. This event may be expected to increase the pit -sure within the ventricles; and, in the curve, the very gentle pise which coincides with the latter and longer part of the ventricular diastole passes into the steep ascent of the commencing ventricular systole by a rounded sweep, which indicates a more rapidly heightened pressure within the ventricle during the auricular systole. As a rule, no angle reveals an instantaneous change of rate to show the beginning or end of the injection of blood by the contracting auricle (see Figs. 22, 23, 24). Occasionally, how- ever, a slight " presystolic " fluctuation of the curve may seem to mark the auricular systole. 1 The Ventricular Pressure-curve and the Valve-play. — It is also exceedingly striking that no curve, whether it be pointed or show the sys- tolic plateau, gives a clear indication of the instant of the closing or open- ing of either valve, auriculo-ventricular or arterial (see Figs. 22, 23, 24). These instants, so important for the significance of the curve, can, however, be marked upon it after they have been ascertained indirectly. A method of general application would be as follows: Two elastic manometers are "absolutely graduated " by causing each of them to record a series of pressures already measured by a mercurial manometer. The two elastic manometers can tlnn be made to mark upon the same revolving drum the simultaneous changes of pressure in a ventricle and in its auricle, or in a ventricle and its artery. The pressure indicated by any point of either curve can then be calculated in terms of millimeter- of mercury. That point upon the intra-ventricular curve which marks a rising pressure just higher than the simultaneous pressure in the auricle or artery, may be taken to mark the closing of the cuspid valve or the opening of the semilunar valve, as the case may be. By a converse process, the moment of opening of the cuspid valve, or of closing of the semi- 1 von Frey and Krehl: op. cit., p. 61. CIRCULATION. 131 lunar, may also be ascertained. The practical difficulties in the way of applying- this method to the ventricle and auricle are much greater than to the ventricle and artery. By another application of the principle just described, a "differential manometer" has been devised for the purpose of registering as a single curve the successive differences, from moment to moment, between the ventricular and auricular pressures, or the ventricular and arterial pressures (see Fig. 25). To this end, two elastic manometers are fastened immovably together, and their two elastic disks, instead of bearing upon separate levers, are made to bear upon a single one, which has its fulcrum between the disks, and is a lever not of the third order, but of the first, like a common balance. Fig. 25.— Diagram of the differential manometer: A, artery: V, ventricle; Z>, drum of kymograph, revolving in the direction of the arrow, and covered with smoked paper; L, recording lever in contact with the revolving drum ; 8, a spring by which the movement of the lever worked by the disks is trans- mitted to the recording lever. (The working details of the instrument are suppressed or altered for the sake of clearness.) As the lever or beam of the balance turns from the horizontal as soon as the scales are pressed upon by unequal weights, so the lever of the differential manometer turns as soon as the disks are unequally affected by the pressures within the ventricle and the auricle, or the ventricle and the artery. As, how- ever, the pressures upon the scales are from above, while those upon the disks are from below, the disk which tends to "kick the beam" is the one acted upon by the greater pressure, instead of by the less, as in the case of the scales. The manometric lever marks its oscillations as a curve upon the kymograph by the help of a second or" writing lever" connected with it. The persistence of exactly equal pressures, no matter what their absolute value, in the two manometers would cause a horizontal line to be drawn by the writing lever. This would serve as a base-line. The differential manometer is ;i valuable instrument, although it is evident that where such minute differences of space and time are recorded as a curve by such complicated mechanisms, the sources of error must be numerous and difficult to avoid. 1 The methods which proceed by the measurement of differences of pressure may sometimes be controlled, or even replaced, by an easier method, as follows: If two manometers simultaneously record on the same kymograph thepressure- 1 K. Hurthle: Pfluger'a Arehiv fur die gesammie Phyiriologie, 1891, Bd. 49, S. 45. 132 AN AMERICAN TEXT-HOOK OF PHYSIOLOGY. curves of the ventricle and the auricle, or of the ventricle and the artery, any \v,t sudden change of pressure, produced in auricle or artery at the opening or shutting of a cardiac valve, will produce a peak or angle in the curve of pres- sure of the auricle or artery. By the rules of the graphic method the point in the pressure-curve of the ventricle can easily be found which was written at the same instant with the peak or angle in the auricular or arterial curve. That point upon the ventricular curve, when marked, will indicate the instant of opening or shutting of the valve in question. In the pressure-curve ob- tained from the aorta close to the heart, there is a sudden angle which clearly marks the instant when the opening of the semilunar valve leads to the sudden rise of pressure which causes the up-stroke of the pulse (see Fig. 23). Again, the fluctuation of aortic pressure which we shall learn to know as the "dicrotic wave" begins at a moment which many believe to follow closely upon the clos- ure of the semilunar valve. That moment may be indicated by a notch in the aortic curve. So, too, the rise of pressure within the auricle produced by its systole may suddenly be succeeded by a fall, the beginning of which must mark the closure of the cuspid valve, which closure thus may correspond with the apex of the auricular curve. In Figure 23, ordinate 1 indicates the closing, and ordinate 4 the open- ing, of the mitral valve. These two points were found by help of the dif- ferential manometer. < Ordinate 2 indicates the opening, and ordinate 3 the closing, of the aortic valve. These two points were marked with the help of the curve of aortic pressure, also shown in Figure 23, each ordinate of which has the same number as the corresponding ordinate of the ventricular curve. In the arterial curve, 2 marks the beginning of the systolic rise, and 3 the beginning of the dicrotic wave, which latter point is treated by the observer as closely corresponding to the closure of the aortic valve. In figure 24 each ordinate has the same number, and, as regards the valve- play, the same significance, as in figure 23. Ordinate 1 corresponds to the apex of a peak in the auricular curve (not here given) which represents the end of the auricular systole. Ordinate 2 corresponds to the beginning of the systolic ascent in the aortic curve (not here given). Ordinate 3 was found by comparing, by means of two elastic manometers, the simultaneous pressures in the ventricle and the aorta. Ordinate 4 corresponds, on the auricular pressure-curve, to a point which marks the beginning of a decline of pres- sure believed by the observer to succeed the opening of the cuspid valve.- In both the figures given of the ventricular curve, and in such curves in general, the points which mark the valve-play occur as follows: The .closure of the cuspid valve corresponds to a point, not tar above the line <>f atmospheric pressure, where the moderate upward sweep of the ventric- ular curve takes on the steepness of the systolic ascent. The systole of the auricle is of little force, and the blood injected by it into the distensible ven- tricle rai-e- the pressure there but little; that little, however, is more than the relaxing auricle presents, and the cuspid valve is closed. Somewhere on the steep -ystolie ascent occur- the point corresponding to the rise of the ven- CIRCULATION. 133 tricular above the arterial pressure, and therefore to the opening <>t' the semi- lunar valve. But other forces beside the arterial pressure must be overcome by the contracting muscle; and the ventricular pressure mounts higher vet, and either stays high for a while, producing the plateau, or, in a peaked curve, at once descends. In either ease, not long after the beginning of the sharp descent, the point occurs at which the ventricular pressure falls below the arte- rial, and the semilunar valve is closed. Beyond this point the curve continues steeply downward, but it is not till a point is reached not far above, or possibly even below, the atmospheric pressure that the pressure in the ventricle falls below that in the auricle, and the cuspid valve is opened. The Period of Reception, the Period of Ejection, and the Two Periods of Complete Closure of the Ventricle. — During the whole of the period when the cuspid valve is open, the pressure is lower in the ventricle than in the artery ; the arterial valve is shut ; and blood is entering the ventricle. This may be called the " period of reception of blood." During the greater part of the period when the cuspid valve is shut, the arterial valve is open ; the pressure is higher in the ventricle than in the artery; and the ejection of blood from the former is taking place. This may be called the "period of ejection," and lies in Figures 23 and 24 between the ordinates 2 and 3. The careful work which has enabled us to mark the valve-play upon the ventricular curve has demonstrated the interesting fact that there occur two brief periods during each of which both valves are shut, and the ven- tricle is a closed cavity. Of these two periods, one immediately precedes the period of ejection, and the other immediately follows it. The first lies, in Figures 23 and 24, between the ordinates 1 and 2 ; the second, between 3 and 4. The explanation of these two periods is simple. It takes a brief but measurable time for the cardiac muscle, forcibly contracting upon the impris- oned liquid contents of the closed ventricle, to raise the pressure to the high point required to overcome the opposing pressure within the artery and to open the semilunar valve. Again, it takes a measurable time, probably seldom quite so brief as the period just discussed, for the cardiac muscle to relax suffi- ciently to permit the pressure in the closed ventricle to fall to the low point required for the opening of the cuspid valve. The ventricular cycle, thus studied, falls into four periods: the first is a brief period of complete closure with swiftly rising pressure; the second is the period of ejection, relatively long, and but little variable ; the third is a period of complete closure, with swiftly falling pressure; the fourth is the period when the pressure is low and blood is entering the ventricle. This last period is very variable in length, but at the average pulse-rate it is the longest period of all. Phenomena of the Period of Reception of Blood. — We have already followed the course of the pressure within the ventricle from the moment of opening of the auriculo-ventrieular valve to that of its closing (p. 128). During this time the ventricle is receiving its charge of blood, the flaccidity of the wall rendering expansion easy and keeping the pressure low. The blood which ent■ Humani corporis fabrica Libri septan. Basilese, ex officina [oannis Oporini, Anno Salutie reparatse MDXLIIL Page 587. 2 Op. cit., 1628, p. 26: Willis's translation, Bowie's edition, 1889, p. 28. CIRCULATION. 135 very near the chest. These same forces produce a slight suction within the ventricles, relaxed in their diastole. But a very slight suction occurs at each ventricular diastole even after the chest has been opened. The causes of this arc -till obscure; but it is to be borne in mind that the relaxing wall of the ventricle, flabby as it is, possesses some little elasticity, especially at the auriculo- ventricular ring, and therefore may tend to resume a somewhat different form from that due to its contraction. As the result of this slight elastic recoil, a feeble suction may occur. N. The Functions of the Auricles. Connections of the Auricle. — Into the right and left auricles open the systemic and pulmonary veins respectively, and each auricle may justly be re- garded as the enlarged termination of that venous system with which it is con- nected. Until modern times the terms of anatomy reflected this view, and from the ancient Greeks to a time later than Harvey, the word " heart "com- monly meant the ventricles only, as it still does in the language of the slaughter-house. This termination of the venous system, the auricle, com- municates directly with the ventricle, at the auriculo-ventrieular ring, by an aperture so wide that, when the cuspid valve is freely open, auricle and ven- tricle together seem to form but a single chamber. The Auricle a Feeble Force-pump ; the Pressure of its Systole. — The wall of the auricle is thin and distensible; it is also muscular and contractile. But the slightest inspection of the dead heart shows how little force can be exerted by the contraction of so thin a sheet of muscle. In the Avail of the appendix, however, the muscular structure is more vigorously developed -than over the rest of the auricle. The auricle, then, should be a very feeble force- pump ; and such in fact, it is ; for the highest pressure scarcely rises above 20 millimeters of mercury in the right auricle of the dog, 1 and an auricular sys- tole often produces a pressure of only 5 or 10 millimeters. 2 This would be but a small fraction of the maximum ventricular pressure of the same heart. The auricle, however, is equal to its work of completing the filling of the ventricle; and the feebleness of the auricle will not surprise us when we consider that, at the beginning of its systole, the pressure exerted by the contents of the relaxed ventricle is but little above that of the atmosphere, and offers small resistance to the injection of an additional quantity of blood. The systole of the auricles is so conspicuous a part of the cardiac cycle when the beating heart is looked at, that its necessity is easily overrated. Even Har- vey, in attacking the errors of his day, was led by imperfect methods to estimate too highly the work of the auricular systole (see p. 184). The error, although a gross one, is not rare, of considering the systole of the auricles to be as im- portant for the charging of the ventricles as the systole of the ventricles is for the charging of the arteries. On page 98 the proof has already been given 1 Goltz und l,>iiif rompurir rfrx ,mi- maux, Paris. 1888, vol. ii. p. 424. 2 von Frey und Krehl: op. cil., p. 59. CIRCULATION. 137 ing pressure within the ventricle. These periods coincide with the earlier part of the auricular diastole. During all this time the forces which cause the venous flow are delivering blood into the flaccid and distensible reservoir of the auricle, and can thus maintain a continuous flow. But the blood of which the veins are thus relieved during the period of closure of the cuspid valve, accumulates just above that valve to await its opening. When it is opened by the superior auricular pressure, the stored-up blood both flows and is drawn into the ventricle promptly from the adjoining reservoir. From this time on, auricle and ventricle together are converted into a common storehouse for the returning blood during the remainder of the repose of the whole heart, which coincides with the later portion of the long auricular diastole. The next auricular systole completes the charging of the ventricle ; and a second use of this systole now becomes apparent, for the sudden transfer by it of blood from auricle to ventricle not only completes the filling of the latter, but lessens the contents of the auricle, and so prepares it to act as a storehouse during the coming systole of the ventricle. The auricle, then, is an apparatus for the maintenance of as even a flow as possible in the veins and for the rapid and thorough charging of the ventricle. It is clear that, for both uses, the auricle's function as a reservoir is certainly no less important than its function as a force-pump. The value of a mechanism for the rapid filling of the ventricle increases with the pulse-rate, and with a very frequent pulse must be of great import- ance, because now time must be saved at the expense of the pause, with its quiet flow of blood through the auricle into the ventricle ; and the auricular systole must follow more promptly than before upon the opening of the cus- pid valve. If the pulse double in frequency, each cardiac cycle must be com- pleted in one-half the former time; but we have seen that the ventricle requires for its systole a time which cannot be shortened with the cycle to the same degree as can its diastole. Of heightened value now to the ventricle will be the adjoining reservoir, which is filling while the cuspid valve remains closed, and from which, as soon as that valve is opened, the necessary supply not only flows, but is sucked and pumped into the ventricle, tor, when increased demands are made upon the heart, the usefulness of an increased frequency of beat disappears if the volume transferred at each beat from veins to arteries diminish in the same proportion as the frequency increases. No increase of the capillary stream can then follow the more frequent strokes of the pump. 1 Negative Pressure within the Auricle ; its Probable Usefulness. — The course of the pressure-curve of the auricle, as shown by the elastic manome- ter, is too complex and variable, and its details are too much disputed, for it to be given here. But certain facts regarding the auricular pressure are of much interest in connection with the use of the auricle which has jus! been discussed. Once, and perhaps oftener, in each cycle, the pressure in the auricle may become negative, perhaps to the degree of from —2 to— 10 millimeters of mercury even in the open chest,-' and of course becomes still more so when 1 von Frey und Kivlil ; op. tit., p. 61. 2 de Jager : op. eit., p. 507. W. T. Porter: op. cit., p. 533. 138 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. the latter is intact, sinking in this case to perhaps— 11.2 millimeters. 1 What is striking in connection with the "quick -charging'" of the ventricle is that the greatest and longest negative pressure in the auricle coincides, as we should expect, with the earlier part <>f its diastole, and therefore with the systole of the ventricle, when the auricle is cut off from it by the shut valve. 2 By this suction within the auricle the flow from the veins into it probably is heightened, and the store of blood increased which accumulates in the reservoir to await the opening of the valve. The quick-charging mechanism itself is quickly charged. Nor should it be forgotten that the work of the ventricle contributes in some degree to this suction within the auricle. The heart is air-tight in the chest, which is a more or less rigid case. At each ventricular systole the heart pumps some blood out of this case, and shrinks as it does so, thus tending to produce a vacuum; in other words, to increase the amount of negative pressure within the chest, and thus help to expand the swelling- auri- cles. Therefore for the suction which helps to charge the auricles during the systole of the ventricles, that systole itself is partly responsible. 3 Is the Auricle Emptied by its Systole ? — Authorities differ still as to the extent to which the auricle is emptied by its systole; some holding the scarcely probable view that, during this time, its contents are all, or nearly all, trans- ferred to the ventricle; 4 and others taking the widely different view that the auricle actually continues to receive blood during its systole, which latter simply increases the discharge into the ventricle. According to this latter opinion the flow from the great veins into the auricle is absolutely unbroken. 5 All are agreed, however, that the auricular appendix is the most completely emptied portion of the chamber. Are the Venous Openings into the Auricle closed during- its Systole ? If not, does Blood then regurgitate, or enter? — As to these questions dif- ferences of opinion are possible, because at the openings of the veins into the auricle no valves exist which are effective in the adult, except at the mouth of the coronary sinus. It is therefore a question, what happens at the mouths of the veins during the auricular systole. These mouths are surrounded by rings composed of the muscular fibres of the auricular wall ; and for some distance from the heart the walls of some of the great veins are rich in circular fibres of muscle. We have seen already (p. 115) that a rhythmic contraction of the venae cavic and pulmonary vein- occurs just before the systole of the auricles and musl accelerate the flow into the latter. Their swiftly following systole is' known to begin at the mouths of the great veins and from these to spread over the rest of each auricle. It is evident at once that the circular fibres must 1 < roltz and < ranle : op. cit., p. 109. 2 von Frey uud Krehl: i>/>. cit., p. 5.",; \\ r . T. Porter: op. cit., p. 523. ' A. Mosso: Die Diagnostik des Pulses, etc. Zweiter Theil : Ueber den negativen Puis, S. 42. 1 M. Foster: .1 Text-book of Physiology, New York, 1896, p. 182. Skoda: " I'eher die Function der Vorkammern des Herzens," Sitzungsberichfe der maihem.- rmturw. Classe der kai*. Akminnif 'lt pathologique, 1890, \>. •">!:. 140 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. increase in the contents of an artery which causes the pulse therein, is accom- modated not merely by the increase of calibre which produces the " up-stroke " of the arterial wall against the finger, but also by an increase in the length df the elastic vessel. If the artery be sinuous in its course, this increase in length suddenly exaggerates the curves of the vessel, and thus produces a slight wriggling movement. This is sometimes very clearly visible in the temporal arteries of emaciated persons. On the other hand, the increase in the calibre of the artery is relatively so slight that it is invisible at the profile even of a large artery, dissected clean for a short distance for the purpose of tying it. Such a vessel appears pulseless to the eye, although its pulse is easilv felt by the finger, which slightly flattens the artery and thus gains a larger surface (if contact. Transmission of the Pulse. — If an observer feel his own pulse, placing the finger of one hand upon the common carotid artery, and that of the other upon the dorsal artery of the foot at the instep, he will perceive that the pulse corresponding to a given heart-beat occurs later in the foot than in the neck. This phenomenon is readily comprehended by considering that room for the " pulse-volume " injected by the heart is made in the root of the arterial system both by local expansion and by a more rapid displacement of blood into the next arterial segment. This next segment, in turn, accommodates its increased charge by local expansion and by a more rapid displacement ; and this same process involves segment after segment in succession, onward toward the capillaries. The expansion of the arterial system, then, is a progressive one, and, as the phrase is, spreads as a wave from the aorta onward to the arteri- oles. The rate of transmission of the "pulse-wave" from a point near the heart to one remote from it, may be calculated. This is done by comparing the time which elapses between the occurrence of the up-stroke of the pulse in the nearer and in the farther artery with the distance along the arterial system which separates the two points of observation. In one case, for exam- ple, that of an adult, the absolute amount of the postponement of the pulse — that is, the time required for the transmission of the pulse-wave from the heart itself to the arteria dorsalis pedis, was 0.193 second. 1 The time of transmission of the pulse-wave from the heart to the dorsalis pedis is often longer than in this case, amounting to 0.2 second or a little more. If we reckon the duration of the ventricular systole at about 0.3 second, it is evi- dent that the fact of the postponement of the pulse in the arteries distant from the heart does not invalidate the general statement that the arterial pulse is synchronous with the systole of the ventricles. The general estimates of the rate, as opposed to the absolute time, of trans- mission of the pulse-wave vary, in different cases, from more than 3 meters to more than !) meters per second. As the blood in the arteries does not pass onward at a -witter rate than about 0.5 meter per second, it is clear that the wave of expansion moves along the artery many times faster than the blood does ; and that t<> confound the travelling of the wave with the travelling of 1 J. N. Czermak: Gcsamm.Uc Schrifim, 1S79, Bd. i. Abth. 2, 8. 711. CIRCULATION. 141 the blood would be a very serious error, easily avoided by bearing in mind the causes of the pulse-wave as already given. Investigation by the Finger. — The feeling of the pulse has beeD a valu- able and constantly used means of diagnosis since ancient times. Indeed, the ancient medicine attached to it more importance than does the practice of to-day. But it is still advisable to warn the beginner that he may not look to the pulse for "pathognomonic" information ; that is to say, he may not expect to diagnosticate a disease solely by touching an artery of the patient under examination. The pulse is most commonly felt in the radial artery, which is convenient, superficial, and well supported against an examining finger by the underlying bone. Many other arteries, however, may be util- ized. Frequency and Regularity. — The most conspicuous qualities of the pulse are frequency and regularity. Usually these can be appreciated not merely by a physician but by any intelligent person. The physiological variations in the frequency of the heart's beats have been referred to already (p. 121). In an intermittent pulse the rhythm is usually regular, but, at longer or shorter intervals, the ventricle omits a systole, and therefore, the pulse omits an up- stroke. Either intermittence or irregularity of the cardiac beats may be caused by transient disorder as well as by serious disease. Tension. — When unusual force is required in order to extinguish the pulse by compressing the artery against the bone, the arterial wall, and hence the pulse, is said to possess high tension, or the pulse is called incompressible, or hard. Conversely, the pulse is said to be of low tension, compressible, or soft, when its obliteration is unusually easy. A very hard pulse is sometimes called "wiry;" a very soft one, "gaseous." High tension, hardness, incompressibil- ity, obviously are directly indicative of a high blood-pressure in the artery ; and the converse qualities of a low pressure. It follows from what has gone before that the causes of changes in the arterial pressure, and hence in the tension, may be found in changes either in the heart's action, or in the periph- eral resistance, or, as is very common, in both. An instrument called a sphygmomanometer 1 or sphygmometer is sometimes applied to the skin over the artery, in order to obtain a better measurement of its hardness or softness, and hence of the blood-pressure within it, than the finger can make. Such instruments are not free from sources of error. Size. — When the artery is unusually increased in calibre at each up-stroke of the pulse, the pulse is said to be large. When, at the up-stroke, the calibre changes but little, the pulse is said to be small. A very large pulse is some- times called "bounding;" a very -mall one, " thready." Largeness of the pulse must be distinguished carefully from largeness of the artery. The for- mer phrase means that the fluctuating pari of the arterial pressure is large in proportion to the mean pressure. But if the mean pressure be great while the fluctuating part of the pressure i- relatively small, the artery, even at the end of the down-stroke, will be of large calibre, while the pulse will be small. ' From r < >v) u6i , pulse. 142 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. It has been seen that the increased charge of blood which an artery receives at the ventricular systole is accommodated partly by increased displacement of blood toward the capillaries, and partly by that increase in the capacity of the artery which is accompanied by the up-stroke of the pulse. The less the con- tents of the artery the less is the arterial pressure, the less the tension of the wall, and the more yielding is that wall. The more yielding the wall, the more of the increased charge of blood does the artery accommodate by an increase of capacity and the less by an increase of displacement. Therefore, a large pulse often accompanies a low mean pressure in the arteries, and hence may appear as a symptom after large losses of blood. In former days, when bloodletting was practised as a remedial measure, imperfect knowledge of the mechanics of the circulation sometimes caused life to be endangered ; for a "throbbing" pulse in a patient who had been bled already was liable to be taken as an "in- dication" for the letting of more blood. If this were done, an effect was combated by repeating its cause. 1 Celerity of Stroke. — When each up-stroke of the pulse appears to be slowly accomplished, requiring a relatively long interval of time, the pulse is called slow, or long. When each up-stroke appears to be quickly accom- plished, requiring a relatively short time, the pulse is called quick or short. These contrasted qualities are among the most obscure of those which the skilled touch is called upon to appreciate. The Pulse-trace. — The rise and fall of a pulsating human artery, if near enough to the skin, may be made to raise and lower the recording lever of a somewhat complicated instrument called a sphygmograph. 2 Of this instru- ment a number of varieties are in use. If the fine point of the lever be kept in contact with a piece of smoked paper which is in uniform motion, a "pulse- trace" or "pulse-curve" is inscribed, which shows successive fluctuations, larger and smaller, which tend to be rhythmically repeated, and which depend upon the movements of the arterial wall produced by the fluctuations of blood- pressure. In an animal, a manometer may be connected with the interior of an artery, and thus the fluctuations of the blood-pressure may be observed more directly. It has been explained (p. 90) that the mercurial manometer is of no value for the study of the finer characters of the pulse, owing to the inertia of the mercury. On the other hand, the best forms of elastic manometer give pulse-traces which are more reliable than those of the sphyg- mograph. This is because the sphygmographic trace is subject to unavoid- able errors dependent upon the physical qualities of the skin and other parts which intervene between the instrument and the cavity of the artery. Nevertheless, the sphygmographic pulse-trace, or " sphygmogram," is the only pulse-trace which can be obtained from the human subject; and, when obtained from an animal, it has so much in common with the trace recorded by the elastic manometer, that the sphygmograph has been much used for the Study of the human pulse, in health and disease, both by physiologists and by 1 Marshall Hall: Researches principally relative to the Morbid and Ourative Effects of Loss of Blood, London, 1830. 2 From a further accumulation more forcibly than friction resists the onward movement of the lymph. The little- known forces which continually produce fresh lymph, and pour it into the tissue-gaps against resistance, cannot be discussed here further than has been done in treating of the origin of the lymph (p. 71). Thoracic Aspiration. — The causes have already been stated fully of that low, perhaps negative, pressure in the veins at the root of the neck which ren- ders possible the continuous discharge of the lymph into the blood (p. 95). It need only be noted here that when inspiration rhythmically produces, or heightens, the suction of blood into the chest, it must also produce, or heighten, the suction of lymph out of the mouths of the thoracic and right lymphatic ducts. Moreover, as the thoracic duct lies with most of its length within the chest, each expansion of the chest must tend to expand the main part of the duct, and thus to suck into it lymph from the numerous lymphatics which join the duct from without the chest ; while the numerous valves in the duct must promptly check any tendency to regurgitation from the neck. The Bodily Movements and the Valves. — Like the flow of the blood in the veins, the flow of the lymph in its vessels is powerfully assisted by the pressure exerted upon the thin-walled lymphatics by the contractions of the skeletal muscles; for the very numerous valves of the lymphatics render it impossible for the lymph to be pressed along them by this means in any other than the physiological direction toward the venous system. Experiment show- that even passive bending and straightening of a limb in which the mus- cles remain relaxed, increases to a very great extent the discharge of lymph from a divided lymphatic vessel of that limb. It is probable, therefore, that movement in any external or internal part of the body, however pro- duced, tends to relieve the tension in the tissues by pressing the Lymph along its path. Conclusion. — The movement of the lymph produced in these various ways is doubtless irregular; but a substance in solution, injected into the blood, can be identified in the lymph collected from an opening in the thoracic dint at the neck in from four to seven minute-, after the injection. 1 The physiological importance of the Ivmph-movement Is shown not only by the large amount of matter which daily leaves the lymphatic system to join the blood, but also by the evil effects which result from an undue accumulation of lymph, more or less changed in character, in the gaps of the tissues. Such an accumulation constitutes dropsy. It may occur in a scroti- cavity or in the subcutaneous tissue; in the latter case giving rise to a peculiar swelling which "pit- on 1 S. Tschirwinsky : "Zur Frage iiber 'lie Schnelligkeil thai date, the reader may consult Tigerstedt's Lehrbueh der Physiolo- gic des Kreislaufes, 1S93. 3 Porter: Journal <>) Experimented Medicine, 1897, ii. p. 391. 'The literature of this subject has been collected by Heymansand Demoor: Archives (Beige) ./. Biologie, 1895, xiii. j>. 619. CIR CULA TION. 1 49 endocardium. Branches from these plexuses form :i third plexus in the myo- cardium or heart muscle, from which arise a vast number of non-medullated terminal nerves, enveloping the muscle-fibres and ending in small enlargements or nodosities of various forms. Similar ,% varicose " enlargements are observed along the course of the nerves. The nerve-endings are in contact with the naked muscle-substance, the mode of termination resembling in general that observed in non-striated muscle. Ganglion-cells are found chiefly in the auricular septum and the auriculo-ventricular furrow, but arc present also beneath the pericardium of the upper half of the ventricle. Xo ganglia have as yet been satisfactorily demonstrated within the apical half of the ventricle, 1 and most observers do not admit their presence within the ventricular muscle itself. The nerve-cells are unipolar, bipolar, or multipolar. Certain unipolar cells in the frog are distinguished by a spherical form, a pericellular network, and two processes — namely, the axis-cylinder or straight process, and the spiral process. The latter is wound in spiral fashion about the axis-cylinder, ending in the pericellular net. According to Retzius and others, the spiral is not really a process of the cell, but arises in a distant extra- cardiac cell and carries to the heart-cell a nervous impulse which is transmitted from the spiral process to the cell by means of the contact between the peri- cellular net and the cell-body. Section of the cardiac fibres of the vagus causes the spiral " process " and pericellular net to degenerate, the cell-body and axis-cylinder process remaining untouched, showing that the spiral process is the terminal of a nerve-fibre running in the vagus trunk. 2 Nerve-theory of Heart-beat. — The theory of the nervous origin of the heart-beat rests in part on the correspondence between the degree of contrac- tility of the various parts of the heart and the number of nerve-cells present in them. Thus the power of rhythmical contraction is greater in the auricle, in which there are many cells, than in the ventricle, in which there are fewer. The properties of the apical half, or "apex," of the ventricle are considered to be of especial importance in the study of this problem, because the apex, as has been said, is believed to contain no ganglion-cells. This part of the ven- tricle stops beating when separated from the heart, while the auricles and the ventricular stump continue to beat. The apex need not be cut away in order to isolate it. By ligating or squeezing the frog's ventricle across the middle with a pair of forceps the tissues at the junction of the upper and the lower half of the ventricle can be crushed to the point at which physiological con- nection is destroyed but physical continuity still preserved. Such frogs have been kept alive as long as six weeks. The apex does not as a rule beat again. The exceptions can be explained as the consequence of accidental stimulation. The conclusion drawn Is that the apex, in which ganglion-cells have not been satisfactorily demonstrated, has not the power of spontaneous pulsation which 'Schwartz: Archiv fur mikroskopiache Anatomie, 1899, liii. S. 63. Compare Dogiel : Ibid., S. 237. 2 Nikolajew: Archiv fur Physiologie, 1893, Suppl. Bd., S. 7.".. 150 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. distinguishes the remainder of the heart. This view is further supported by the observation thai a slight stimulus applied to the base of a resting ventricle will often provoke a series of contractions, while the same stimulus applied to th«' apex will cause but ;i single contraction. Much may be hoped from comparative studies. In the medusas, for ex- ample, the margin of the swimming bell, by the rhythmical contraction of which the animal is driven through the water, is provided with a double nerve-ring and ganglion-cells, while the centre contains only scattered and infrequent ganglion-cells. \i' the margin is separated from the centre and both arc placed in sea-water, only the pari containing many nerve-cells beats rhythmically. Loeb concludes that inasmuch as the whole medusa (Gonione- iiiiis) beats in sea-water in the rhythm of the margin, the failure of the iso- lated centre to beat in that medium can only be explained by the lack of nerve-cells. 1 The fact that the normal contraction begins in the sinus, Howell explains by the greater sensitiveness of that part to chemical stimulation. 2 The action of muscarin on the heart is often held to indicate the nervous origin of the heart-beat. Muscarin arrests the heart of the frog and other vertebrates, but has no similar action on any other muscle either striped or smooth, nor does it arrest the heart of insects and mollusks. It follows that muscarin does not cause arrest by acting directly upon the contractile material of the heart. The contractile material being excluded, the assumption of a nervous mechanism on the integrity of which the heart-beat depends seems necessary to explain the effect of the poison. Further arguments are based on uncertain analogies between the heart and other rhythmically contracting organs. Muscular Theory of Heart-beat? — The evidence just stated cannot be re- garded as proof of the nervous origin of the heart-beat. The most that can be claimed is that it makes such a conception plausible. The cause of the beat probably lies in the contractile substance rather than the nerve-cells. It is. at all events, certain that the cardiac muscle is capable of prolonged rhythmic contraction. It has been shown that a strip of muscle cut from the apex of the tortoise ventricle and suspended in a moist chamber begins in a few hours to beat apparently of its own accord with a regular but slow rhythm, which has been seen to continue as long as thirty hours. If the strip i- cut into pieces and placed on moistened glass slides, each piece will contract rhythmically. Vet in the apex of the heart no nerve-cells have been found. The apex of the batrachian heart will beat rhythmically in response to a constant stimulus. Thus if the apex is suspended in normal saline solution and a constant electrical current kept passing through it, beats will appear after a time, the frequency of pulsation increasing with the strength of the 1 Loeb: American Journal of Physiology, L900, iii. p. 383. » Howell: Ibid., ii. p. 47. 3 A valuable bibliography is given by Engelmann: Archiv fur die gesammte Physiologic, 1896, lxv. p. lO'.t; see also Ibid., p. 035. CIRCULATION. 151 current. 1 Very strong currents cause tonic contraction. An apex made inac- tive by Bernstein's crushing can be made to beat again by clamping the aorta and thus raising the endocardiac pressure. Chemical stimulation is also effec- tive. Delphinin, quinine, muscarin with atropin, atropin alone, morphin and various other alkaloids, dilute mineral acids, dilute alkalies, bile, sodium chloride, alcohol, and other bodies, 2 when painted on the resting ventricle, call forth a longer or shorter series of beats. Stimulation with induction shocks gives a similar result. Other muscles in which no nerve-cells have been discovered can contract rhythmically. Thus the bulbus aortse of the frog beats regularly after its removal from the body, even the smallest pieces showing under the microscope rhythmical contractions. Engelmann, who observed this fact, declares that the entire bulbus is lacking in nerve-cells. This is contradicted by Dogiel ; yet it seems hardly reasonable that these " smallest pieces " which Engelmann mentions were each provided with ganglion-cells. It is more probable that the contractions were the result of a constant artificial stimulus. Curarized stri- ated muscles placed in certain saline solutions may contract from time to time. The hearts of many invertebrates in which ganglion-cells are apparently absent beat rhythmically. Much has been made of the fact that the ganglion-cells grow into the heart long after the cardiac rhythm is established, showing that the embryonic heart muscle has rhythmic contractile powers. The adult heart muscle, it is alleged, retains certain embryonic peculiarities of structure, and as structure and func- tion are correlated, should also retain the embryonic power of contraction without nerve-cells. A positive demonstration that the nerve-cells in the heart are not essential to its contractions is secured by removing the tip of the ventricle of the dog's heart and supplying it with warm defibrinated blood through a cannula tied into its nutrient artery. Long-continued, rhythmical, spontaneous contrac- tions are thus obtained. 3 As the part removed contains no nerve-cells, the observed contractions can only arise in the muscular tissue, provided we make the (at present) safe assumption that the nerve-fibres d<> not originate im- pulses capable of inducing rhythmic muscular contractions. The demonstra- tion that the nerve-cells are not essential to contraction, places us one step nearer the true cause of contraction. It is some agency acting on the con- tractile substance. Evidence is accumulating that this agent is a chemical substance, or substances, brought to the contractile matter by the blood. For this chemical stimulation calcium is apparently essential, and for rhythmic contraction and relaxation Howell 4 finds a certain proportion of potassium 1 Langendorff: Archivfur die gesammte Physiologic, L895, Ixi. p. 33(5. 2 Kaiser: Zeitschnfi fur Biologic, L895, xxxii. p. (>. 3 Porter: Journal of Experimental Medicine, 1X97, ii. p. 391. * Howell : American Journal of Physiology, 1898, ii. p. 17; Loeb: Ibid., 1900, iii. p. 394. The reader is recommended to examine these BUggestive papers for himself. 152 AN AMERICAN TENT-BOOK OF PHYSIOLOGY. also accessary. Sodium chloride must bo present to preserve the osmotic equilibrium between contractile tissue and surrounding liquid. As phrased by Loci), it may be assumed that the sodium, calcium, and potassium ions must exist in definite proportions in the tissue which is expected to show rhythmical activity. Only so long as these proportions are preserved does the tissue possess such physical properties and such labile equilibrium as to be capable of rhythmical processes or contractions. The Excitation-wave. — The change in form which constitutes what com- monly is called the cardiac contraction is preceded by a change in electrical potential, supposed to be a manifestation of the unknown process by which the heart-muscle is excited to contract. Both the contraction and the electrical change sweep over the heart in the form of waves, and it has become the cus- tom to speak of the electrical change as the excitation-wave. It should not be forgotten, however, that this usage rests merely on an assumption, for the real nature of the excitation is still a mystery. The contraction-wave begins nor- mally at the great veins, travels rapidly through the auricle, and, after a dis- tinct interval, spreads through the ventricle. The excitation-wave, which pre- cedes and is the cause of the contraction, probably takes the same course, 1 and in fact it is possible to show that the change in electrical potential actually begins under normal conditions at the great veins and passes thence over the entire heart. But this sequence is not invariable. The ventricle under abnor- mal conditions has been seen to contract before the auricle, the normal sequence of great veins, auricle, and ventricle being reversed. 2 The energy of the ven- tricular muscle-cell may, therefore, be discharged by an excitation arising within the ventricle itself. Evidence of this is afforded also by the experi- ment of Wooldridge, who isolated the ventricles by drawing a silk ligature tightly about the auricles at their junction with the ventricles, completely crushing the muscle and nerves of the auricle in the track of the ligature with- out tearing through the more resistant pericardium. This experiment was repeated the following year by Tigerstedt, who devised a special clamp for crushiug the auricular tissues. Both observers found that the auricles and ventricles continued to beat. The rhythm, however, was no longer the same. The ventricular beat was slower than before and was independent of the brat of the auricle. Thus the ventricle, no longer connected physiologically with the auricle, develops a rhythm of its own, an idio-ventricular rhythm. It seems improbable that the very small part of the auricular tissue which cannot be included in Wooldridge's ligature for fear of closing the coronary arteries should be able to maintain the ventricular contractions. Independent contraction is said to be secured by properly regulated excita- tion of the cardiac end of the cut vagus nerve. Stimuli of one second duration applied to the vagus at intervals of six to seven seconds arrest the auricles completely, but do not stop the ventricles, except during the second of stimu- lation. The ventricles, now dissociated from the auricles, beat with a rhythm 1 Bottazzi : Lo sperimentale, 1 898, li. No. 2. 1 Recently studied by En^elmann : An hiv fur die gesammte Physiologic, 1895, lxi. p. 275. CIRCULATION. 153 different from that which characterized the normal heart. The force of this demonstration is somewhat weakened by the possibility that the auricles, although not beating themselves, might still excite the ventricles to contraction. Conduction of the Excitation. — If the points of non-polarizable electrodes are placed on the surface of the ventricle and connected with a delicate galvan- ometer, a variation of the galvanometer needle will be seen with each ventric- ular beat. If one electrode is placed near the base of the heart and the other near the apex it is seen that the former electrode becomes negative before the latter, indicating that the part of the heart muscle on which the basal electrode rests is stimulated before the apical portion, and that the difference in electrical potential, or excitation-wave, according to the prevailing hypothesis, travels as a wave over the ventricle from the base to the apex (see Fig. 27). Burdon- Sanderson and Page have found that the duration of the difference of poten- tial is about two seconds in the frog's heart at ordinary temperatures. Cooling lengthens the period of negativity, warming diminishes it. Some observers believe that the excitation-wave under certain conditions returns toward the base after having reached the apex. The speed of the excitation-wave has been measured by the interval between the appearance of negative variation in the ventricle when the auricle is stimulated first near and then as far as possible Fig. 27.— The electrical variation in the spontaneously contracting heart of the frog, recorded by a capillary electrometer, the apex being connected with the sulphuric acid ami the base with the mercury of the electrometer. The changes in electrical potential are shown by the line e, > , which is obtained by throwing the shadow of the mercury in the capillary <>n a travelling sheet of sensitized paper. The con traction of the heart is recorded by the line h, h : time, in „',, second, by I. t. The curves read from hit P. right. The electrical variation is diphasic; in the first phase the base is negative to the apex ; in the second, the apex is negative to the base; the negative variation passes as a wave from base to apex (Waller, 1887, p. 231). from the non-polarizable electrodes. The interval is the time which the excita- tion-wave requires to pass the distance between the two points stimulated. The average rate is at least 50 millimeters per second. 1 The negative variation begins apparently instantly ai'ter the application of the stimulus. Its phases and their characteristics have been described by Engelmann. The latent period of a frog's heart muscle is about 0.08 second. 1 Burdon-Sanderson and Page (Journal of Physiology, 1880, ii. j>. 4Jti i give 125 millimeters per second. 154 AX AMERICAN TEXT-BOOK OE PHYSIOEOGY. Although the normal course of the excitation-wave is from base to apex, it can be made to travel in any direction. If the frog's ventricle is cut with fine scissors into a number of pieces in such a way as to leave small bridges of heart-tissue between each piece, and any one of the pieces is stimulated, the contraction will begin in the stimulated piece and then run from piece to piece over the connecting bridges until all have successively contracted. The direc- tion in which the excitation-wave travels can thus be altered at the pleasure of the operator. Whether the excitation is propagated from mnscle-cell to muscle-cell or by means of nerve-fibres has given rise to much discussion. Anatomical evidence can be adduced on both sides. On the one hand the rich plexus of nerve- fibres everywhere present in the heart-muscle suggests conduction through nerves ; on the other is the intimate contact of neighboring muscle-cells over a part at least of their surface, thus bringing one mass of irritable protoplasm against another and offering a path by which the excitation might travel from cell to cell. If the excitation-wave were conducted by means of nerves, the difference between the moment of contraction of the ventricle when the auricle is stimu- lated near the ventricle, and again as far as possible from the ventricle, should be very slight, because of the great speed at which the nervous impulse travels (about 33 meters per second). If, on the contrary, the conduction were by means of muscle, the difference would be relatively much greater, correspond- ing to the much slower conductivity of muscular tissue. It has been found by Engelmann that the ventricle contracts later when the auricle is stimulated far from the ventricle than when it is stimulated near the ventricle. The rate of propagation being calculated from the difference in the time of ventricular con- traction was found to be 90 millimeters per second, which is about 300 times less than the rate which would have been obtained had conduction over the measured distance taken place through nerves. 1 Hence the stimulus that trav- els through the auricle to the ventricle and causes its contraction should be propagated in the auricle by muscle-fibres and not by nerves. It is possible to cut the ventricular muscle in a zigzag or spiral fashion that makes probable the severance of all the nerve-fibres in the line of the cut, and yet the contraction will pass from one end to the other of the isolated strip. 2 Passage of Excitation-wave from Auricle to Ventricle. — The normal con- ' traction of the heart begins, as has been said, at the junction of the great veins and the auricle, spreads rapidly over the auricle and, after a distinct pause, reaches the ventricle. The normal excitation-wave preceding the con- traction passes likewise from the auricle to the ventricle and is delayed at or 1 Engelmann : Archivfiir die gesammte Physiologie, 1896, lxii. p. 549. 2 I'urter: American Journal of Physiology, 1899, ii. p. 127. The co-ordination of the ven- tricles is discussed in this paper, and also by von Vintschgau : Archiv fur die gesammte Physi- ologie, 1899, lxxvi. p. 59. CIR CULA TION. 1 55 near the auricula- ventricular junction. The controversy over the nervous or muscular conduction of the excitation within the auricle and ventricle has been extended to its passage from auricle to ventricle. A path for conduction by nerves is presented by the numerous nerves which go from the auricle to the ventricle. It has been shown recently that muscular connections also exist. In the frog, muscle-bundles pass from the auricle to the ventricle where the auricular septum adjoins the base of the ventricle. Muscular bridges pass also from the sinus venosus to the auricles and from the ventricle to the bulbus arteriosus. 1 These muscle-fibres appear to be in intimate con- tact with the muscle-cells of the divisions of the heart which they unite. Gas- kell believes that the connecting fibres are morphologically and physiologically related to embryonic muscle, and therefore possess the power of contracting rhythmically. The delay experienced by the excitation in its passage from the auricle to the ventricle — in other words, the normal interval between the contraction of the auricle and the contraction of the ventricle — is explained by those favoring the nervous conduction as the delay which the excitation experiences in dis- charging the ganglion-cells of the ventricle, in accordance with the well-known hypotheses of the retardation of the nerve-impulse in sympathetic ganglia and the slow passage of the nervous impulse through spinal cells. The explanation given by those who believe in muscular conduction is that the small number of muscular fibres composing the bridge between auricle and ventricle acts as a " block " to the excitation-wave. If the auricle of the tortoise heart is cut into two pieces connected by a small bridge of auricular tissue, the stimulation of one piece will be followed immediately by the con- traction of that piece, and after an interval by the contraction of the other. The smaller the bridge, the longer the interval ; that is the longer the excita- tion-wave will be in passing from one piece to another. The duration of the pause or " block " in the frog has been found to be from 0.15 to 0.30 second. The length of the muscle-fibres connecting auricle and ventricle is about one millimeter. The speed of the excitation-wave in em- bryonic heart muscle is from 3.6 to 11.5 millimeters per second. The duration of the pause agrees, therefore, with the time which would be required for muscular conduction. 2 The extensive extirpations of the auricular nerves which have been made without stopping conduction from auricle to ventricle 8 — for example, the ex- tirpation of the entire auricular septum of the frog's heart — are of little importance to this question, since the great number of aerve-cells revealed by recent methods make it improbable that any extirpation short of total removal of both auricles could cut off all the nerve-cells of the auricle. It is possible to explain the occurrence of intermittent or irregular eon- 1 Engelmann: Archiv fur die geaammUe Physiologic, 1894, lvi. j>. 158. ' Engelmann : Tbid., p. 159. •Hofinann: Ibid., L895, lx. j>. 169. 156 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. tractions by alterations in the conductivity or irritability of the several parts of the heart successively traversed by the excitation wave. For example, a Lessening of the normal conductivity at the auriculo-ventricular junction might permit only every second sino-auricular impulse to reach the ventricle; in this ease the ventricle would drop every second beat. The same inter- mittence would result if the irritability ol* the ventricle were so far reduced that it could not respond to the normal excitation. 1 Engelmann has recently found that ventricular systole lowers the conductivity of the ventricle for a time. 2 Refractory Period and Compensatory Pause. — Schiff found in 1850 that the heart which contracted to each stimulus of a series of slowly repeated mechanical stimuli would not contract to the same stimuli if they followed each other in too rapid succession. Kronecker got a similar result with induction shucks. The heart contracted to every stimulus only when the interval between them was not too brief. The following year Marey published a systematic study of the phenomenon. He observed that the irritability of the heart sank during a part of the systole, but returned during the remainder of the systole and the following diastole. The stimulus which fell between the beginning of the systole and its maximum produced no extra contraction, whilst that which fell between the maximum of one systole and the beginning of the next called forth an extra contraction. During a part of the cardiac cycle therefore the heart is " refractory " toward stimuli. The irritability of the heart is removed for a time by an adequate stimulus. Kronecker and Marey noticed further that stimulation with the induction shock during the non-refractory period did not influence the total number of systoles. The extra systole called forth by the artificial stimulus was followed by a pause the length of which was that of the normal pause plus the interval between the appearance of the extra systole and what would have been the end of the cardiac cycle in which the extra systole fell. The extra length of this pause restored the normal frequency or rhythm. It was called the compensa- tory pause (see Fig. 28). 3 The systole following the extra contraction and its compensatory pause is of marked strength, at least in the surviving mammalian heart (cat). The weaker the extra systole the stronger the first subsequent contraction. The unusual force of this "compensatory systole" may serve to compensate the loss in the output of the heart incident to the disturbance in its rhthym. 4 If the heart, or the isolated apex, is beating at a rate so slow that an extra contraction falling in the interval between two normal contractions has time to complete its entire phase before the next normal contraction is due, there will be no compensatory pause. 5 1 Oehrwall: Skandinavisches Archiv fiir Physiologie, 1898, viii. p. 1. 2 Engelmann: Archiv fur geswnmte Plu/xiologie, 1896, Ixii. p. 543. ' ( lourtade: Archives de Physioloffie, 1897, p. 69. * Langendurfl": Archiv fiir >li> gr.mminti' f'ln/siolagie, 1898, lxx. p. 473. 5 Kaiser: Zeituclirifl fiir Biologic, 1895, xxxii. p. 449. CIRCULA TIOX. 1 57 The refractory phase disappears with sufficiently strong stimuli, especially if the heart is warmed. In such a case an artificial stimulus falling in the beginning of a spontaneous contraction produces an extra contraction. This extra contraction, however, comes first after the end of the systole during which the artificial stimulation is made, occurring in fact toward the end of the Fig. 28. — The refractory period and compensatory pause. The curves are recorded by a writing lever resting on the ventricle of the frog's heart. They read from left to right. A break in the horizontal line below each curve indicates the moment at which an induction shock was sent through the ventricle. In curves 1, 2, and :; the ventricle proved refractory to this stimulus; in the remaining curves, the stimulus having fallen outside t.he refractory period, an extra contraction and compensatory pause are seen. Many of the phenomena mentioned in the text are illustrated by this figure (Marey, 1876, p. 72 following diastole. The latent period of such a contraction Lengthens with the length of the interval between the artificial stimulation and the end of the systole. A refractory period has been demonstrated in the auricle of the frog 1 and dog; 2 in the ventricle of the cat, rabbit, and dog, and in the sinus venosus and bulbus arteriosusof the frog, h is said noi to be present in the lobster. 3 1 Engelmann: Archiv fitr die gescmmU Physiologic, 1894, li\. p. 322. 'Meyer: Archives de Physiologic, 1893, p. 185; Cushny and .Matthews: Journal of Physiology, 1897, xxi. p. 213. 8 Hunt, Bookman, and Tierney : Centrcdblatt fur Physiologic, 1897, \i. p. 276. 158 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. In some cases, the extra stimulus provokes not merely one, but two or three extra contractions. The amplitude of the extra contraction increases with the length of the interval between the maximum of contraction and the extra stimulus. If the extra stimulus is given at the beginning of relaxation, the extra contraction is exceedingly small ; on the other hand, the extra contraction may be greater than the primary one, when the stimulus falls in the pause between two normal beats. The supplementary systole of the auricle is sometimes followed by a sup- plementary systole and compensatory pause of the ventricle, sometimes by the compensatory pause alone, probably because the excitation wave reaches the ventricle during its refractory period. Multiple extra contractions of the auricle are often followed by the same number of extra contractions of the ventricle. If the frog's heart is made to beat in reversed order, ventricle first, auricle second, extra contractions of the ventricle may be produced, and will cause extra contractions of the auricle with compensatory pause. If the reversed excitation wave travelling from the ventricle to the auricle reaches the latter during auricular systole, the extra auricular contraction is omitted, but a distinct though shortened compensatory pause is still observed. The phenomena with reversed contraction are therefore similar to those seen under the usual conditions. 1 Kaiser finds in frogs poisoned with muscarin that stimulation of the ven- tricle during the refractory period causes the contraction in which the stimulus falls to be more complete, as shown by the contraction curve rising above its former level. He concludes that the ventricle is not wholly inexcitable even during the refractory period. The question whether the refractory state and compensatory pause are properties of the muscle-substance or of the nervous system of the heart has excited considerable attention. If the ganglion-free apex of the frog's ven- tricle is stimulated by rapidly repeated induction shocks it can be made to con- tract periodically for a time. By momentarily increasing the strength of any one induction shock an extra stimulus can be given from time to time. When the extra stimulus falls after the contraction maximum or during diastole an extra contraction results, otherwise not. The refractory period exists, there- fore, independently of the cardiac ganglia. The compensatory pause can also, though not always, be secured with the ganglion-free apex. 2 The refractory period has been used to show how a continuous stimulus might produce a rhythmic heart-beat. The continuous stimulus cannot affect the heart during tin; refractory period from the beginning to near the maxi- mum of systole. At the close of the refractory period the constant stimulus 1 Kaiser : Zeitschrift fur Biologic, L895, xxxii. p. 19. -Kaiser: Ibid., p. 449; for experiments on the embryo, see Pickering : Journal of Physi- ology, 1896, xx. j>. 165. CIRCULATION. 159 becomes effective, causing an extra contraction with long latent period. This latent period is, according to this theory, the interval between the first and the second contraction. A tonic contraction 1 of the heart muscle is sometimes produced by strong, rapidly repeated induction shocks and by various other means, such as filling the ventricle with old blood, by weak sodium hydrate solution, and by certain poisons, such as digitalin and veratrin. A. The Cardiac Nerves. The cardiac nerves are branches of the vagus and the sympathetic nerves. In the dog the vagus arises by about a dozen fine roots from the ventro- lateral aspect of the medulla and passes outward to the jugular foramen in company with the spinal accessory nerve. In the jugular canal the vagus bears a ganglion called the jugular ganglion. The spinal accessory nerve joins the vagus here, the spinal portion almost immediately leaving the vagus to be distributed to certain muscles in the neck, while the medullary portion passes to the heart through the trunk ganglion and thereafter in the substance of the vagus. Directly after emerging from the skull, the vagus presents a second ganglion, fusiform in shape and in a fairly large dog about one centi- meter in length. From the caudal end or middle of this " ganglion of the trunk " is given off the superior laryngeal nerve, slightly behind which a large nerve is seen passing from the sympathetic chain to the trunk of the vagus. This nerve is in reality the main cord of the sympathetic chain, the sympathetic nerve being bound up with the vagus from the " inferior" cervical ganglion to the point just mentioned. Posterior to the trunk ganglion of the vagus, the vago-sympathetic runs caudalward as a large nerve dorsal to the common carotid artery as far as the first rib or near it, where it enters the so-called inferior cervical ganglion. This ganglion belongs to the sympathetic system and not to the vagus; from a morphological point < if view it is the middle cervical sympathetic ganglion. The true inferior cervical sympathetic ganglion is fused with the first one or two thoracic ganglia to form the gan- glion stellatum, situated opposite the first intercostal space. At the " inferior cervical" ganglion the vagus and the sympathetic part company, the vagus passing caudalward behind the root of the lung and the sympathetic passing to the stellate ganglion, dividing on its way into two portions (the annulus of Yieussens), which embrace the subclavian artery. In many cases the lower loop of the annulus of Vieussens joins the trunk of the vagus caudal to the ganglion. The cardiac nerves spring from the vagus and the sympathetic nerve in the region of the inferior cervical ganglion. They may lie divided into an inner and an outer group. The inner group is composed of one medium, one thick, and two or three slender nerves. The nerve of medium thickness springs fr the gan- 1 Hunt, Bookman, and Tierney: CeniraJblait fur Physiologic, 1897, xi. p. 274. 100 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. glion itself. The thick branch rises from the trunk of the vagus near the origin of* the inferior laryngeal nerve about 1.25 centimeters caudal to the inferior cervical ganglion. It can be easily followed to its final distribution. It passes behind the vena cava superior, perforates the pericardium, and runs parallel with the ascending aorta across the pulmonary artery, on which it lies in the connective tissue already divided into two or three tolerably thick twigs or spread in a fan of smaller branches. These now bend beneath the artery, pass round its base on the inner side, and reach the anterior inter-ventricular groove. Here they spread over the surface of the ventricle. The slender branches leave the vagus trunk caudal to the branch just described. The outer group comprises two thick branches — namely, an upper nerve, springing from the ganglion or from the trunk of the vagus near it, and a lower nerve, from the lower loop of the annulus, or from the vagus 1-1 £ centimeters lower down. Each of these thick branches may be replaced by a bundle of finer branches, and in fact the description of the cardiac nerves here given can be regarded as a close approximation only, so frequent are the individual variations. 1 In the rabbit the cervical sympathetic and the vagus trunk are not joined, as in the dog, but run a separate course. Cardiac fibres from the spinal cord reach the lower cervical and first thoracic ganglion (ganglion stellatum) along their rami eommunicantes and pass to the heart by two sympathetic cardiac nerves, one from the interior cervical ganglion and one from the ganglion stellatum. The arrangement of the cardiac nerves in the cat is shown in Figure 29. In the frog the cardiac nerves, both vagal and sympathetic, reach the heart through the splanchnic branch of the vagus. The sympathetic fibres pass out of the spinal cord with the third spinal nerve, through the ramus comniunicans of this nerve into the third sympathetic ganglion, 2 up the sympathetic chain to the ganglion of the vagus, and down the vagus trunk to the heart. 1 Details concerning the composition of the cardiac plexuses in the dog are given by Lim Boon Keng: Journal of Physiology, 1893, xiv. p. 467. ' It is probable that the fibres of spinal origin end in the sympathetic ganglia, making con- tacta there with sympathetic ganglion cells, the axis-cylinder processes of which pass up the cervical chain and descend to the heart in company with the vagus. -;-' l Fig. 29.— Cardiac plexus and stellate ganglion of the cat, drawn from nature after the removal of the arteries and veins ; about one and one-half times natural size (Boehm, 1875, p. 258): R, right; /..left: 1,1, vagus nerve; 2, cervical sympathetic ; 2', annulus of Vieussens ; 2", thoracic sympathetic; 3, recurrent laryngeal nerve; 4, de- pressor nerve, entering the vagus on the right, on the left running a separate course to the heart ; 5, middle (often called "inferior") cervical gan- glion ; 5', communicating branch between middle cervical ganglion and vagus nerve; 6, stellate gan- glion; (I', 6" 6'", spinal roots of stellate ganglion; 7, communication between stellate ganglion and vagus ; 8', 8", 8'", cardiac nerves. CIRCULATION. 161 The connection of the extrinsic cardiac nerves with the intracardiac mus- cle and nerve-cells is not yet determined satisfactorily. ( lertain fibres in the vagus, said to be derived from the spinal accessory nerve, terminate in " end- baskets" embracing sympathetic ganglion-cells, the axis-cylinder processes of which end on the cardiac muscle-fibres. Probably the inhibitory action of the vagus is exercised through these cells, as it is lost in animals poisoned with nicotine, which is known to paralyze, in other situations, either the end- baskets about sympathetic cells or the body of the cell itself. Other vagus fibres apparently terminate (or arise) in an end-brush in the pericardium and endocardium. The augmentor apparatus consists of two, possibly three, neurons. The cell-body of one lies in the spinal cord ; its axis-cylinder process leaves the cord in the white ramus and terminates in a ganglion of the sympathetic chain (inferior cervical, stellate ganglion). The axis-cylinder process of the sympa- thetic ganglion-cell passes directly to the cardiac muscle-fibre on which it ends, or, possibly, terminates in physiological contact with the dendrites of a third neuron lying in the heart, the neuraxon of which carries the augment- ing impulse to the muscle-cell. Stimulation of the white ramus causes aug- mentor effects. In nicotine-poisoning, these effects cannot be obtained ; but stimulation on the distal side — the cardiac side — of the cell-body about which the neuraxon ends, still causes augmentation. If nicotine paralyzes the sympathetic cell-body, this experiment proves that there is no cell in this neuron chain between the point stimulated and the muscle-fibre ; if it par- alyzes the end-basket and not the cell-body, the existence of the third (intra- cardiac) neuron in the chain is possible, provided the communication between the second and the third neuron is not by means of an end-basket ; but, as Dogiel and Huber assume, by a contact with the dendrites, similar to that observed by them in other sympathetic cells, and not sensitive to nicotine. The Inhibitory Nerves. In 1845, Ernst Heinrich and Eduard Weber announced that stimulation of the vagus nerves or the parts of the brain where they arise slows the heart even to arrest. When one pole of an induction apparatus was placed in the nasal cavity of a frog and the other on the spinal cord at the fourth or fifth vertebra, the heart was completely arrested after one or two pulsations and remained motionless several seconds after the interruption of the current. During the arrest, the heart was relaxed and filled gradually with blood. When the stimulus was continued many seconds, the heart began to beat again, at first weakly and with long intervals, then more strongly and frequently, until at length the beats were as vigorous and as frequent as before, though all this time the stimulation was uninterrupted. In order to determine from what part of the brain this influence proceed-, the electrodes were brought very near together and placed upon the cerebral hemispheres. The movements of the hear! were not affected. Negative results followed also the stimulation of the spinal cord. Not until the medulla oblon- VOL. I.— 11 162 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY gata between the corpora quadrigernina and the lower end of the calamus scrip- torius was stimulated did the arrest take place. Cutting away the spinal cord and the remainder of the brain did not alter the result. Having determined that the inhibitory power had its seat in the medulla oblongata, the question arose through what nerve the inhibitory influence is transmitted to the heart. In a frog in which the stimulation of the medulla had stopped the heart, the vagus nerves were cut and the ends in connection with the heart stimulated. The heart was arrested as before. Thus the fundamental fact of the inhibition of a peripheral motor mechan- ism by the central nervous system through the agency of special inhibitory Fig. 30.— Pulsations of frog's heart, inhibited by the excitation of the left vagus nerve (Tarchanoff, 1876, p. 296): C, pulsations of heart ; 6, electric signal which vibrated during the passage of the stimu- lating current, one vibration for each induction shock. nerves was firmly established. A great number of investigations have demon- strated that this inhibitory power is found in many if not all vertebrates and not a few invertebrates. The effect of vagus stimulation on the heart is not immediate ; a latent period is seen extending over one beat and sometimes two, according to the moment of stimulation (see Fig. 30). Fig. 31.— Showing the lengthened diastole and diminished force of ventricular contraction during weak stimulation of the peripheral end of the cut vagus nerve. The heart (cat) was isolated from both Bystemic and pulmonary vessels, and was kept beating by circulating defibrinated blood through the coronary arteries : A, Pressure in lefl ventricle, which was filled with normal saline solution, and com- municated with a Bilrthle membrane manometer by means of a cannula which was passed through the auricular appendix and the mitral orifice; B, line drawn by the armature of an electro-magnet in the primary circuit ; the heavy line indicates the duration <>f stimulation ; C, time in seconds. Changes in the Ventricle. — The periodicity of the ventricular contraction is altered by vagus excitation, a weak excitation lengthening the duration of dias- tole, while leaving the duration of systole unchanged (see Fig. 31). A stronger excitation, capably of modifying largely the force of the contraction, Lengthens both Bystole and diastole. 1 The difficulty of producing a continued 'Meyer: Archives de Phy$iologie, 1894, p. 698; Arloinij: Ibid., p. 88. CIR C ULA TIOX. 1 63 arrest in diastole is much greater in some animals than in others. Even when easily produced, the arrest soon gives away in the manner described by E. H. and E. Weber, the heart beginning to beat in spite of the vagus excitation. 1 The force of the contraction, measured by the height of the up-stroke of the intra-ventricular pressure curve, or by placing a recording lever on the heart, is lessened, this diminution in force appearing often before any noticeable change in periodicity. The diastolic pressure increases, as is shown by the lower level of the curve gradually rising farther and farther above the atmospheric pressure line. The volume of blood in the ventricle at the close of diastole is increased. So also is the volume at the close of systole (residual blood) — sometimes to such a degree that the volume of the heart at the end of systole may be greater than the volume of the organ at the end of diastole before the vagus was excited. The output and the input of the ventricle, that is, the quantity of blood dis- charged and received, are both diminished by vagus excitation. The ventricular tonus, or state of constant slight contraction on which the systolic contractions are superimposed, is also diminished, as is well shown by an experiment of Stefani. 2 In this experiment the pericardial sac is filled with normal saline solution under a pressure just sufficient to prevent the expansion of the heart in diastole. On stimulation of the vagus, the heart dilates fur- ther. A considerably higher pressure is necessary to overcome this dilatation. Stefani finds also that the pressure necessary to prevent diastolic expansion is much greater with intact than with cut vagi. Furthermore, the heart is much more easily distended by the rise of arterial pressure through compression of the aorta when the vagi are severed than when they are intact. Franck has noticed that the walls of the empty ventricle become softer when the vagus is stimulated. 3 The propagation of the cardiac excitation is more difficult during vagus excitation. JBayliss and Starling demonstrate this on mammalian hearts made to contract by exciting the auricle three or four times per second ; the ven- tricle as a rule responds regularly to every auricular beat. If, then, the vagus is stimulated with a weak induced current, the ventricle may drop every other beat, or may for a short time cease to respond at all to the auricular contrac- tions. The defective propagation is not due to changes in the auricular con- traction, for even an almost inappreciable beat of the auricle can cause the ventricle to contract. Nor is it due to lowered excitability of the ventricle, for the effect described is seen with currents too weak to depress the irrita- bility of the ventricle to an appreciable extent. The sino-auricular and auriculo-ventricular contraction intervals arc usu- ally lengthened by vagus excitation ; sometimes, however, they are dimin- 1 Hough: Journal of Physiology, 1895, xviii. p. Kit. The terrapin heart is said not t<> es- cape, as a rule, from vagus inhibition. 2 Compare Stefani : Archives italiennes de Biologie, 1895, sxiii. p. 175. 3 .See also Fischel : Archiv fur experimentelk Palhologie und Pharmakologie, L897, \\\\iii. p. 228. l»;l AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. ished ; the one may be increased, while the other is diminished. The vagus effect quickly reaches a maximum and then slowly decreases. The interval between the contractions of different parts of the sinus is sometimes increased by vagus excitation, so that the different parts are dissociated and heat at measurably different times. Attempts have been made to explain the sev- eral actions of the vagus nerve, together with the various forms of intermit- tent ami irregular pulse, by variations in the transmission of the cardiac ex- citation ; ' hut it is probable that alterations in the condition of the muscle-cells in the sinus, auricle, and ventricle are of equal or greater importance. 2 The action of the vagus is accompanied by an electrical variation. This has been shown in the muscular tissue of the resting auricle of the tortoise (see Fig. 32). The auricle is cut away from the sinus without injuring the coronary nerve, which in the tortoise passes from the sinus to the auricle and contains the cardiac fibres of the vagus. After this operation the auricle and ventricle remain motionless for a time, and this quiescent period is utilized for the experiment. The tip of the auricle is injured by immersion in hot water, and the demarcation current (the injured tissue being negative toward the unin- jured) is led off to a galvanometer. On exciting the vagus in the neck, the demarcation current is markedly increased. No visible change of form is seen in the auricular strip. Fig. 32.— The tortoise heart prepared for the demonstration of the electrical change in the cardiac muscle accompanying the excitation of the vagus nerve: t', vagus nerve; C, coronary nerve; S, sinus and part of auricle in connection with it ; (7, galvanometer, in the circuit formed by two uon-polarizable electrodes and the part of the auricle between them ; /■-', induction coil (Gaskell, 1887). Changes in the Sinus and Auricle. — There is little probability that the action of the vagus on the sinus and auricle, or greal veins, 3 differs essentially from the action on the ventricle. The force of the contraction is diminished. 1 Muskens: American Journal of Phygiolor/t/, 1 898, i. p. 486. - Bofmann : Archivfur 'lit <\,~• Physiologie, L894, p. 10. 3 Kouget: I hid., p. 398. * Arloing: Ibid., L893, y. 112. 5 Frank : Zeitschrift fur Biologie, 1899, xxxviii. 6 Hunt, Bookman, ami Tierney: Centralblatt fur Physiologie, 1897, xi. p. 274. 7 Walther : Archivfur die gesammte Physiologie, 1900, lxxviii. p. 597. L66 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Comparative Inhibitory Power. — One vagus often possesses more inhibi- tory power than the other. 1 Septal Nerves in Frog. — The electrical stimulation of the peripheral stump of either of two large nerves of the inter-auricular septum in the frog alters the tonus and the force of contraction of the ventricle, but not the fre- quency. After section of these nerves, the excitation of the vagus has very little effect on the tonus, and almost none on the force of the ventricular beat, while the frequency is diminished in the characteristic manner. Evidently, therefore, the two large septal nerves take no part in the regulation of fre- quency, but leave this to the nerves diffusely distributed through the auricles. There i< then an anatomical division of the septal branches of the frog's vagus, the fibres affecting periodicity running outside the septal nerves, while those uaodifying the force of contraction and thetonusof the ventricle run within them. 2 Nature of Vagns Influence on Heart. — The nature of the terminal apparatus by which the vagus inhibits the heart is unknown. It is probable that the same intracardiac apparatus serves for both nerves, for Hurler finds that when the heart escapes from the inhibition caused by continued stimula- tion of one vagus, the prolonged diastole growing shorter again, the immediate stimulation of the second vagus has no effect upon the heart. 3 Dogiel and Grahe have recently observed that the lengthening of diastole which follows stimulation of the peripheral stump of the vagus, the other vagus being intact, is less marked than when both vagi are cut. 4 The earlier attempts to form a satisfactory theory for the inhibitory power of the vagus met with little success. The statement of the Webers' that the vagus inhibits the movements of the heart gave to nerves a new attribute, but is hardly an explanation. The view of Budge and Schiff, that the vagus is the motor nerve of the heart and that inhibition is the expression of its exhaustion, is now of only historical iutere.-t. Nor has a better fate overtaken the theory of Brown-Sequard, who saw in the vagus the vaso-motor nerve of the heart, the stimulation of which, by narrowing the coronary arteries, deprived the heart of the blood that, according to Brown-Sequard, is the exciting cause of the contraction. Of recent years, the explanation that has commanded most attention is the one advanced by Stefan i '' andGaskell, namely, that the vagus is the trophic nerve of the heart, producing a dis-assimilation or katabolism in systole and an as-imilation or anabolism in diastole. Gaskell supports this theory by the observation that the after-effect of vagus excitation is to strengthen the force of the cardiac contraction and to increase the speed with which the excitation 1 Ilofinann: Archie fiir die gegammte Physiologic, 1895, lx. p. 169. 3 For other unusual alterations in the heart-beat in consequence of vagus excitation see Arloing: Archives <{■• I'fui.tioloijie, 18U4, p. lti:;; and Knoll: Archil) fiir die gesammte Physiologic, 1897, Ixvii. p. 587. 3 Hough Journal of Physiology, 1895, xviii. p. 198. * Dogiel and Grahe: Archiv fur Physiologie, 1895, p. 393. Changes in the peripheral effi- ciency of the vagi are discussed by McWilliams : Proceedings Royal Society, 1893, liii. p. 475. 5 Stefani : Archives italiennesde Biologie, 1895, xxiii. p. 17G. CIR CULA TION. 167 wave passes over the heart, while the contrary effects are witnessed after the excitation of the augmentor nerves. Various attempts have been made to prove a trophic action of the vagus on the heart by cutting the nerve in animals kept alive until degenerative changes in the heart-muscle should have had time to appear. The important distribu- tion of the vagus nerve to many organs, and the consequently wide extent of the loss of function following its section, makes it difficult to decide whether the changes produced in the heart are not secondary to the alterations in other tis- sues. The work of Fantino will serve for an example of these investigations. Fantino cut a single vagus to avoid the paralysis of deglutition and the inani- tion and occasional broncho-pneumonia that follow section of both nerves. Young and perfectly healthy rabbits and guinea-pigs were selected. The opera- tion was strictly aseptic, and all cases in which the wound suppurated were excluded. A piece of the nerve about one centimeter long was cut out, so that no reunion could be possible. After the operation the animals were as a rule lively, ate well, and gained weight. Post-mortem examination of animals killed two days or more after section of the vagus nerve disclosed no patho- logical changes in the lungs, spleen, liver, and stomach. In the heart, areas were found in which the nuclei and the striation of the muscle-cells had disap- peared. Eighteen days after section the atrophy of the cardiac muscle in these areas was observed to be extreme. The degenerations following section of the right vagus were situated in a different part of the ventricular wall from those following; section of the left nerve. The effects of stimulation of the vagus nerve in the new-born do not differ essentially from those seen in the adult. 1 The relation between the action of the vagus and (lie intracardiac pressure has been recently studied by Stewart. He finds that an increase in the pressure in the sinus or auricle makes it difficult to inhibit the heart through the vagus. The inhibitory action of the vagus diminishes as the temperature of the heart falls. At a low limit the inhibitory power is lost, but may return when the heart is warmed again. Even when the stimulation of the trunk of the nerve has failed to affect the cooled heart, the direct stimulation of the sinus can still cause distinct inhibition. The power of inhibiting the ventricle is first lost. Loss of inhibitory power does not follow the raising of the heart to high temperatures. The vagus remains active to the verge of heat arrest, mid resumes it.^ power as soon ;is the temperature is lowered. The Augmentor Nerves. v. Bezold observed in 1862 that stimulation of the cervical spinal cord caused an increased frequency of heart-beat. This seemed to him to prove the existence of special accelerating nerves. Ludwig and Thiry, however, soon pointed out that stimulation of the spinal cord in the cervical region excited many vaso-constrictor fibres, leading to the narrowing of many vessels and a corresponding rise of blood-pressure. The acceleration of the heart-beal 'Meyer: A rehire* tie Phyaiolngie, 1893, p. 477. 168 AN AMERICAN TEXT- HOOK OF PHYSIOLOGY. accompanying this rise in blood-pressure would alone explain the observation of von Bezold. Three years later Bever and von Bezold were more suc- cessful. The influence of the vaso-motor nerves was excluded by section of the spinal cord between the first and second thoracic vertebrae. Stimulation of the cervical cord now caused an increase in the frequency of the heart-beat without a simultaneous increase of blood-pressure. The fibres carrying the accelerating impulse were traced from the spinal cord to the last cervical gan- glioD and from there toward the heart. In the dog the " augmenting " or " accelerating " nerves thus discovered leave the spinal cord mainly by the roots of the second dorsal nerves, and enter the ganglion stellatum, whence they pass through the anterior and posterior loops of the annulus of Vieussens into the inferior cervical ganglion, from which they go, in the cardiac branches of the latter, to the heart. Some of the cardiac fibres in the annulus pass directly thence to the cardiac plexus and do not enter the inferior cervical ganglion. In the rabbit, the course of the augmentor fibres is probably closely similar to that in the dog. In the cat, the augmentor nerves spring from the ganglion stellatum, and very rarely from the inferior cervical ganglion as well. The right cardiac sympathetic nerve communicates with the vagus. The stimulation of the sympathetic chain in the frog, " between ganglion 1 and the vagus ganglion, and also stimulation of the chain between ganglia 2 and 3, causes marked acceleration and augmentation of the auricular and ven- tricular contractions. Stimulation be- tween ganglia 3 and 4 produces no effect whatever upon the heart." This ex- periment of Gaskell and Gadow's shows that augmentor fibres enter the sympa- thetic from the spinal cord along the ramus communicans of the third spinal nerve and pass upward in the sympa- thetic chain. In this animal the sym- pathetic chain, after dividing between the first and second ganglia to form the annulus of Vieussens, joins the trunk of the vagus between the united vagus and glosso-pharyngeal ganglia and the vertebral column (see Fig. 33). Here the sympathetic again divides, some of the fibre- passing alongside the vagus into the cranial cavity, the rest accompany- in- the vagus nerve peripherally. The augmentor nerve- for the heart are amonar the latter, for the stimulation of the intracranial vagus results in pure inhibition, while the stimulation of the vagus trunk after it is joined by the sympathetic may give either inhibition or augmentation. We may say. there- fore, that the augmentor nerves of the frog pass out of the spinal cord by the V-Sy Fig. 33.— The cardiac sympathetic nervt- in Rana temporalis (twice natural size): V-Sy, mpathetic; A.v, arteria vertebralis; II, TV, second and fourth spinal nerves (.Gaskell ami Oa.low, lsMj. CIRCULATION. 169 third spinal nerve, through the ramus communicans of this nerve, into the third sympathetic ganglion, up the sympathetic chain to the ganglion of the vagus, and down the vagus trunk to the heart. Stimulation of Augrnentor Nerves. — The most obvious effect of the stim- ulation of the augrnentor nerves is an increase of from 7 to 70 per cent, in the frequency of the heart-beat (see Fig. 34). The quicker the heart is beating before the stimulation, the less marked is the acceleration. The absolute maxi- Fig. 34.— Curve of blood-pressure in the cat, recorded by a mercury manometer, showing the increase in frequency of heart-beat from excitation of the augrnentor nerves. The curve reads from right to left. The augrnentor nerves were excited during thirty seconds, between the two stars. The number of beats per ten seconds rose from 24 to 33 (Boehm, 1875, p. 258). mum of frequency is, however, independent of the frequency before stimulation. The maximum of acceleration is largely independent of the duration of stimula- tion. The duration of stimulation and the duration of acceleration are not related, a long stimulation causing no greater acceleration than a short one. The force of the ventricular beat is increased. The ventricle is filled more completely by the auricles, the volume of the ventricle being increased. The JSrcJfJV.yice.y Fig. 35.— Increase in the force of the ventricular contraction (curve of pressure in right ventricle) from stimulation of augrnentor fibres. There is little or no change in frequency (Franck, 1890, p. 819). output of the heart is raised. There is no definite relation between the in- crease of contraction volume or force of contraction and the increase in fre- quency (see Fig. 35). Either may appear without the other, though this is rare. The simultaneous stimulation of the nerves of both sides does not give a greater maximum frequency than the stimulation of one nerve alone. The strength and the volume of the auricular contractions are also in- creased. The increase in volume is not due to a rise of pressure in the veins — in fact, the pressure falls in the veins — but to a change in the elasticity of the relaxed auricle, a lowering of its tonus. This change is not related to the increase in the force of the auricular contractions that stimulation of the aug- rnentor nerves also causes. It varies much in amount and i- less constantly met with than the change in force. The changes in the ventricle and auricle 170 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. probably account for the rise of blood-pressure in the systemic arteries and the fall in both systemic and pulmonary veins observed by Roy and Adami. The speed of the cardiac excitation waive is increased. Its passage across the auriculo-ventricular groove is also quickened, as is shown in the following experiment of Bayliss and Starling. In the dog, the artificial excitation of the ventricle may cause the excitation wave; to travel in a reverse direction, namely, from ventricle to auricle. If the ventricles are excited rhythmically and the rate of excitation is gradually increased, a limit will be reached beyond which the auricle no longer beats in response to every ventricular contraction. With intact vagi, a rate of 3 per second is generally the limit. If now the augmentor nerve is stimulated, the "block" is partially removed, and the auricle beats during and for a short time after the stimulation at the same rapid rate as the ventricle. The Intent period of the excitation is long. In the dog, about two seconds pass between the beginning of stimulation and the* beginning of acceleration, and ten seconds may pass before the maximum acceleration is reached. The after-effect may continue two minutes or more. It consists of a weakening of the contractions and an increase in the difficulty with which the excitation wave passes from the auricle to the ventricle. The return to the former fre- quency is more rapid after short than after long stimulations. The effect upon the heart-rate of simultaneous stimulation of the vagi and accelerator nerves, according to Hunt, is determined by the relative strength of the two stimulating currents. For sub-maximal stimuli the result for both systole and diastole is approximately the arithmetical mean of the re- sults of stimulating the two nerves .separately.' The acceleration that is seen after the stimulation of the vagus is due to the after-effect of the stimulation of accelerating fibres in the vagus. The simultaneous stimulation of the augmentors and the vagi, the strength of the current being sufficient to stop the auricular contractions, causes accel- eration of the ventricular contractions. The acceleration of the heart may be more or less intermittent, although the excitation of the augmentor nerves continues. It is probable that this is due to irradiation from the bulbar respiratory centre. 2 Other Centrifugal Heart-nerves. In the vago-sym pathetic trunk and the annulus of Vieussens fibres pass to the heart that cannot he classed either with the vagus or the augmentor nerves. The evidence for their existence is furnished by Hoy and Adami's observation that when the intracardiac vagus mechanism is acting strongly, so that the auricles are more or less completely arrested, the stimulation of the vago- sympathetic trunk sometimes causes a decided increase in the force both of the ventricles and the auricles, usually accompanied by an acceleration of the rhythm of the heart. These changes are too rapidly produced to be aug- mentor effects. 1 I I nut : Aini'rinni Journal of l'lii/xio!one, 1 liering: Archiv fur die gesammte Physiologic 1894, Ivii. p, 78. 172 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. cut across, and the cut end raised on a thread in the air, is without effect on the blood-pressure and pulse-rate. The stimulation of the central stumps of these nerves, <>n the contrary, is followed by changes both in the blood-pressure and the pulse, showing that they carry impulses from the heart to the cardiac (•(litres in the central nervous system, or perhaps, according to the views of some recent investigators, to peripheral ganglia, thus modifying the action of the heart reflex ly. Sensory Nerves of the Heart. — The stimulation of intracardiac nerves l>y the application of acids and other chemical agents to the surface of the heart causes various reflex actions, such as movements of the limbs. The afferent nerves in these reflexes are the vagi, for the reflex movements dis- appear when the vagi are cut. On the strength of these experiments the vagus has been believed to carry sensory impressions from the heart to the brain. Direct stimulation of the human heart, in cases in which a defect in the chest-wall has made the organ accessible, give evidence of a dim and very limited recognition of cardiac events — for example, the compression of the heart. Changes in the force, periodicity, and conduction of the contraction- wave may be produced by direct electrical stimulation of the ventricle. The centre of these reflexes probably lies in the bulb. 1 Vagus. — The stimulation of the central end of the cut vagus nerve, 2 the other vagus being intact, causes a slowing of the pulse-rate. The section of the second vagus causes this retardation of the pulse to disappear, indicating that the stimulation of the central end of the one affects the heart reflexly through the agency of the other vagus. The blood-pressure is simultaneously affected, being sometimes lowered and sometimes raised, the difference seeming to depend largely on the varying composition of the vagus in different ani- mals and in different individuals of the same species. The stimulation of the pulmonary branches, by gently forcing air into the lungs, loud speaking, singing, etc., is said to increase the frequency of the heart-beat. Yet the chemical stimulation of the mucous membrane of the lungs is alleged to slow the pulse- rate and lower the blood-pressure. Observers differ as to the results of stim- ulation of the central end of the laryngeal branches of the vagus on the pulse- rate and blood-pressure. Depressor Nerve. — The earlier stimulations of the nerves that pass betweeD the central nervous system and the heart, with the exception of the vagus, altered neither the blood-pressure nor the pulse-rate. Ludwig and Cyon suspected that the negative results were owing to the fact that the stimulations were confined to the end of the cut nerve in connection with the heart. Some of the nerves, they thought, should carry impulses from the heart to the brain, and such nerves could be found only by stimulation of the brain end of the cut nerve. They began their research for these afferent nerves with the branch which springs from the rabbit's vagus high in the neck and passes downward to the ganglion stellatum. Their suspicion was at once confirmed. The stimu- 1 Muskens: Archivfur die gesammte Physiologie, 1897, lxvi. p. 328. -Jlmit: Journal of Physiology, 1895, xviii. p. 381. CIRCULA TION. 1 73 lation of the central end of this nerve, called by Ludwig and Cyon the depres- sor, caused a considerable fall of the blood-pressure. The depressor nerve arises in the rabbit by two roots, one of which comes from the trunk of the vagus itself, the other from a branch of the vagus, the superior laryngeal nerve. Frequently the origin is single ; in that case it is usually from the nervus laryngeus. 1 The nervus depressor runs in company with the sympathetic nerve to the chest, where communications are made with the branches of the ganglion stellatum. The stimulation of the peripheral end of the depressor nerve is without effect on the blood-pressure and heart-beat. The stimulation of the central end, on the contrary, causes a gradual fall of the general blood-pressure to the half or the third of its former height. After the stimulation is stopped, the blood-pressure returns gradually to its previous level. Simultaneously with the fall in blood-pressure a lessening of the pulse-rate sets in. The slowing is most marked at the beginning of stimulation, and after rapidly reaching its maximum gives way gradually until the rate is almost what it was before the stimulation began. After stimulation the frequency is commonly greater than previous to stimulation. After section of both vagi, the stimulation of the depressor causes no change in the pulse-rate, but the blood-pressure falls as usual. The alteration in fre- quency is therefore brought about through stimulation of the cardiac inhibitory centre, acting on the heart through the vagi. The experiment teaches, further, that the alteration in pressure is not dependent on the integrity of the vagi. Poisoning with curare paralyzes all motor mechanisms except the heart and the muscles of the blood-vessels. Yet curare-poisoning does not affect the result of depressor stimulation. The cause of the fall in blood-pressure must be sought then either in the heart or the reflex dilatation of the blood-vessels. It cannot be in the heart, for depressor stimulation lowers the blood-pressure after all the nerves going to the heart have been severed. It must therefore lie in the blood-vessels. Ludwig and Cyon knew that the dilatation of the intestinal vessels could produce a great fall in the blood-pressure and turned at once to them. Section of the splanchnic nerve caused a dilata- tion of the abdominal vessels and a fall in the blood-pressure. Stimula- tion of the peripheral end of the cut splanchnic caused the blood-pressure to rise even beyond its former height. Ludwig and Cyon reasoned that if the depressor lowers the blood-pressure el. icily by affecting the splanchnic uerve lvllexlv, the stimulation of the central end of the depressor after section of the splanchnic nerves ought to have little effeel on the blood-pressure. This proved to be the case. The investigators concluded thai the depressor re- duces the blood-pressure chiefly by lessening the tonus of the vessels governed by the splanchnic nerve, thus allowing their dilatation and in consequence lessening the peripheral resistance. The fallacy in this argument has re- cently been pointed out l>v Porter and Beyer. 2 The stimulation of the >\<'- 1 Tseliirwinsky : Centralblatt fur Physiologie, 1896, i\. \< 778, gives :> somewhat different account. * Porter and Beyer: American Journal of Physiology, L900, \\iii. 174 AN AMERICAN TEXT- BO OK OF PHYSIOLOGY. pressor after .section of the splanchnic nerves has little effect, because the blood-pressure is already so low when the stimulation is made that it can sink but little more. When, however, the pressure is restored to its normal level, alter section of the splanchnic nerve- by the stimulation of their peripheral ends, or by the injection of normal saline; solution into the vessels and the depressors then stimulated, the fall in blood-pressure is nearly and some- times quite as great as that obtained by the stimulation of the depressor nerve when the splanchnic nerves are intact. Jt is improbable, therefore, that the depressor acts chiefly through the splanchnic nerves. It probably acts mi all the vasomotor nerves connected with the vasomotor centre. This view is somewhat strengthened by the observations of Bayliss (Fig. 37). It has already been said that the depressor fibres pass from the heart to the vaso-motor mechanism in the central nervous system. The cardiac fibres are probably stimulated when the heart is overfilled through lack of expulsive force or through excessive venous inflow, and, by reducing the peripheral resist- ance, assist the engorged organ to empty itself. The depressor nerve is not in continual action ; it has no tonus; for the sec- tion of both depressor nerves causes no alteration in the blood-pressure. Sewall and Steiner have obtained in some cases a permanent rise in blood- pressure following section of both depressors, yet they hesitate to say that the depressor exercises a tonic action. Spallita and Consiglio have stimulated the depressor before and after the Fig. 37.— Showing the fall in blood-pressure and the dilatation of peripheral vessels from stimula- tion of the central end of the depressor nerve i Bayliss) : A, curve of blood-pressure in the carotid artery ; B, volume of hind limb, recorded by a plethysmograph ; (7, electro-magnet lino, in which the elevation the time of stimulation of the nerve ; D, atmospheric pressure-line ; E, time in seconds. section of the spinal accessory nerve near its junction with the vagus. They find that after section of the spinal accessory, the stimulation of the depressor does not affect the pulse, whence they conclude that the depressor fibres that affect the blood-pressure are separate from those that affect the rate of beat, the latter being derived from the spinal accessory nerve. A recent study by Bayliss 1 brings out several new facts. If a limb is placed 1 Bayliss: .J<»inxtl of Physiology, 1893, xiv. p. 303. The relation between the depressor nerve and the thyroid i- pointed nut by v. ( 'von : ( ' ,.- • .' \ttfur Physiologic, 1897, ii. pp. 279, 357. CIRCULA TION. 1 7 5 in Mosso's plethysmograph and the central end of the depressor stimulated, the volume of the limb increases, showing an active dilatation of the vessels that supply it. The latent period of this dilatation varies greatly. The vessels of the skin play a large part in its production. A similar local action is seen on the vessels of the head and neck (see Fig. 37). The depressor fibres vary much in size in different animals. When the nerve is small, a greater depressor effect can be obtained by stimulating the central end of the vagus than from the depressor itself. But the course of the fall is different in the two cases. With the depressor, the fall is maintained at a constant level during the whole excitation, however long it lasts, whereas in the case of the vagus the pressure very soon returns to its original height although the excitation still continues. Bayliss believes, therefore, that there is a considerable difference between the central connections of the depressor nerve itself and the depressor fibres sometimes found in other nerves. The left depressor nerve usually produces a greater fall of pressure than the right. The excitation of the second nerve dui'ing the excitation of the first produces a greater fall than the excitation of one alone. The fibres of the depressor, in part at least, end in the wall of the ventricle. A similar nerve has been demonstrated in the cat, horse, dog, sheep, swine, and in man. Sensory Nerves. — The first and usually the only effect of the stimulation of the central end of a mixed nerve like the sciatic, according to Roy and Adami, is an increase in the force and the frequency of the heart-beat. Other observers have sometimes found quickening and sometimes slowing of the pulse- rate, so that sensory nerves, as Tigerstedt suggests, appear to affect both the inhibitory and the augmenting heart-nerves. When a sensory nerve is weakly excited the augmentor effect predominates, when strongly excited the inhibi- tory. A well-known demonstration of the reflex action of the sensory nerves on the heart is seen in the slowing of the rabbit's heart when the animal is made to inhale chloroform. The superior laryngeal and the trigeminus nerves, especially the latter, convey the stimulus to the nerve-centres. The stimulation of t he nerves of special sense, optic, auditory, olfactory and glosso-pharyngeal nerves, also sometimes slows and sometimes quickens the heart. Sympathetic. — The reflex action of the sympathetic nerve upon the heart is well shown by the celebrated experiment of F. Goltz. In a medium-sized frog, the pericardium was exposed by carefully cutting a small window in the chest-wall. The pulsations of the heart could be seen through the thin peri- cardial membrane. Goltz now began to heat upon the abdomen aboul 1 10 times a minute witli the handle of a scalpel. The heart gradually slowed, and at length stood still in diastole. Goltz now ceased the rain of little blows. The heart remained quiet for a time and then began to beat again. ;it firsl slowly and then more rapidly. Some time after the experiment, the heart beal about five strokes in the minute faster than before the experiment was begun. The effect cannot be obtained after section of the vaffi. 176 AN AMERICAN TEXT-HOOK OF PHYSIOLOGY. Bernstein found that the afferent nerves in Goltz's experiment were branches of the abdominal sympathetic, and discovered that the stimulation of the cen- tral end of the abdominal sympathetic in the rabbit was followed also by reflex inhibition of the heart. The stimulation of the central end of the splanchnic produces a reflex rise of blood-pressure and, perhaps secondarily, a slowing of the heart. In some cases acceleration has been observed. According to Roy and Adami splanch- nic stimulation sometimes produces a combination of augmentor and vagus effects, the augmentation appearing during stimulation and giving place abruptly to well-marked inhibitory slowing at the close of stimulation. The results of stimulating various abdominal viscera have been studied by Mayer and Pribram. One of the most interesting of the reflexes observed by them was the inhibition of the heart called forth by dilating the stomach. The stimulation of the cervical sympathetic does not give any very constant results on the action of the heart. B. The Centres op the Heart-nerves. Inhibitory Centre. — It has been already mentioned that the brothers Weber localized the cardiac inhibitory centre in the medulla oblongata. The efforts to fix the exact location of the centre by stimulation of various parts, either mechanically, by thrusting fine needles into the medulla, or electrically, cannot inspire great confidence because of the difficulty of distinguishing between the results that follow the excitation of a nerve-path from or to the centre and those following the excitation of the centre itself. According to Laborde, who also used this method, the cardiac inhibitory centre is situated at the level of the mass of cells known as the accessory nucleus of the hypoglossus and the mixed nerves (vagus, spinal accessory, glosso-pharyngeal). The localization of the centre by the method of successive sections is per- haps more trustworthy. Franck has found that the separation of the bulb from the spinal cord cuts off the reflexes called forth by nerves that enter the spinal cord, while leaving undisturbed the reflex produced by stimulation of the trigeminus nerve. On the whole, there seems to be no doubt that the cardiac inhibitory centre is situated in the bulb. Tonus of Card/in- Inhibitory Centre. — The cardiac inhibitory centre is prob- ably always in action, for when the vagus nerves are cut, the heart-beat becomes more frequent. 1 The source of this continued or "tonic" activity may lie in the continuous discharge of inhibitory impulses created by the liberation of energy in the cell independent of direct external influences, or the cells may be discharged by the continuous stream of afferent impulses that must constantly play upon them from the multitude of afferent nerves. This latter theory, the conception of a reflex tonus, is made probable by the observations that section of the vagi docs not increase the rate of beat after the greater part of the afferent impulses have been cul oil* by division of the 1 Hunt : American Journal oj Physiology, 1899, ii. p. 397. CIRCULATION. 177 spinal cord near its junction with the bulb, and that the sudden decrease in the number of afferent impulses caused by section of the splanchnic nerve quickens the pulse-rate. Irradiation. — The slowing of the rate of beat observed chiefly during the expiratory portion of respiration disappears after the section of both vagus nerves. The slowing may perhaps be due to the stimulation of the cardiac inhibitory centre by irradiation from the respiratory centre. 1 Origin of Cardiac Inhibitory Fibres. — Since the researches of Waller and others, it has been generally believed that the cardiac inhibitory fibres enter the vagus from the spinal accessory nerve, for the reason that cardiac inhibi- tion was not secured in animals in which the fibres in the vagus derived from the spinal accessory nerve were made to degenerate by tearing out the latter before its junction with the vagus. These results have lately been called in question by Grossmann. 2 The method employed by his predecessors, according to him, probably involved the destruction of vagus roots as well as those of the spinal accessory. Grossmann finds that the stimulation of the spinal accessory nerve before its junction with the vagus does not inhibit the heart. Nor does inhibition follow the stimulation of the bulbar roots supposed to be contributed to the mixed nerve by the spinal accessory. Augmentor Centre. — The situation of the centre for the augmentor nerves of the heart is not definitely known, although from analogy it seems probable that it will be found in the bulb. That this centre is constantly in action is indicated by the lowering of the pulse-rate after section of the vagi followed by the bilateral extirpation of the inferior cervical and first thoracic ganglia. 3 The division of the spinal cord in the upper cervical region after the section of the vagi has the same effect. Vagus inhibition, moreover, is said to be more readily produced after section of the augmentor nerves. McWilliam ' has remarked that the latent period and the character of the acceleration often accompanying the excitation of afferent nerves may differ entirely from the characteristic effects of the excitation (if augmentor nerves. The stimulation of the latter is followed by a long latent period, after which the rate of beat gradually increases to its maximum and, after excitation is over, as gradually declines. The excitation of an afferent nerve, on the con- trary, causes often, with almost no latent period, a remarkably sudden accel- eration, that reaches at once a high value and often suddenly gives way to a slow heart-beat. These facts seem to show that reflex acceleration of the heart- beat is due to chaDges in the cardiac inhibitory centre, and not to augmentor excitation. This view is strengthened by the fad that if the augmentor nerve- are cut, the vagi remaining intact, the stimulation of afferent fibres, for exam- ple in the brachial nerves, can still cause a marked quickening of the pulse- rate. In short, the action of afferent nerves upon the rateofbeal is essentially L Laulani£: Comptes rendus Soci&i de Biologie, 1893, p. ~'2'.\. Compare Wood: American Journal of I'/iiisi<>h,,/,i, Is'.i'.i, ii. p. :>.VJ. ' < rrossmann : Archiv fur die gesammte Physiologic, 1895, liv. p. 6 3 Hunt: Amrrirun Jniirwtl <>f /'//i/.si'o/of/;/, IS",)',), ii. p. 397. * McWilliam : Proceedings Royal Society, L893, liii. p. I7"_\ Vol. 1.— 12 ITS AJS AMERICAN TEXT-BOOK OF PHYSIOLOGY. the same, according to this observer, whether the augmentor nerves are divided or intact. Roy and Adami believe that the stimulation of afferent nerves, such as the sciatic or the splanchnic, excites both augmentor and vagus centres. The augmentor centre is almost always the more strongly excited of the two, so that augmentor effects alone are usually obtained. Action of Higher Parts of the Brain on Cardiac Centres. — Repeated efforts have been made to find areas in the cortex of the brain especially related to the inhibition or augmentation of the heart, but with results so con- tradictory as to warrant the conclusion that the influence on the heart-beat of the parts of the brain lying above the cardiac centres does not differ essen- tially from that of other organs peripheral to those centres. Voluntary control of the heart, by which is meant the power to alter the rate of beat by the exercise of the will, is impossible except as a rare indi- vidual peculiarity, commonly accompanied by an unusual control over muscles, such as the platysma, not usually subject to the will. Cases are described by Tarchanoff and Pease, in which acceleration of the beat up to twenty-seven in the minute was produced, together with increase of blood-pressure, from vaso-constrictor action. The experiments are dangerous. 1 Peripheral Reflex Centres. — It is now much discussed whether the periph- eral ganglia can act as centres of reflex action. According to Franck 2 the excita- tion of the central stump of the divided left anterior limb of the annulus of Vieussens is transformed within the first thoracic ganglion, isolated from the spinal cord by section of its rami communicantes, into a motor impulse trans- mitted by the posterior limb of the annulus. This motor impulse causes, inde- pendently of the bulbo-spinal centres, a reflex augmentation in the action of the heart, and a reflex constriction of the vessels in the external ear, the submaxil- lary gland, and the nasal mucous membrane. This experiment, in conjunction with the tacts in favor of other sympathetic ganglia acting as reflex centres/ seems to demonstrate that some afferent impulses are transformed in the sym- pathetic cardiac ganglia into efferent impulses modifying the action of the heart. It' this conclusion is confirmed by future investigations it will pro- foundly modify the views now entertained regarding the innervation of the heart. The exp&irnenU of Stannius, published in 1852, have been the starting- point of a very -rent number of researches on the innervation of the frog's heart. Stannius observed, among other facts, that the heart remained for a time arrested in diastole when a ligature was tied about the heart precisely at the junction of the sinus venosus with the right auricle. No sufficient explanation of this result has yet been given, nor is one likely to be found until the innervation of the heart is better understood. Stannius further 1 Van de Velde : Archivfur die gesammte Physiologic, 1897, lxvi. p. 232. 2 Franck : Archives de Physiologic, 1894, p. 721. 3 Langley and Anderson : Journal of Physiology, 1894, xvi. p. 435. The attempt of Prof. Kxonecker to demonstrate a co-ordinating centre in the ventricles may be mentioned here (Zeit- schrift fur Biolagie, 1896, xxxiv. p 529). CIRCULATION. 17;) observed that after the ligature just described had been drawn tight, thus arresting the heart, the placing of a second ligature around the heart at the junction of the auricle and ventricle caused the latter to begin to beat again, while the auricle remained at rest. This second ligature, it is generally admitted, stimulates the ganglion of Bidder, and the ventricle responds by rhythmic contractions to the constant excitation thus produced. Loosening the ligature and so interrupting the excitation stops the ventricular beat. PART III.— THE NUTRITION OF THE HEART. The cells of which the heart-wall are composed are nourished by contact with a nutrient fluid. In hearts consisting of relatively few cells no special means of bringing the nutrient fluid to the cells is required. The walls of the minute globular heart of the small crustacean Daphnia, for example, arc com- posed of a single layer of cells, each of which is bathed by the fluid which the heart pumps. In larger hearts with thicker walls only the innermost cells could be fed in this way. Special means of distributing the blood throughout the substance of the organ are necessary here. Passages in the Prog's Heart. — In the frog this distribution is accom- plished chiefly through the irregular passages which go out from the cavities of the heart between the muscle-bundles to within even the fraction of a milli- meter of the external surface. These passages vary greatly in size. Many arc mere capillaries. They are lined by a prolongation of the endothelium of the heart. Filled by every diastole and emptied by every systole, they do the work of blood-vessels and carry the blood to every part of the cardiac muscle. Henri Martin ! describes a coronary artery in the frog, analogous to the coronary arteries of higher vertebrates. This artery supplies a part of the auricles and the upper fourth of the ventricle. In the rabbit, cat and dog, and in man a well-developed system of cardiac vessels exists, the coronary arteries and veins. Their distribution in the dog deserves especial notice, because the physiological problems connected with these vessels have been studied chiefly in this animal. Coronary Arteries in the Dog. — In the dog the coronary arteries and their larger branches lie upon the surface of the heart, covered as a rule only by the pericardium and a varying quantity of connective tissue and fat. The left coronary artery is extraordinarily short. A few millimeters after its origin from the aorta it divides into the large ramus circumflex and the descen- dens, nearly as large. The former runs in the auriculo-ventricular furrow around the left side of the heart to the posterior surface, ending in the pos- terior inter-ventricular furrow. The left auricle and the upper anterior and the posterior portion of the left ventricle arc supplied by this artery. The descen- dens runs downward in the anterior inter-ventricular furrow to the apex. ( Hose to its origin the descendens gives oil" the artcria septi, which al once enter- the 'Martin : Comptes rendus Socteti de Biologie, 1893, p. 754, 180 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. inter-ventricular septum and passes, sparsely covered with muscle-bundles, obliquely downward and backward on the right side of the septum. The descendens in its farther course gives off numerous branches to the left ventricle and the anterior part of the septum. Only a few small branches go to the right ventricle. Thus the descendens supplies the septum and the inferior anterior pari of the left ventricle. The right coronary artery, imbedded in fat, runs in the right auriculo-ventricular groove around the right side of the heart, supplying the right auricle and ventricle. It is a much smaller artery than either the circumflex or descendens. Each coronary artery keeps to its own boundaries and does not, in the dog, pass into the field of another artery, :i~ sometimes happens in man. 1 Terminal Nature of Coronary Arteries. — The coronary arteries in the dog, as in man, are terminal arteries, that is, the anastomoses which their branches have with neighboring vessels do not permit the making of a collateral circula- tion. Their terminal nature in the human heart is shown by the formation of infarcts in the areas supplied by arteries which have been plugged by embo- lism or thrombosis. That part of the heart-wall supplied by the stopped artery speedily decays. The bloodless area is of a dull white color, often faintly tinged with yellow ; rarely it is red, being stained by haemoglobin from the neighboring capillaries. The cross section is coarsely granular. The nuclei of the muscle-cells have lost their power of staining. The muscle-cells are dead and connective tissue soon replaces them.- This loss of function ami rapid decay of cardiac tissue would not take place did anastomoses permit the establishment of collateral circulation between the artery going to the part and neighboring arteries. The terminal nature of the coronary arteries in the dog has been placed beyond doubt by direct experiment. It is possible to tie them and keep the animal alive until a distinct infarct has formed. 3 The objection that one of the coronary arteries can be injected from another, 4 and that therefore they are not terminal, is based on the incorrect premise that terminal arteries cannot be thus injected, and has no weight against the positive evidence of the complete failure of nutrition following closure. The passage of a fine injection-mass from one vascular area to another proves nothing concerning the possibility of the one area receiving its blood-supply from the other. Such supply is impossible if the resistance in the communi- cating vessels i- greater than the blood-pressure in the smallest branches of the arterv through which the supply imi-i come, it is the fact of this high resist- ance, due to the small size of the communicating branches, which makes the artery ••terminal." This c lit ion of high resistance is really present during life, or infarction could not take place. The terminal nature of the coronary arteries is of great importance with regard to the part taken by them in the nutrition of the heart. Being ter- 1 Baumgarten : American Journal oj Physiology, 1899, ii. p. 243. also the description by Kolster: Skandinavisches Archiv fur Physiologie, 1893, iv. p. 14, of the infarctions produced experimentally in t lie il"-'- heart. Porter: Archiv fiir du gt ammt Physiologie, 1893, lv. p. 366. 4 Michaelis : Zeitschrifl fur klinische Medicin, 1894, xxiv. p. 289. CIRCULATION. 181 minal, their experimental closure enables us to study the effects of the sudden stopping of the blood-supply (ischsemia) of the heart muscle upon the action of the heart. Results of Closure of the Coronary Arteries. — The sudden closure of one of the large coronary branches in the dog has as a rule cither no effect upon the action of the heart beyond occasional and transient irregularity, 1 or is fol- lowed after the lapse of seconds, or of minutes, by the arrest of the ventricu- lar stroke, the ventricle falling a moment later into the rapid, fluttering, Fig. 'S8.—A, curve of intraventricular pressure, written by a manometer connected with the interior of the left ventricle; B, atmospheric pressure; C, time in two-second intervals. At the first arrow the ramus circumflexus of the left coronary artery was ligated ; at the second arrow the hear! fell Into fibril- lary contractions. The lessening height of the curve shows the gradual diminution of the force of con- traction after ligation. The rise of the lower line of the curve above the atmospheric pressure indicates a rise of intra-ventricular pressure during diastole. The small elevations in the pressure-curve after the second arrow are caused by the left auricle, which continued to beat after the arrest of the ventricle (Porter, 1893). undulatory movements known as fibrillary contractions and produced by the inco-ordinated, confused shortenings of individual muscle-cells, or groups of cells. The auricles continue to beat for a time, but the power of the ventricles to execute co-ordinated contractions is lost. The Frequency of Arrest. — The frequency with which closure is fol- lowed by ventricular arrest depends on at least two factors — namely, the size of the artery ligated and the irritability of the heart. That the size of the artery is of influence appears from a series of ligations performed on dogs, arrest being never observed after ligation of the arteria septi alone, rarely observed (14 per cent.) with the right coronary artery, more frequently (28 per cent.) with the descendens, and still more frequently (80 per cent.) with the arteria circumflexa. 2 The irritability of the heart is an important factor. In animals cooled by long artificial respiration, or by section of the spinal cord at its junction with the bulb, the ligation of the descendens arrests the hearl less frequently than in vigorous animals which have been operated upon quickly. The frequency of arrest is increased by the use of morphia and curare/' Changes in the Heart-beat. — Ligation destined to arrest the heart i- fol- lowed almost immediately by a continuous fall in the intra-ventricular pressure during systole and a gradual rise in the pressure during diastole (see Fig. 38). The contraction and relaxation of the ventricle are often slowed. The force of the ventricular stroke is diminished. As arrest draw- near, irregularities in the force of the ventricular beat are seldom absent. The frequency of beat is sometimes unchanged throughout, but is usually diminished toward the end j 1 The changes produced by subsequent degeneration are 1 1 < • t considered bere. * Porter: Journal of Physiology, 1893, sv. p. 131. 8 Porter: Journal of Experimented Medicine, 1896, i, p. 49. 182 AX AMERICAN TEXT-BOOK OF PHYSIOLOGY Fig. 39.— Showing fall in arte- rial pressure and diminished out- put of left ventricle inconsequence of the ligation "f the circumflex artery. 'I he curve reads from left to right, it isone-balf the original I In- upper curve is the pres- sure in the carotid artery. The unbroken line is atmospheric pres- sure. The next curve is the na nremenl >>i the outflow from the left ventricle, each rise and each fall indicating the passage of 50 c.cm. of bl l i ii t • > the aorta i he lower line is a time-curve in sec- onds. At * the circumflex artery was ligated (Porter, L896, p. 51). occasionally the frequency is increased. Both ven- tricles as a rule cease to heat at the same instant. The work done hy the heart, measured by the blood thrown into the aorta in a unit of time, is lessened by ligation when followed by arrest (see Fig. 39). The Exciting' Cause of Arrest. — There are two opinions concerning the exciting cause of the changes following closure of a coronary artery, some investigators holding for anaemia and others for mechanical injury of the cardiac muscle or its nerves in the operation of ligation. The latter base their claim on the frequent failure of ligation of even a main branch to stop the heart; on the fact that the heart of the dog has been seen to beat from 115 to 150 seconds after the blood-pres- sure in the aorta was so far reduced, by clamping the auricle and opening the carotid artery, as to make a continuance of the coronary circulation very improbable; 1 on the revival of the arrested heart by the injection of defibriuated blood into the coronary arteries from the aorta, by which means the dog's heart and even the human heart has been made to beat again many minutes after the total arrest of the circulation, 2 — it being as- sumed, incorrectly, that the dog's heart cannot be made to beat after arrest with fibrillary contrac- tions; and, finally, on the arrest with fibrillary contractions which some experimenters have caused by mechanical injury to the heart. To sum up, the argument in favor of explain- ing arrest with fibrillary contractions simply by the mechanical injury done the heart in the pro- cess of ligation consists of two propositions : first, anemia without mechanical injury does not cause; arrest with fibrillary contractions; and second, me- chanical injury without anemia does cause arrest. Against the second of these propositions must be placed the extreme infrequency of arrest from mechanical injuries."' In more than one hundred 1 Tigerstedt : Skandinavischea Archiv fiir Physiologie, 1S93, v. p. 71 ; Michaelis : Zeitschrifl fin- klinisehe Medicin, 1894, xxiv. p. 'J7<>. - Langendorff: Archiv fiir die gesammte Physiologie, L895, ].\i. p. 320; 1898, Ixx. p. 281 ; Batke: Ibid., 1898, Ixxi. p. 412. :; Rodel ami Nicolas: Archives de Physiologie, 1896, p. 167. CIRCULA TJOJY. 1 83 ligations Porter observed not a single arrest in consequence of laying the artery bare and placing the ligature ready to be drawn, the only effect of the mechanical procedure being an occasional slight irregularity in force. Ligation of the periarterial tissues in ten dogs, the artery itself being excluded from the ligature, directly injured both muscular and nervous substance, but was only once followed by arrest. Nor does arrest follow the ligation of a vein, although the mechanical injury is possibly as great as in tying an artery. The direct stimulation of the superficial ventricular nerves exposed to injury in the opera- tion of ligation does not produce the effects that appear after the ligation of coronary arteries. Against the remaining proposition stated above — namely, that anaemia with- out mechanical injury does not cause arrest with fibrillary contractions — it should be said that the frequency of arrest after ligation is in proportion to the size of the artery ligated, and hence to the size of the area made anaemic, and is not in proportion to the injury done in the preparation of the artery. The circumflex and descendens may be prepared without injuring a single muscle-fibre, yet their ligation frequently arrests the heart, while the ligation of the arteria septi, which cannot be prepared without injuring the muscle- substance, does not arrest the heart. It is, moreover, possible to close a coro- nary artery without mechanical injury. Lycopodium spores mixed with de- fibrinated blood are injected into the arch of the aorta during the momentary closure of that vessel and are carried into the coronary arteries, the only way left open for the blood. The lycopodium spores plug up the finer branches of the coronary vessels. The coronary arteries are thus closed without the operator having touched the heart. Prompt arrest with tumultuous fibrillary contractions follows. There seems, then, to be no doubt that fibrillary contrac- tions can be brought on bv sudden anaemia of the heart muscle. 1 The gradual interruption of the circulation in the coronary vessels — by bleeding from the carotid artery, for example — is followed by feeble inco- ordinated contractions not essentially different in kind from those commonly termed fibrillary contractions. The manner of interruption probably explains the difference in result. In the former case, namely, ligation or other sudden closure, the supply of blood to the heart muscle is suddenly slopped while the heart continues to work against a high peripheral resistance ; in the latter, the anaemia is gradual and the heart works against little or no peripheral resistance. Recovery from Fibrillary Contractions. — Fibrillary contract ions brought on by clamping the left coronary artery in the rabbit's heart are often gradually replaced by normal contractions when the clamp is removed. The isolated cat's heart after showing marked fibrillary contractions during forty-five minutes lias given strong regular beats for more than an hour. McWilliam and others have seen a number of spontaneous regular beats after the termi- nation of fibrillary contraction. The dog's heart can be recovered by cool- ing the ventricles until all trace of fibrillation has disappeared, and then bringing the hearf back to normal temperature by circulating warmed defi- 1 Porter: Journal oj Experimentul Medicine, 1896, I. p. 65. 184 AN AMERICAN TEXT-BOOK OE PHYSIOLOGY. brinated blood through the coronary vessels. 1 Recovery has also been obtained by passing immediately (within 15 seconds) a very rapid alternating current of not too great intensity. 2 Closure of the Coronary Veins. — Closure of all the coronary veins in the rabbit produced fibrillary contractions alter from fifteen to twenty minutes had passed. Their closure in the dog is said to be without effect 3 — a negative result perhaps to be explained by the fact that a portion of the coronary blood finds its way to the cavities of the heart through the venae Thebesii. Volume of Coronary Circulation. — Bohr and Henriques, 4 taking the average of six experiments on dogs, found that 16 cubic centimeters of blood passed through the coronary arteries per minute for each 100 grams of heart muscle. The quantity passing through both coronary arteries varied in dif- ferent animals from 20 to 64 cubic centimeters per minute; the quantity passing through the left coronary artery varied from 22.5 to 60 cubic centi- mm ^^mmmmmm^M-u^ U-44-f4WirWW^ Fig. 40.— Diminution of the force of contraction of the ventricle of the Isolated cat's heart in con- sequence of diminishing the supply of blood to the cardiac muscle : A, blood-pressure at the root of the aorta, recorded bya mercury manometer; B, intra-ventrieular pressure-curve, left ventricle: the indi- vidual beats do not appear, l ause of the slow >i d of the smoked surface; C, time in seconds; D, the number of drops of blood passing through the coronary arteries, each vertical mark recording one drop. As the number of drops of blood passing through the coronary arteries diminishes, the contractions of the hit ventricle become weaker, but ret-over again when the former volume of the coronary circula- tion Is restored. meters per minute. The hearts weighed from 51 to 350 grams. The method which Bohr and Henriques found it necessary to employ placed the hear! under such abnormal conditions that their results can be regarded as only approximate. Porter 8 supplied the left coronary artery of the dog with blood diluted one-half with sodium chloride solution (0.6 per cent.) by means of a tube ( lumen 2.75 millimeters I inserted into the aortic opening of the left coro- 1 Porter: American Journal of Physiology, L898, i. p. 71. 2 Prevost and Battelli : Journal de physiologie it de paihologie generate, 1900, p. 440. 'Michaelis: Zeitsehrift fur klinische Median, L894, xxiv. |>. 291. * Bohr and Henriques: Skandinavisches Archivfur Physiologie, 1895, v. p. 232. iter: Journal of Experimental Medicine, 1896, i. p. 64. CIRCULATION. 185 nary artery and connected with a reservoir placed 150 centimeters above the heart. In one dog, weighing 11,500 grams, 318 cubic centimeters flowed through in eight minutes. In a second dog, weighing 9500 grams, 114 cubic centimeters passed through in four minutes. In the isolated heart of the caf strong and regular contractions are made on a circulation of about 4 cubic centimeters per minute, or even less, through the coronary system. The quantity passing through the veins of Thebesius into the left auricle and ventricle is very slight. The supply of blood to the heart-muscle is modified by ventricular con- traction, not only in that the mean blood-pressure in the aorta is a function of the force of the heart-beat, but directly by the compression of the intra- mural vessels during systole. Thus, when a piece of the mammalian ven- tricle is kept beating by supplying it with defibrinated blood through its nutrient artery at a constant pressure, each beat can be seen to force the blood out of the severed vessels in the margin of the fragment. The effect of the contractions on the contents of the intramural vessels can also be demon- strated in the living animal by incising a vein, or a ligated artery on the distal side of the ligature, and slowing the heart by stimulation of the vagus. At each systole of the ventricle blood is forced from the vessel. More- over, lessening the frequency of contraction diminishes the volume of the coro- nary circulation — i. e., the outflow from the coronary veins, as may be shown in a record similar to that illustrated by Fig. 40. It is conceivable that the emptying of the intramural vessels by the contraction of the heart may favor the flow of blood through the heart-walls in two ways: first, by the diminished resistance which the empty patulous vessels should offer to the inflow of blood from the aorta when the heart relaxes ; and, secondly, by the suction which might accompany the sudden expansion of the compressed vessels — expanding either by virtue of their intrinsic elasticity, or because of the pull of the surrounding tissues upon their walls, as the heart quickly regains its diastolic form. The problem thus raised may be attacked by sud- denly connecting the distal portion of a coronary artery in the strongly beat- ing heart of the living animal with a small reservoir <>f normally warm de- fibrinated blood at the atmospheric pressure. The connection can be made through a cannula tied into the artery (ramus descendens of the dog) or through a tube passed into the left coronary artery by way of the innominate artery and aorta. If each compression of the deeper branches of the artery were followed by an expansion sufficient to cause a noteworthy suction, the blood in the reservoir should be drawn into the artery, for this blood is the sole source of supply throughout the experiment, as the " terminal " nature of the coronary arteries prevents any material backflo\n from the distal branches. The results of these experiments showed that no appreciable suc- tion can be demonstrated in the larger coronary arteries, even when a very sensitive minimum valve is interposed between the artery and the reservoir in order to prevent the possible masking of the suction b\ rising pressure accompanying the contraction of the ventricle. It is, therefore, necessary 186 IV AMERICAN TEXT-BOOK OF PHYSIOLOGY. to conclude that the emptying of the intramural vessels by the contraction of the heart favors the flow of blood through the heart-walls chiefly by the diminished resistance which the empty patulous vessels offer to the inflow from the aorta when the heart relaxes. 1 The Vessels of Thebesius and the Coronary Veins. — The vessels of Thebesius probably have a part in the nutrition of the heart. If a glass tube two or three inches long is tied into the ventricle of the extirpated heart of the cat and tilled with warm defibrinated blood, the heart will begin to beat, and, it' the blood is oxygenated from time to time, may continue its contrac- tions tor many hours, although its only supply is through the vessels of The- besius. If a vein on the surface of the ventricle is incised, the blood which enters the ventricle arterial in color will emerge from the cut vein a dark venous hue. showing that it has given up its oxygen and presumably other nutrient substances on its way through the heart-wall. This experiment also demonstrates a connection between the coronary vessels and the vessels of Thebesius ; the same may be shown by corrosion preparations of hearts, the veins of which have been injected with celloidin. The extirpated heart may be kept contracting a longer time, when to the supply received through the vessels of Thebesius is added that which may reach the heart from the auricle by baekffow through the coronary veins, the valves of which are incompetent. It is evident that these accessory channels of nutrition must be of impor- tance when the main supply through the arteries is diminished, as in arterio- sclerosis. 2 Blood-supply and Heart-beat. — The relation between the volume of blood passing through the coronary arteries and the rate and force of the ventricular contraction has been studied by Magrath and Kennedy. 3 Varia- tions in the volume of the coronary circulation in the isolated heart of the cat, unless very considerable, are not accompanied by changes in the rate of beat. The force of contraction, on the contrary, appears to be closely dependent on the volume of the coronary circulation (Fig. 40). Distention of the ventricle diminishes the volume of blood flowing through the coronary vessels, except when this effect is compensated by the distention stimulating the ventricle to contract more forcibly, and thus to pump more blood through its walls by alternate compression and expansion of the intramural vessels. 4 Lymphatics of the Heart. — A rich plexus of lymphatic vessels has been demonstrated in the heart. 8 Valuable information concerning the nutrition of the hearl could probably be gained by the systematic study of these vessels. 1 Porter: American Journal "/ Physiology, 1S9S, i. p. 145; consult also von Vintschgau : Archiv jiir die gesammte I'hysiolor/ie, 1890, lxiv. p. 79. - Pratt: Tbid., p. 86. :; Magrath and Kennedy: Journal of Experimental Medicine, 1897, ii. p. 13. 4 I. II. Hyde: American Journal of Physiology, 1898, i. p. 215. 5 Nystroin : Archiv fur Physiologie, 1897, p. 361. CIBCULA TION. 187 0. Solutions which Maintain the Beat of the Heart. The beat of the heart is maintained during life by a constant supply of oxygenated blood. The blood, however, is a very complex fluid, and it can hardly be supposed that all of its constituents are of equal value to the heart. The systematic search for those constituents of the blood which are of import- ance to the nutrition of the heart was begun in Lud wig's laboratory iu 1875 by Merunowicz. The first step toward the method used by Merunowicz and his successors was taken by ('yon. Cyon tied cannulas in the vena cava inferior and in one of the aortse of the extirpated heart of the frog, and joined them by a bowed tube filled with serum. The ventricle pumped the serum through the aortic cannula and the bowed tube into the vena cava, whence it reached the ventricle again. The force of the contraction was measured by a mercury manometer which was joined by a side branch to one limb of the bowed tube. The frog heart manometer method thus introduced by Ludwig and (yon has undergone various modifications at the hands of Blasius and Fick, Bow- ditch, Luciani, Kronecker, and others. Blasius and Fick were the firs! to register changes in the volume of the heart by the plethysmography method, the organ being enclosed in a vessel filled with normal saline solution and connected with a manometer. This idea reappears in the Strassburg apparatus described below. A valuable improvement was made by Kronecker, who invented a double cannula, through one side of which the " nutrient " fluid enters the ventricle while it passes out through the other (Fig. 4 1 ). The contents of the ventricle are thus contin- ually renewed. In 1878, Hoy constructed the instrument shown in Figure 42, by means of which the changes in the volume of the heart at each contraction are recorded on a moving cylin- der. A great advance was made by Williams, in the invention known as " Williams's valve," which is the essential feature of the apparatus devised by this investigator and others in Schmiedeberg's laboratory at Strassburg. The present form of this apparatus is illustrated in Figure 43. A perfusion cannula is introduced into the ventricle through the aorta. Through one tube of the cannula the heart is fed from a reservoir placed above it. Through the other the heart pumps its contents into a higher reser- voir or into the same reservoir. Thus the heart is " Loaded " with a column of liquid of known height and pumps againsl ;i measurable resistance. A Williams valve in the inflow lube prevents any flow except in the direction of the heart. A similar valve reversed in the outflow tube prevents any How Fig. 41.— The perfusion cannula of Kronecker. The ventricle is tied ..n the cannula at d, a ring heing placed here to prevent the ligature from slipping. The double tube, shown in cross section at ■ , 'li\ Idea into the large brani b a and the small branch 6, The nutrient BOlU- tinn enters tic bearl through '- and escapee through <<. The Bilver wire e can ho connected \\ Itb one pole of 11 battery, the cannt ae one electrode, and the fluid Burrounding the bearl as i be other. 188 AN AMERICAN TEXT-HOOK OF PHYSIOLOGY except away from the heart. The ventricle is rilled and emptied alternately as is the normal heart, the artificial valves replacing the heart-valves, which are often necessarily rendered useless by the introduction of the cannula and are at best less certain in their action than the artificial valve. The changes in the volume of the heart are shown by the movements of a liquid column in a Fig. 42— Roy's apparatus: the heart is tied on a perfusion cannula and enclosed in a bell glass rest- in- ..ii a brass plate,?*, the centre of which presents an opening covered by a rubber membrane. Vari- ations in the volume of the heart cause the mem- brane to rise and fall. The movements of the membrane are recorded by a lever. Fig. 43.— Williams's apparatus: H, frog's heart; V,V, Williams's valves ; MS, millimeter scale. The apparatus is arranged to feed the heart from the reservoir into which the heart is pumping. horizontal tube which communicates with the bottle filled with "nutrient" fluid in which the heart is enclosed. In the original method of Cyon the ventricle is left in connection with the auricle, the ganglion-cells of the ventricle and the neighboring portions of the auricle being kept intact. This "whole heart" preparation is to be distin- guished from the "apex" preparation of Bowditch, which has also been used in studies of the effects of nutrient solutions on the heart. In Bowditeh's "apex" preparation, the ventricle is bound to the cannula by a thread tied at the junction of the upper and middle thirds of the ventricle. By this means the lower two-thirds of the ventricle, which contains no ganglion-cells, is cut off from any physiological connection with the base of the ventricle and a " ganglion-free apex " secured. The isolated " apex " at first stands still, but after from ten to sixty minutes commences to beat again and can then be kept beating for several hours. In the use of these various methods certain general precautions should be kept in mind. Special attention should be directed to the difficulty of remov- ing the blood from the capillary fissures in the wall of the frog's heart. A small amount of blood remaining in these passages is frequently a source of error. It should be remembered that, as Cyon pointed out, a change in the nutrient solution is of itself a stimulus to the heart, increasing or diminishing the frequency of contraction and obliging the investigator to wait until the heart CIRCULATION. 189 has become accustomed to the new solution before making an observation. The heart should, as a rule, be constantly supplied with fresh fluid, as in the natural state. The resistance against which the heart works is also a factor of import- ance. The water with which the solutions are made should be distilled in glass, as the minutest trace of the compounds of heavy metals in non-colloidal solu- tions affects the heart. 1 Nutrient Solutions. — Cyon found that the beat of the extirpated frog's heart is very dependent on the nature of the solution with which the heart is fed. Hearts supplied with normal saline solution (NaCl, 0.6 per cent.) ceased to beat much sooner than those left empty. The serum of dog's blood seemed almost poisonous. Rabbit's serum, on the contrary, postponed the exhaustion of the heart for many hours, provided the limited quantity contained in the apparatus was renewed from time to time. Serum used over and over again caused the beats to lose force after an hour or two. The renewal of the serum seemed a stimulus to the heart, causing it to contract very strongly during a half minute or more, after which the contractions became less energetic. Cyon's immediate successors, Bowditch, Luciani, and Rossbach, confirmed his observations. None of these investigators, however, was concerned pri- marily with the nutrition of the heart. The first systematic work on this sub- ject was done, as has been said, by Meruuowicz, who attempted to maintain the beat of the heart with normal saline solution containing various quantities of blood, with normal saline alone, with a watery solution of the ash of an alcholic extract of serum, and with a normal saline solution containing a minute amount of sodium carbonate. The direction taken by him has been pursued to the present day, the chief objects of study being the importance to the heart of sodium carbonate or other alkali, sodium and potassium chloride, the salts of calcium, oxygen, proteids and some other organic bodies such as dextrose, and, finally, of fluids possessing the physical characteristics of the blood. The outcome of this work we must now consider. The value of an alkaline reaction has been generally recognized. Sodium carbonate is the alkali commouly preferred. The favorable influence of this salt probably does not depend on any specific action, but simply upon its alkalinity. The alkali promotes the beat of the heart by neutralizing the carbon dioxide and other acids formed in the metabolism of the contracting muscle; this, however, may not be its only use. Certain of the salts normally present in the blood are necessary i" main- tain the beat of the heart. Sodium chloride is one of these. The solution employed should contain a " physiological quantity." Such a solution is said to be " isotonic." The amount required t<» make a sodium chloride solution "normal" or " isotonic" for the frog is <).(> per cent., for the mammal Dearly 1 per cent. Enough of a calcium salt to prevent the washing ouf of lime from the tissues is also essential for prolonged maintenance of the contractions. A heart fed with normal saline solution is before long brought t<> a stand ; the addition of a calcium salt to the solution postpones the arrest. The character 'Locke: Journal of Physiology, lK'.t.">, xviii. p, 331. 190 AN AMERICA* TEXT-BOOK OF PHYSIOLOGY. of the contraction, however, is altered by the calcium, the relaxation of the ventricle being sometimes so much delayed that the next contraction takes place before the relaxation from the previous contraction has commenced, the ventricle falling- thereby into a state of persistent or " tonic" contraction. The additiou of a potassium sail restores the normal character of the contraction, calcium and potassium having an antagonistic action on the heart. 1 The importance of calcium to the heart is said to be demonstrated by the disap- pearance of the spontaneous contractions of the heart which follows the pre- cipitation of the calcium in the circulating fluid by the addition to it of an equivalent quantity of a soluble oxalate, and by the return of spontaneous contractions which is seen when the calcium is restored to the solution. The antagonistic action of calcium and the oxalates was first pointed out by (yon. According; to Ringer, the substances thus far mentioned are effective in the following order : normal saline is the least effective; next is saline containing sodium bicarbonate; then saline containing tricalcium phosphate; and best of all, saline containing tricalcium phosphate together with potassium chloride. He recommends the following mixture: Sodium chloride solution ().(> per cent., saturated with tribasic calcium phosphate, 100 cubic centimeters; solu- tion potassium chloride 1 per cent., or acid potassium phosphate (HK 2 POJ 1 per cent., 2 cubic centimeters. 2 There has been considerable dispute over the part played by oxygen in the beat of the frog's heart. McGuire and Klug were of opinion that the beat is largely independent of the amount of oxygen in the circulating fluid. Yeo concluded that the contracting heart uses more oxygen than the resting heart, and that the consumption of oxygen increases with the work done. Kronecker and Handler, on the contrary, believe that the oxygen con- sumption is increased by an increase in the rate of beat, but is independent of the work done. More recent observers are united on the necessity of oxygen to the working heart. Oehrwall's studies in this field are especially interesting. He finds that a volume of blood sufficient to fill the frog's ventricle will main- tain contractions for hours provided the heart is surrounded by an atmosphere of oxygen. The heart is brought to a stand by lack of oxygen and may be made to beat again, even after an arrest of twenty minutes, by giving it a fresh sup- ply. The heart fails in oxygen-hunger probably because the chemical process by which the stimulus to contraction is called forth no longer takes place, and not because of a failure in contractility, for even after long inaction a gentle touch on the pericardium will cause a vigorous contraction.' 5 Haldane 4 discovered that the corpuscles of the blood are not essential to the contractions of the warm-blooded heart, provided the oxygen which the 'Bottazzi: Archives de Physiologic, L896, xxviii. p. 882. Ringer : Journal of Phusiolixjij, 1893, xiv. p. 128. The bibliography has recently been given by Unwell: American Journal of Physiology, 1898, ii. p. 47 ; and Greene : Ibid., p.82; consult also White : Journal of Physiology, 1896, xix. p. 344. Oehrwall: Skandinavisches Archivfur Physiologic, 1898, viii. p. 1. * Haldane: Journal of Physiology, 1895, xviii. p. 211. CIRCULATION. 191 heart needs is supplied by increasing the tension of the gas in the plasma. Haldane kept his animals alive in oxygen at a pressure of two atmospheres after the oxygen-carrying function of the red corpuscles had been destroyed with carbon monoxide. The experiment has been repeated with the extir- pated mammalian heart by Porter, 1 Locke, 2 and Rusch. 3 Serum and even saline solutions will serve, if the oxygen tension is high or if the volume of oxygen reaching the tissues is increased simply by causing the nutrient liquid to circulate more rapidly. Carbon dioxide 4 is injurious to the heart when present in the circulating fluid in considerable quantities. The force of the contraction is reduced before the rate of beat. The heart poisoned with carbon dioxide often falls into irregular contractions, exhibiting at times "grouping" and the "staircase" phenomenon, a series of beats regularly increasing in strength. Organic Substances. — An unsuccessful effort has been made to prove that only solutions containing proteids, for example blood-serum, chyle, and milk, can keep the heart active. Recent observers have shown the incorrectness of this claim. A mixture of the inorganic salts, sodium chloride, potassium chloride, and calcium chloride, alone suffices. Locke 5 found that tin- addi- tion of 0.1 per cent, of dextrose to a suitable inorganic solution kept a frog's heart working under a load of 3.5 centigrams, and under an " after-load " of 3 centigrams in spontaneous activity for more than twenty-four hours. The sustaining action which dextrose appears to exercise is shared, according to him, by various other organic substances. Physical Characteristics. — Heffter and Albanese, 6 having observed that the addition of gum-arabic to the circulating fluid was of advantage, declared that the nutrient solutions should possess the viscosity of the blood. The favorable action of gum-arabic may, however, more probably be ascribed to the compounds which it contains rather than to its physical properties. 7 Mammalian Heart. — The success attained within the past two years in the isolation of the mammalian heart opens up an hitherto unexplored region in which systematic investigation will surely bring to light facts of wide interest anil value. At present, however, little is known as to the constituents of the blood which are essential to the life of the mammalian heart. An abundant supply of oxygen is certainly highly important. 8 1 Porter: American Journal of Physiology, 1K9S, i. p. 511. 2 Locke: Centralblatt fur Physiologic 1808, xii. p. 5(58. 5 Rusch : Archil' filr di<> gesammte Physiologie, 189S, lxxiii. p. 535. *Langendorff: Archivfur Physiologie, 1893, p. 417 j [de: Ibid., p. 492; Oehrwall: Skcmdin- avisches Archivfur Physiologie, 1897, vii. p. 222. 5 Locke: Journal of Physiology, 1895, xviii. p. 332. 6 Albanese: Archivfur experimenteUe Pathologie unci Pharmakologie, 1893, \\\ii. p. 311; Archives ilaliennes de Biologic, 1896, xxv. p. 308. 7 Howell and Cooke: Journal of Physiology, 1893, xiv. p. 216. 8 Literature is given by Magrath and Kennedy : Journal of Experimental Medicine, 1897, ii. p. 13; and I led bom : Skandinavisches Archivfur Physiologie, 1898, viii. p. H7. See also tiering: Archivfur die gesammte Physiologie, 1 s '. ,s , lxxii. p. 163 ; Bock: Archiv fur experimenteUe Path- ologie und Pharmakologie, 1898, xli. p. 158 ; and Cleghorn : American Journal of Physiology, 1899, ii. p. 273. 192 AN AMERICAN TEXT- HOOK OF PHYSIOLOGY. Blood of Various Animals. — Roy gives some data as to the effect on the froe's ventricle of the blood of various animals. The blood of the various her- bivora (rabbit, guinea-pig, horse, cow, calf, sheep), as well as that of the pigeon, were found to have nearly the same nutritive value in each case. That of the dog, of the cat, and more especially of the pig, while in some instances equal in effect to that from the horse or rabbit, were in other examples (from the newly killed animals) apparently almost poisonous. Cyon's early observation of the in- jurious action of dog's blood on the frog's ventricle has already been mentioned. 1 Regarding the mammalian heart, experience has shown that it is best to supply the heart with blood from the same species of animal. The difficulties attending the use of blood from a different species are seen in the case of the dog's heart supplied with calf's blood. The heart dies sooner; cedema of the lungs takes place, impeding the pulmonary circulation and leading to engorge- ment of the right heart and paralysis of the right auricle ; exudation into the pericardium often seriously interferes with the beat of the heart; and, finally, the elastic modulus of the cardiac muscle is apparently altered, permitting the heart to swell until it tightly fills the pericardium, when the proper filling of the heart is no longer possible through lack of room for diastolic expansion. PART IV.— THE INNERVATION OF THE BLOOD- VESSELS. 2 About the middle of the eighteenth century more or less sagacious hypotheses concerning the contractility of the blood-vessels began to appear in medical literature, but it was not until Ifenle demonstrated the existence of muscular elements in the middle coats of the arteries in 1840 that a secure foundation was laid for the present knowledge of the mechanism by which that contractility is made to control the distribution of the blood. More than a hundred years before, indeed, Pourfour du Petit had shown that redness of the conjunctiva was one of the consequences of the section of the cervical sympathetic, but had called the process an inflammation, in which false idea he was supported by Cruikshank and others; and Dupuy of Alfort had noted redness of the con- junctiva, increased warmth of the forehead, and sweat-drops on ears, forehead, and neck following his extirpation of the superior cervical ganglia in the horse; Brachet, also, cutting the cervical sympathetic in the dog, had gone so far as to attribute the resulting congestion to a paralysis of the blood-vessels. Hut the-e were merely clever -peculations, for the anatomical basis necessary for a real knowledge of this subject was wanting as yet. Henlc furnished this basis, and at the same time reached the modern point of view. ''The part taken by the contractility of the heart and the blood-vessels in the circulation," -aid Henle, "can be expressed in two words: the movement of the blood depends on the heart, but its distribution depends on the vessels." Nor did Henlc; stop here. It was now known that the vessels possessed contractile walls ; it was 1 See also Bardier: Comptes rend/us Societi de Biologic, 1898, p. 548. 'See footnote t<> Part II., p. lis. CIRCULATION. 193 known further that these walls contracted when mechanically stimulated; for example, by scraping them with the point of a scalpel ; and various observers had traced sympathetic nerves from the greater vessels to the lesser until lost in their finest ramifications. It was therefore easy to construct a reasonable hypothesis of the control of the blood-vessels by the nerves. Henle declared that the vessels contract because their nerves are stimulated, either directly, or reflexly through the agency of a sensory apparatus. The ground was thus prepared for the physiological demonstration of the existence of " vaso- motor" nerves, as Stilling began to call them. Four names are associated with this great achievement — Schiff, Bernard, Brown-Sequard, and Waller, each of whom worked independently of the others. Foremost among them is Claude Bernard, though not the first in point of time, for it was he who put the new doctrine on a firm basis. In his first publication Bernard stated that section of the cervical sympathetic, or removal of the superior cervical ganglion, in the rabbit, causes a more active circulation on the correspond- ing side of the face together with an increase in its temperature. The greater blood-supply manifests itself in the increased redness of the skin, particularly noticeable in the skin of the ear. The elevation of temperature may be easily felt by the hand. A thermometer placed in the nostril or in the ear of the operated side shows a rise of from 4° to 6° C The elevation of temperature may persist for several months. Similar results are obtained in the horse and the dog. The following year Brown-Sequard announced that " if galvanism is applied to the superior portion of the sympathetic after it has been cut in the neck, the dilated vessels of the face and of the ear after a certain time begin to contract ; their contraction increases slowly, but at last it is evident that they resume their normal condition, if they are not even smaller. Then the temperature diminishes in the face and the ear, and becomes in the palsied side the same as in the sound side. When the galvanic current ceases to act, the vessels begin to dilate again, and all the phenomena discovered by Dr. Bernard reappear." Brown-Sequard concludes that "the only direct effect of the section of the cervical part of the sympathetic is the paralysis, and consequently the dilata- tion, of the blood-vessels. Another evident conclusion is that the cervical sympathetic sends motor fibres to many of the blood-vessels of the head." While Brown-Sequard was making these important investigations in America, Bernard, in Paris, quite unaware of Brown-Kequard's labors, was reaching the same result. The existence of nerve-fibres the stimulation of which causes constriction of the blood-vessels to which they are distributed was thus established. A considerable addition to this knowledge was presently made by Schiff, who pointed out in 185b' that certain vaso-motor nerves take origin from the spinal cord. The destruction of certain parts of the spinal cord causes the same vascular dilatation and rise of temperature that follows the section of the vaso-motor nerves outside the spinal cord. At this time Schiff also offered evidence of vaso-dilator nerves. When Vol. I.— 13 194 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. the left cervical sympathetic is cut in a dog, and the animal is kept in his kennel, (he left ear will always be found to be 5° to 9° warmer than the right, [f the dog is now taken out for a run in the warm sunshine, and allowed to heat himself until he begins to pant witli outstretched tongue, the temperature of both ears will lie found to have increased. The right ear is now, however, the warmer of the two, being from 1° to 5° warmer than the left. The blood-vessels of the right ear are, moreover, now fuller than those of the left. When the animal is quiet again the former condition returns, the redness and warmth in the right becoming again less than in the left ear. The increase of the redness and warmth of the right ear over the left, in which the vaso-constrictor nerves were paralyzed, must be the result of a dilatation of the vessels of the right ear by some nervous mechanism. For if the dilatation of the vessels was merely passive, the vessels in the right ear cotdd not dilate to a greater degree than those in the left ear which had been left in a passive state by the section of their nerves. This experiment, however, is by no means con- el nsive. The existence of vaso-dilator fibres was placed beyond doubt by the follow- ing experiment of Bernard on the chorda tympani nerve, new facts regarding the vaso-constrietor nerves being also secured. Bernard exposed the submax- illary gland of a digesting dog, removed the digastric muscle, isolated the nerves going to the gland, introduced a tube into the duct, and, finally, sought out aud opened the submaxillary vein. The blood contained in the vein was dark. The nerve-branch coming to the gland from the sympathetic w T as now ligated, whereupon the venous blood from the gland grew red and flowed more abundantly; no saliva was excreted. The sympathetic nerve was now stimu- lated between the ligature and the gland. At this the blood in the vein became dark again, flowed in less abundance and finally stopped entirely. On allow- ing the animal to rest the venous blood grew red once more. The chorda tympani nerve, coming from the lingual nerve, was now ligated, and the end in connection with the gland stimulated. Then almost at once saliva streamed into tiie duct, and large quantities of bright scarlet blood flowed from the vein in jets, synchronous with the pulse. This experiment may be .-aid to close the earlier history of the vaso-motor oerves. It was now established beyond question that the size of the blood- vessels, and thus the quantity of blood carried by them to different parts of the body, is controlled by nerves which when stimulated either narrow the blood vessels (vaso-constrictor aerves) and thus diminish the quantity of blood that (lows through them, or dilate the vessels (vaso-dilator nerves) and increase the flow. The section of vaso-constrictor nerves, for example those found in the cervical sympathetic, causes the vessels previously constricted by them to dilate. The section of a vaso-dilator nerve, for example the chorda tympani, running from the lingual nerve to the submaxillary gland, does not. however, cause the constriction of the vessels to which it is distributed. And finally, it was now determined that vaso-motor fibres are found in the sympathetic system as well as in the spinal cord and the cerebro-spinal nerves. CIRCULATION. 195 It remained for a later day to show that vasomotor nerves arc present in the veins as well as in the arteries. Mall has found that when the aorta is compressed below the left subclavian artery, the portal vein receives no more blood from the arteries of the intestine, yet remains for a time moderately full, because it cannot immediately empty its contents through the portal capil- laries of the liver against the resistance which they offer. If the peripheral end of the cut splanchnic nerve is now stimulated, the portal vein contracts visibly and may be almost wholly emptied. Thompson ' has extended the discovery of Mall to the superficial veins of the extremities. He finds that the stimulation of the peripheral end of the cut sciatic nerve, the crural arterv being tied, causes the constriction of the superficial veins of the hind limb. The contraction begins soon after the commencement of the stimulation, and usually goes so far as to obliterate the lumen of the vein. Often the contrac- tion begins nearer the proximal portion of the vein and advances toward the periphery. More commonly, however, it is limited to band-like constrictions between which the vein is filled with blood. After stimulation ceases the constrictions gradually disappear. A second and third stimulation produce much less constriction. The superficial veins of the rabbit's abdomen are constricted by the stimulation of the cervical spinal cord at the second ver- tebra. The observations of Bernard and his contemporaries led to a very great number of researches on the general properties and the distribution of the vaso-motor nerves, in the course of which a variety of ingenious methods of observation have been devised. Methods of Observation. — One fruitful method of research has been already incidentally mentioned, namely, the direct inspection of the vessel, or region, the vaso-motor nerves of which are being studied. A second method consists in accurately measuring the outflow from the vein. If the blood-vessels of the area drained by the vein are constricted by the stimulation of a vaso-motor nerve, the quantity escaping from the vein in a given period previous to constriction will be greater than that escaping in an equal period during constriction. This well-known method is especially avail- able where an artificial circulation is kept up through the organ studied, as the blood drained from the vein does not then weaken the animal and thus disturb the accuracy of the observations. 2 A third method is founded on the principle in hydraulics that the lateral pressure at any point in a tube through which a liquid How- depends, othei things being equal, on the resistance to be overcome below the poinl at which the pressure is measured. In the animal body the resistance to be overcome by the blood-stream varies with the state of contraction of the smaller vessels, and thus the variations in the lateral pressure of a given artery may. under certain restrictions, be used to determine variations in the size of the smaller 1 Thompson: Archivfur Physiologic, isii.",, p. KM; Bancroft: American Jou mI of Physiology, 1898, i. p. 177. 'Cavazzani ami Manca: Archives italiennes de Biologie, 1895, xxiv. p. '■'*'.'>. 196 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. vessels distal to the artery. The restrictions are, that the variations in the lateral pressure in the artery are indicative of changes in the size of the distal vessels only when the general blood-pressure remains unaltered, or alters in a direction opposite to the change in the artery investigated. An example will make this plain. Dastre and Morat, in order to demonstrate the presence of vaso-motor fibres for the hind limb in the sciatic nerve, connected a manometer with the central end of* the left femoral artery, and a second manometer with the peripheral end of the right femoral artery, distal to the origin of the pro- funda femori-. The anastomoses between the principal branches of the fem- oral artery are so numerous and so large that the circulation in the limb can be maintained by the profunda femoris alone. Dastre and Morat could there- fore compare the general blood -pressure with the blood-pressnre in the right hind limb. On stimulating the peripheral end of the right sciatic nerve, the blood-pressure rose in the arteries of the limb, but remained stationary in the arteries of the trunk, connected with the first manometer through the central end of the left femoral artery. The rise of blood-pressnre in the operated limb, while the blood-pressnre in the rest of the body remained unchanged, proved that the vessels in the operated limb were constricted. Many investigators have studied vaso-motor phenomena by means of the plcthysmograph, an apparatus invented by Mosso for recording the changes in the volume of the extremities. The member, the vaso-motor nerves of which are to be studied, is placed within a cylinder rilled with water, from which a tube leads to a recording tambour. An increase in the volume of the member, such as would be brought about by the expansion of its vessels, causes a corre- sponding volume of water to enter the tambour tube, thus raising the pressure in the tambour and forcing its lever to rise. A constriction of the vessels, on the contrary, causes the recording lever to fall. In addition to these general methods, special devices have been employed in the researches into the vaso-motor nerves of the brain. In considering the observations made with these various methods it will be advisable to begin with the differences between the two kinds of vaso-motor nerves. Differences between Vaso-constrictor and Vaso-dilator Nerves. — The differences between vaso-constrictor and vaso-dilator nerves are particularly interesting for the reason that both vaso-constrictor and vaso-dilator fibres are often found in one and the same anatomical nerve. The sciatic nerve is a ' g I example of this. By taking advantage of these differences the investi- gator may determine whether one or both kinds of fibres are present in an}' anatomical nerve; whereas, without this knowledge, the effects produced by the stimulation of the one mighl be wholly masked by the effects produced by the stimulatioD of the other. The vaso-constrictors are less easily excited than the vaso-dilators. The Hinnltaneous and equal stimulation of the dilator and constrictor nerves going to the submaxillary gland causes vaso-constriction, dilatation appearing after tin stimulation ceases, for the after-effect of excitation is of shorter duration CIRCULATION. 197 with the constrictors than with the dilators. Warming increases and cooling diminishes the excitability of the vaso-constrictors to a greater degree than is the case with the vaso-dilators. Thus if the hind limb of an animal be warmed, the stimulation of the sciatic nerve will cause vaso-constriction ; while if it be cooled the same stimulation will cause vaso-dilatation. 1 Vaso- constrictors are more sensitive to rapidly repeated induction shocks (tetaniza- tion) and less sensitive to single induction shocks than are vaso-dilators. Thus if the sciatic nerve is stimulated with induction shocks of the same strength, it will be found that a rapid repetition of the stimuli will give vaso-constriction, while with single shocks at intervals of five seconds vaso-dilatation is the result. Vaso-constrictors degenerate more rapidly than vaso-dilators after separation from their cells of origin. The stimulation of the peripheral end of the frog's sciatic nerve immediately after section causes constriction. Several days later the same stimulation causes vaso-dilatation, the constrictor nerves having already degenerated (see Fig. 44, B). The maximum effect of stimulation is more quickly reached with the vaso-constrictor than with the vaso-dilator nerves. There is also a difference in the latent period, or interval between stimulation A B Fig. 44.— Curves obtained by enclosing the hind limb of a cat in the plethysmograph and stimu- lating the peripheral end of the cut sciatic nerve (Bowditch and Warren, 1886, p. 447). The curves read from right to left. In each case the vertical lines show the duration of the stimulus — namely, fifteen induction shucks per second during twenty seconds. Curve A shows the contraction of the vessels pro- duced by the excitation of the freshly-divided nerve; curve B, the dilatation produced by an equal excitation of the nerve of the opposite side four days after section, the vaso-constrictor nerves having degenerated more rapidly than the vaso-dilators. and response. Bowditch and Warren have found the latent period of the vaso-constrictor fibres iu the sciatic to be about 1.5 seconds, while that of the vaso-dilators is 3.5 seconds. Finally, the two sorts of nerves have been said to differ in the manner in which they are distributed. The vaso-constrictor nerves leave the cord as medullated fibres, enter the sympathetic chain of gan- glia and end in terminal branches probably in contact with a sympathetic ganglion-cell. The constrictor impulse is forwarded to the vessel by a process of this cell, either directly or by means <>f -till other sympathetic ganglion-cells. The vaso-dilator fibre, on the contrary, was thought to run directly from the cord to the blood-vessel ; but recent investigations make it probable that all spinal vaso-motor fibres end in sympathetic ganglia. Origin and Course. — The vaso-motor nerves the general properties of which have just been studied are axis-cylinder processes of sympathetic gan- glion-cells. They follow, fir a time at least, the course of the corresponding 'Howell, Budgett, and Leonard: Journal of Physiology, L894, \\i. p. 298. 198 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. spinal nerve. According to Langley, 1 they do not differ from the pilo-motor and secretory nerves except in the nature of the structure in which they termi- nate. They are not interrupted by other nerve-cells on their course. The action of the sympathetic vaso-motor cells is influenced by the vaso-motor cells of the spinal cord and bulb. These are probably small cells situated at various levels in the anterior horn and lateral gray substance. Their axis- cylinder processes leave the cerebro-spinal axis by the anterior roots 2 of certain spinal and by certain cranial nerves, and enter sympathetic ganglia, where they end in terminal twigs probably in contact with the sympathetic vaso-motor cells. The vaso-motor cells lying at various levels in the cerebro- spinal axis are in turn largely controlled by an association of cells situated in the bulb and termed the vaso-motor centre. The neuraxons (axis-cylinder processes) of the cells composing this "centre" pass in part to the nuclei of certain cranial nerves and in part down the lateral columns of the cord, to end in contact with the spinal vaso-motor cells. The vaso-motor apparatus consists, then, of three classes of nerve-cells. 3 The cell-bodies of the first class lie in sympathetic ganglia, their neuraxons passiug directly to the smooth mus- cle- in the walls of the vessels; the second are situated at different levels in the cerebro-spinal axis, their neuraxons passing- thence to the sympathetic gan- glia by way of the spinal and cranial nerves; and the third are placed in the bulb and control the second through intraspinal and intracranial paths. The nerve-cell of the first class lies wholly without the cerebro-spinal axis, the third wholly within it, while the second is partly within and partly without, and binds together the remaining two. The evidence for the existence of these vaso-motor nerve-cells must now be considered. We shall begin with those of the third class, constituting the so-called bulbar vaso-motor centre. Bulbar Vaso-motor Centre. — The section of the spinal cord near its junction with the bulb is followed by the general dilatation of the blood- vessels of the trunk and limbs. The dilated vessels are again constricted when the severed fibres in the spinal cord are artificially stimulated. Hence the section caused the dilatation by interrupting the vaso-constrictor impulses passing from the bulb to parts below. The position of the bulbar vaso- constrictor centre has been determined by Owsjannikow and Dittmar. The former observer divided the bulb transversely at various levels. When the section fell immediately caudal to the corpora quadrigeraina, only a slight temporary rise in blood-pressure was observed. When, however, the section fell a millimeter or two nearer the cord, a considerable and permanent fall in the blood-pressure was noted. Further lowering was seen as the sections were carried still farther toward the spinal cord, until at length, about four millimeters from the corpora quadrigemina, no further fall took place. The ' Langley ' f Physiology, 1894, xvii. p. 314. 'Compare Werziloff: Centralblalt fur Physiologi' , ISO*), x. p. 194. I'.\ "nerve-cells" is meant the cell-body with nil its processes, namely, the neuraxon, or axis-cylinder process, and the dendrites, <>r protoplasmic processes. CIRCULA TION. 199 ana from which the vaso-constrictor nerves receive a constant excitation extends, therefore, in the rabbit, over about three millimeters of the bulb not far from the corpora quadrigemina. Two years after this investigation I>itt- mar added to the observations of Owsjannikow the fact that the vaso-con- strictor centre is bilateral, lying in the anterior part of the lateral columns on both sides of the median line. At this site is found a group of ganglion-cells known as the antero-lateral nucleus of Clarke. It is possible, though far from certain, that these are the cells of the vaso-constrictor centre. The vaso-constrictor centre in the bulb is always in a state of action, or "tonic" excitation, as is shown by the dilatation of the vessels when deprived of their constrictor impulses through the section of the spinal cord. It is not definitely known whether a vaso-dilator centre is present in the bulb. Spinal Centres. — A complete demonstration of the existence of vaso-motor centres in the spinal cord, first suggested by Marshall Hall, was made by Goltz and Freusberg in their experiments on dogs which had been kept alive after the division of the spinal cord at the junction of the dorsal and the lumbar regions. This operation cuts off both sensory and motor communication between the parts lying above and below the plane of section, and divides the animal physiologically into a fore dog and a hind dog, to use the author's expression. The investigator can now explore the lumbar cord unvexed by cerebral impulses. A great number of motor reflexes formerly thought to have their centres exclusively in the brain are by this means found to take place in the absence of the brain. 1 That vaso-motor reflexes were among them was discovered by accident. It was noticed that the mechanical stimulation of the skin of the abdomen and penis while the animal was being washed provoked erection, which, as Eckhard had discovered some years before, is a reflex action due to the dilatation of the arteries of the penis through impulses conveyed by the nervi erigentes. Pressure on the bladder, or the walls of the rectum, also had this effect. After the destruction of the lumbar cord this reflex was no longer possible. The vessels of the hind limb are also connected with vaso- motor cells in the lumbar cord. Soon after the section of the cord in the dorsal region the hind paws are observed to be warmer than the fore paws, and the arteries of the hind limb are seen to beat more strongly. This is the resuli of cutting off the vaso-constrictor impulses from the bulbar centre to the vessels in question. If the animal survives a considerable time the hind paws will be observed to grow cooler from day to day until they are again no warmer than the fore paws. Destruction of the lumbar cord now causes the tempera- ture of the hind limbs to rise again. The conclusion drawn from these observations is that vaso-motor cells are present in the spinal cord. It is probable that they are normally subordinated to the bulbar nerve-cells and requires certain time after separation from the bulb in order to develop their previously rudimentary powers. Hence the 1 Later experiments by < roltz \w\ Ewald, showing the degree of independence of the spinal cord possessed by sympathetic vaso-motor neurons, will presently be cited. 200 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. interval of many days between the section and the return of arterial tone in areas distal to the section. It has been suggested that during this period the power of the spinal nerve-cell is inhibited by impulses proceeding from the cut sur- face of the cord, 1 but this long inhibition is questionable in view of the fact that transverse section of the cord in rabbits and dogs does not inhibit the phrenic nuclei. 2 The spinal nerve-cell take- part in vaso-motor reflexes. Thus the stimu- lation of the central end of the brachial nerves after section of the spinal cord at the third vertebra causes a dilatation of the vessels of the fore limb. The stimulation of the central end of the sciatic nerve after the division of the spinal cord causes a general rise of blood-pressure indicating the constriction of many vessels. The sensory stimulation of one hind limb may cause reflexly a narrowing of the vessels in the other, after the spinal cord is severed in the mid-thoracic region. In asphyxia, after the separation of the cord from the brain, vascular constriction is produced reflexly through the spinal centres. This constriction is not observed if the cord is previously destroyed. Goltz and Ewald find that the tonic constriction of the vessels of the hind limbs returns after the extirpation of the lower part of the spinal cord. Sympathetic Vaso-motor Centres. — Gley 3 finds that after the destruc- tion of both bulbar and spinal centres some degree of vascular tone is still maintained. The extraordinary experiments of Goltz and Ewald place this fact beyond question. These physiologists remove the lower part of the spinal cord completely, taking away 80 millimeters or more. For a few days after the operation the hind limbs are hot and red, from dilatation of their blood- vessels. Soon, however, the hind limbs become as cool, and sometimes even cooler, than the fore limbs, their arterial tonus being re-established and main- tained without the help of the spinal cord. The sympathetic ganglia are probably also centres of reflex vaso-motor action. The fact that these ganglia act as centres for other motor reflexes would itself suggest this possibility. Evidence of the vaso-motor reflex function of the first thoracic ganglion has been offered recently by Francois- Franck. 4 The two branches composing the annulus of Vieussens contain both afferent and efferent fibres. If one of the branches is cut, and the end in con- nection with the first thoracic ganglion is stimulated, the ganglion having been 6 sparated from the spinal cord by the section of the communicating branches, a constriction of the vessels of the ear, the submaxillary gland, and the nasal mucous membrane may be observed. This evidence, together with the probability that the neuraxons of all the spinal vaso-motor cells end in sympathetic ganglia, 5 makes it fairly credible that the sympathetic vaso-motor nerve-cell possesses central functions. 1 Goltz and Ewald: Arrhiv fiir die gesammte Physiologie, 1896, lxiii. p. 397. 'Porter: Journal 'of Physiology, 1895, xvii. p. 459. 3 Gley: Archives de Physiologic, 1894, p. 704. * Franck : Archives de Physiologie, 1894, p. 721. 5 See the statement of Langley's results with the nicotin method on page '208. CIR CULA TION. 20 1 There has been much discussion over the meaning of the rhythmic con- tractions observed in certain blood-vessels apparently independent of the cen- tral nervous system. 1 The median artery of the rabbit's ear, the arteria saphena in the same animal, and the vessels in the frog's web and frog's mes- entery, slowly contract and relax. This rhythmic contraction is easily seen in the ear of a white rabbit. The movements are possibly of purely muscular origin, but are more probably the result of periodical discharges by vaso-motor nerve-cells. Rhythmical variations in the tonus of the vaso-constrictor centres are often held to explain the oscillations seen in the blood-pressure curve after the influence of thoracic aspiration has been eliminated by opening the chest and cutting the vagus nerves. These oscillations are of two sorts. In the one, the blood-pressure sinks with every inspiration and rises with every expiration, though the rise and fall are not precisely synchronous with the respiratory movements ; in the other, the so-called Traube-Hering waves, the oscillations embrace several respirations. It has also been suggested that these phenomena are due to periodical changes in the respiratory centre affecting the vaso-con- strictor centre by " irradiation." Vaso-motor Reflexes. — The vaso-motor nerves can be excited reflexly by afferent impulses conveyed either from the blood-vessels themselves or from the end-organs of sensory nerves in general. The existence of reflexes from the blood-vessels may be shown by Heger's experiment. Heger observed a rise of general blood-pressure with a subsequent fall, and at times a primary fall, after the injection of nitrate of silver into the peripheral end of the crural artery of a rabbit. The limb, with the exception of the sciatic nerve, was severed from the trunk. The quantity injected was so small that it probably was decomposed before passing the capillaries or escaping from the blood- vessels. Thus the effect exerted by the nitrate of silver on the general blood- pressure was probably caused by afferent impulses set up in the blood-vessels themselves and transmitted through the sciatic nerve to the vaso-motor cen- tres. Vaso-motor reflexes are, however, much more commonly produced by the stimulation of sensory nerves other than those present in the blood- vessels. The reflex constriction or dilatation 2 appears usually in the vascular area from which the afferent impulses arise. For example, the stimulation of the central end of the posterior auricular nerve in the rabbit causes a passing con- striction followed by dilatation, or a primary dilatation often followed by constriction of the vessels in the ear. The stimulation of the nervi erigentes causes dilatation of the vessels of the penis. Gaskell found thai tin 1 vessels of the mylo-hyoid muscle widened on stimulating the mucous membrane at the entrance of the glottis. 1 Franck : Archives de Physiologic, 1803, p. 729; Lui: Archives ilaliennes de Biologic, 1894, xxi. p. 416 ; Goltz and Ewald : Archivf&r die gesammte Physiologic, 1890, lxiii. p. 396. ' z Hegglin : Zeitschrifl filr klinische Medicin, 1894, xxvi. p. 25. 202 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. The vascular reflex ' may appear in a part associated in function with the sensory surface stimulated. Thus the stimulation of the tongue causes dilata- tion of the blood-vessels in the submaxillary gland. Frequently the vascular reflex is seen on both ^i«lts of the body. The stimulation of the mucous membrane on one side of the nose may cause vascular dilatation in the whole head; the effect in this case is usually more marked on the side stimulated. The vessels of one hand contract when the other hand is put in cold water. Sometimes distant and apparently unrelated parts are affected. Vulpian noticed that the stimulation of the central end of the sciatic caused the vessels of the tongue to contract. 2 The vascular changes produced reflexly in the splanchnic area are of especial importance because of the great number of vessels innervated through these nerves and the great changes in the blood-pressure that can follow dilata- tion or constriction on so large a scale. There is in some degree an inverse relation between the vessels of the skin and deeper parts on reflex stimulation of the vaso-motor centres. The super- ficial vessels are often dilated while those of deeper parts are constricted. 3 Thus the stimulation of the central end of the sciatic nerve may cause a dilata- tion of the vessels of the lips, hand in hand with a rise in general blood-pres- sure. 4 Exposing a loop of intestine dilates the intestinal vessels in the rabbit, but constricts those of the ear. In asphyxia, the superficial vessels of the ear, face, and extremities dilate, while the vessels of the intestine, spleen, kidneys and uterus are constricted. Relation of Cerebrum to Vaso-motor Centres. — A rise of general blood- pressure has been produced by the stimulation of different regions of the cortex and of various other parts of the brain ; for example, the crura cerebri and corpora quadrigemina. Yaso-dilatation has also been observed. The motor area of the cortex especially seems closely connected with the bulbar vaso- motor centres. There is, however, no conclusive evidence that special vaso- motor centres exist in the brain aside from the bulbar centres already described. At present the safer view is that the changes in blood-pressure called forth by the stimulation of various parts of the brain are reflex actions, the afferent im- pulse starting in the brain as it might in any other tissue peripheral to the vaso-motor centres. Pressor and Depressor Fibres. — The stimulation of the same afferent nerve sometimes causes reflex dilation of the vessels of a part, instead of the more usual reflex constriction. Two explanations of this fact have been sug- gested. The first assumes that the condition of the vaso-motor centre varies in such a way that the same stimuli might produce contrary effects, depending on the relation between the time of stimulation and the condition of the centre. 1 The general arrangement of the matter in this paragraph is that given hy Tigerstedt, Der mf 1893, p. 519. * Compare Sergejew : Gentralblatt fur die medicinische Wissemehaft, 1894, ]>. 162. s Wertheimer : Gomptes rendus, 1893, cxvi. p. 595; rlallion and Franck: Archives de Physi- olo'ii , 1896, p. 502; Bayliss and Bradford: Journal of Physiology, 1SU4, xvi. p. 17. i [sergin: Arehivfur Physiologic, L894, p. 448. CIRCULATION. 203 The second assumes the existence of special reflex constrictor or "pressor" fibres, and reflex dilator or "depressor" fibres. The existence of at least one depressor nerve is beyond question, namely the cardiac depressor nerve, which it will be remembered runs from the heart to the bulb and when stimulated causes a dilatation of the splanchnic and other vessels reflexly through the bulbar vaso-motor centre. Evidence of other reflex vaso-dilator nerves and of reflex vaso-constrictor fibres as well has been offered by Latschenberger and Deahna, Howell, 1 and others. Howell, for example, has found that if a part of the sciatic nerve is cooled to near 0° C. and the central end stimulated periph- erally to this part, the blood-pressure falls, instead of rising, as it does when the nerve is stimulated without previous cooling. Howell's experiments have been recently extended by Hunt, who finds that the stimulation of the sciatic during its regeneration after section gives at first vaso-dilatation only, but when regeneration has progressed still further, vaso-constriction is secured. These results point to the existence of both pressor and depressor fibres, the latter being the first to regenerate after section. A reflex fall in blood-pressure is also produced by stimulating various mixed nerves with weak currents and bv the mechanical stimulation of the nerve-endings in muscle. The fall is more readily obtained when the animal is under ether, chloroform, or chloral, less readily under curare. Topography. — We pass now to the vaso-motor nerves of various regions. Brain. 2 — The study of the innervation of the intracranial vessels is ren- dered exceptionally difficult by the fact that the brain and its blood-vessels are placed in a closed cavity surrounded by walls of unyielding bone. The funda- mental difference created by this arrangement between the vascular phenomena of the brain and those of other organs was recognized in part at least by the younger Monro as long ago as 1783. Monro declared that the quantity of blood within the cranium is almost invariable, " for, being enclosed in a case of bone, the blood must be continually flowing out of the veins that room may be given to the blood which is entering by the arteries, — as the substance of the brain, like that of the other solids of our body, is nearly incompress- ible." Further differences between the circulation in the brain and in other organs are introdueed by the presence of the cerebrospinal fluid in the ventri- cles and in the arachnoidal spaces at the base of the brain. This fluid may pass out into the spinal canal and thus leave room for an increase in the amount of blood in the cranium. Finally, a rise of pressure in the arteries too great to be compensated by the outflow of cerebro-spinal fluid may lead to com- pression of the venous sinuses and a decided change in the relative distri- bution of the blood in the arteries, capillaries and vein — conditions which are not present in extracranial tissues. It is evident, therefore, thai the methods employed in the search for vaso-motor nerves within the cranium must take 'Howell, Budgett, and Leonard Journal of Physiology, 1894, xvi. p. .' : Bayliss: Ibid., 1893, xiv. p. 317 ; Bradford and Dean: Ibid,, 1894, xvi. p. 67 ; Hunt: Ibid., 1895, xviii. p. 381. 1 Cavazzani: Archives italiennes de Biologie, 1893, xviii. p. 54, lix. p. 214; Bayliss and Hill: Journal of Physiology, 1895, xviii. p. 334; Gulland: Ibid., p. 361. 204 AN AMERICAN TEXT- BOOK OF PHYSIOLOGY. into account many sources of error that are absent in vaso-motor studies of other regions. It is, indeed, probable that incompleteness of method will go far Toward explaining the disagreement of authors as to the presence of vaso- motor nerves in the brain. According to Bayliss and Hill, who have recently studied this subject, it is necessary to record simultaneously the arterial pressure, the general venous pressure, the intracranial pressure and the cerebral venous pressure, the cranium as in the normal condition being kept a closed cavity. In their experiments, "a cannula was placed in the central end of the carotid artery. A second long cannula was passed down the external jugular vein, and on the same side, into the right auricle. The torcular Herophili was trephined, and a third cannula, this time of brass, was screwed into the hole thus made." The intracranial pressure was recorded by a cannula connected through another trephine-hole with the subdural space. Bayliss and Hill could find no evidence of the existence of cerebral vaso- motor nerves. The cerebral circulation, according to them, passively follows the changes in the general arterial and venous pressure. Gulland has examined the cerebral vessels by the Golgi, Ehrlich, and other methods, to determine whether nerve-fibres could be demonstrated in them. None were found. It is probable that the blood-supply to the brain is regnlated through the bulbar va-n-eonstrictor centre. Anaemia or asphyxia of the brain stimulates the cells composing this centre, vascular constriction of many vessels follows, and more blood enters the cranial cavity. The vessels of the splanchnic area play a chief part in this regulative process. 1 Their importance to the circulation in the brain is shown by the fatal effect of the section of the splanchnic nerves in the rabbit. On placing the animal on its feet, so much blood flows into the relaxed abdominal vessels that death may follow from anaemia of the brain. Vaso-motor Nerves of Head. — The cervical sympathetic contains vaso-con- strictor fibres for the corresponding side of the face, the eye, ear, salivary glands and tongue, and possibly the brain. The spinal vaso-constrictor fibres tor the vessels of the head in the cat and dog leave the cord in the first five thoracic nerves ; in the rabbit, in the second to eighth thoracic, seven in all. Vaso-dilator fibres for the face and month have been found in the cervical sympathetic by Dastre and Morat, leaving the cord in the second to tilth dorsal nerves, and uniting (at least for the most part) with the trigeminus by passing, according to Morat, from the superior cervical >yinpathetic ganglion to the ganglion of Gasser. Other dilator fibres for the skin and mucous membrane of the face and mouth arise apparently in the trigeminus, for the stimulation of this nerve between the brain and Gasser's ganglion causes dila- tation of the vessels of the face, 2 and in the nerve of Wrisberg. The vaso-motor nerves of the tongue have been recently studied by Isergin. 3 1 Wertheiiner : Archives de Physiologic, 1893, p. 297. 2 Langley: Philosophical Transactions, 1892, j). 104 ; Piotrowsky : Ccntralblatt fiir Physiologic 1892, vi. p. 464. 3 Isergin : Archie fiir Physiologic, 1894, p. 441. CIRCULATION. 205 The lingual and the glossopharyngeal nerves are recognized by all authors as dilators of the lingual vessels. The sympathetic and the hypoglossus contain constrictor fibres for the tongue. It is possible that the lingual contains also a small number of constrictor fibres. Most if not all these vasomotor fibres arise in the sympathetic and reach the above-mentioned nerves by way of the superior cervical ganglion. They degenerate in from three to five weeks after the extirpation of the ganglion. Morat and Doyon cut the cervical sympathetic in a curarized rabbit and examined the retinal arteries with the ophthalmoscope. They were found dilated. The excitation of the cervical sympathetic caused constriction, the excitation of the thoracic sympathetic dilatation of these vessels. The retinal fibres leave the sympathetic at the superior cervical ganglion and pass along the communicating ramus to the ganglion of Gasser, whence they reach the eye through the ophthalmic branch of the fifth nerve, the gray root of the ophthalmic ganglion, and the ciliary nerves. Most, or all, of the fibres for the anterior part of the eye are found in the fifth nerve. Lungs. — The methods ordinarily employed for the demonstration of vaso- motor nerves cannot without danger be used in the studv of the innervation Fig. 45.— The excitation of the central end of the inguinal branch of the crural (sciatic) nerve causes a rise in the aortic pressure (Pr A.F.), a rise in the pressure in the pulmonary artery (Pr.A.P.) of 10 to 16 mm Hg, accompanied by a falling pressure in the left auricle (Pr.O.G.) (Franck, 1896, p 184). The rise of pressure in the pulmonary artery, together with the fall in the left auricle, demonstrate, according to Franck, a constriction of the pulmonary vessels. of the pulmonary vessels. 1 A fall in the blood- pressure in the pulmonary artery, for example, produced by stimulating any nerve cannot be taken as final evidence that the stimulation caused the constriction of the pulmonary vessels. The lesser circulation is so connected that changes in the calibre of the vessels of a distant part, the liver for example, may alter the quantity of blood in the lungs. The method of Cavazzani avoid- these difficulties. Cavazzani establishes an artificial circulation through one lobe of' a lung in 1 Doyon : Archives de Physiologic, 1893, p. L0] ; Henriques : SkaTidinavisches Archiv fur Physi- ologic, 189.3, iv. p. 2'2\) ; Bradford and Dean : Journal, of Physiology, L894, xvi. p. 34 ; Franck: Archives de Physiologie, L896, |>. L78. 206 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. a living animal, and measures t h< - outflow per unit of time. An increase iu the outflow means a dilatation of the vessels, diminution means constriction. He finds thai the outflow diminishes in the rabbit when the vagus is stimulated in the neck, and increases when the cervical sympathetic is stimulated. Franck measures the pressure simultaneously in the pulmonary artery and left auricle, a method apparently also trustworthy. The stimulation of the inner surface of the aorta causes a rise of pressure in the pulmonary artery and a simul- taneous fall in the left auricle, indicating, according to Franck, the vaso-con- strictor power of the sympathetic nerve over the pulmonary vessels. A reflex constriction is also produced by the stimulation of the central end of a branch of the sciatic, intercostal, abdominal pneumogastric, and abdominal sympa- thetic nerves (see Fig. 45). Heart. — Vaso-motor fibres lor the coronary arteries of the heart have been described. 1 Intestines.' 2 — The mesenteric vessels receive vaso-constrictor fibres from the sympathetic chiefly through the splanchnic nerve. The vaso-constrictors of the jejunum, as a rule, begin to be found in the rami of the fifth dorsal nerves ; a little lower down, those for the ileum come off; and still lower down, those for the colon ; none arise below the second lumbar pair. According to Hal- lion and Franck, vaso-dilator fibres are present in the same sympathetic nerves that contain vaso-constrictors. The dilator fibres are most abundant or most powerful in the rami of the last three dorsal and first two lumbar nerves. There is some evidence of the presence of vaso-dilator fibres in the vagus. The excitation of the vaso-constrictor centres by the blood in asphyxia pro- duces constriction of the abdominal vessels. The vaso-dilator as well as the vaso-constrictor fibres of the splanchnic probably end in the solar and renal plexuses. Liver. — Cavazzani and Manca 3 have recently attempted to show the pres- ence of vaso-motor fibres in the liver. Their method consists in passing warm normal saline solution from a Mariotte's flask at a pressure of 8 to 10 milli- meters Hg through the hepatic branches of the portal vein and measuring the outflow in a unit of time from the ascending vena cava. On stimulating the splanchnic nerve they observed that the outflow was usually diminished though sometimes increased, indicating perhaps that the splanchnics contain both vaso-constrictor and vaso-dilator fibres for the hepatic branches of the portal vein. The vagus appeared to contain vaso-dilator fibres. Further studies are necessary, however, before pronouncing definitely upon these questions. 'Porter: Boston Medical and Surgical Journal, 1896, ex xxiv. 39 ; Porter and Beyer: Ameri- Journal of Physiol xj ij, 1900, iii. j>. xxiv. ; Maass : Archiv fiir du : ,< ammte Physialogie, 1899, Ixxiv. p. 281. - rlallion ami Franck : Archives de Physiologie, 1896, xxviii. pp. 478, 193 ; Bunch : Journal <>f Physiology, 1899, xxiv. p. 72. '< avazzani and Manca: Archives italiennes ' Biologic, L895, xxiv. p. :;:;; Franpois-Franck and Hallion: Archives d Physiologie, L896, pp. 908, 923; 1897, pp. 134, 148. CIRCULATION. 207 Kidney} — The vasomotor nerves of the kidney leave the cord from the sixth dorsal to the second lumbar nerve. In the dog, most of the renal vaso- motor fibres are found in the eleventh, twelfth, and thirteenth dorsal nerves. The stimulation of the nerves entering the hilus of the kidney between the artery and vein causes a marked and sudden renal contraction, hut the organ soon regains its former volume. Constriction follows also the stimulation of the peripheral end of the cut splanchnic nerve. Bradford has demonstrated renal vaso-dilator fibres for certain nerves by stimulating at the rate of one induction shock per second. For example, the excitation of the thirteenth dorsal nerve with 50 to 5 induction shocks per second gave always a constric- tion of the kidney, but when a single shock per second was employed, the kidney dilated. If the cells connected with the renal vaso-motor fibres are stimulated directly by venous blood as in asphyxia, the animal being curarized, a decided constriction of the kidney results. The reflex excitation of these cells is of especial importance. The stimulation of the central end of the sciatic or the splanchnic nerves causes renal constriction. The same effect is easily produced by stimulating the skin, for example, by the application of cold. The stimulation of the sole of the foot in a curarized dog caused contraction of the renal vessels. There is some evidence that the splanchnic vaso-motor fibres for the kidney end in the cells of the renal plexus. Spleen. — The stimulation of the peripheral end of the splanchnic nerves causes a sudden and large diminution in the volume of the spleen/ It is, however, not certain whether the constriction of the spleen is to be referred primarily to a constriction of its blood-vessels or to the contraction of the intrinsic muscular fibres which play so large a part in the changes of volume of this organ. The doubt is strengthened by the fact that section of the splanchnic nerves does not alter the volume of the spleen ; dilatation would be expected were these nerves the pathway of vaso-constrictor fibres for the spleen. Pancreas. — Francois-Franck and Hallion find vaso-constrictor fibres in the sympathetic chain between the sixth and eleventh ribs; they leave the spinal cord from the fifth dorsal to the second lumbar ramus ( imunicans, pass into the greater and lesser splanchnic nerves, and reach the gland along the pancreatic artery. A few dilator fibres were found in the sympathetic ; more in the the vagus.' 5 Externa/ Generative Organs/ — The recent history of the vaso-motor nerves of the external generative organs— namely, those developed from the urogenital sinus and the skin surrounding the urogenital opening — begins with Eck- 1 Wertheimer : Archives de Physiologic, 1894, p. 308; Baylisa ami Bradford: Journal of Physiology, 1894, \vi. p. 17. "Schaferand Moore: Journal of Physiology, 1896, xx. p. 1. 3 Franck and Hallion: Archives de Physiologie, L896, pp. 908,923. *Franck: Archives de Physiologie, 1895, p. 122; Langle; and Anderson: Journal of Physi- ology, 1895, six. p. 76. l'hs AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. hard, who showed that the stimulation of certain branches of the first and second, and occasionally the third, sacral nerves (dog) caused a dilatation of the blood-vessels of the penis and erection of that organ, and with Goltz, who found an erection centre in the lumbo-sacral cord. Numerous researches in recent years, among which the reader is referred especially to the work of Langley and Langley and Anderson, have shown that the vaso-motor nerves of the external generative organs of both sexes may be divided into a lumbar and a sacral group. The lumbar fibres pass out of the cord in the anterior roots of the second, third, fourth, and fifth lumbar nerves, and run in the white rami communi- cant'- to the sympathetic chain, from which they reach the periphery either by way of the pudic nerves or by the pelvic plexus. The greater number take the former course, running down the sympathetic chain to the sacral ganglia, and passing from these ganglia through the gray rami communicantes to the sacral nerves. None of the fibres thus derived enter the nervi erigentes of Eckhard. Of the various branches of the pudic nerves (rabbit), the nervus dorsalis causes constriction of the blood-vessels of the penis and the peri- neal nerve contraction of the blood-vessels of the scrotum. The course by way of the pelvic plexus is taken by relatively few fibres. They run for the most part in the hypogastric nerves, a few sometimes joining the plexus from the lower lumbar or upper sacral sympathetic chain, or from the aortic plexus. The presence of vaso-dilator fibres in the lumbar group is disputed. The sacral group of nerves leave the spinal cord in the sacral nerve roots. Their stimulation causes dilatation of the vessels of the penis and vulva. Internal Generative Organs (those developed from the Miillerian or the Wolffian ducts). — Langley and Anderson find vaso-constrictor fibres for the Fallopian tubes, uterus, and vagina in the female, and the vasa deferentia and seminal vesicles in the male, in the second, third, fourth, and fifth lumbar nerves. The internal generative organs receive no afferent, and probably no efferent, fibres from the sacral nerves. The position of the sympathetic ganglion-cells, the processes of which carry to their peripheral distribution the efferent impulses brought to them by the efferent vaso-motor fibres of the spinal cord, may be determined by the nicotin method of Langley. About 10 milligrams of nicotin injected into a vein of a cat prevent for a time, according to Langley, 1 any passage of nerve-impulses through a sympathetic cell. Painting the ganglion with a brush dipped in nicotin solution has a similar effect. The fibres peripheral to the cell, on the contrary, are not paralyzed by nicotin. Now, after the injection of nicotin the stimulation of the lumbar nerves in the spinal canal has no effect on the vessels of the generative organs. Hence all the vaso-motor fibres of the lumbar nerves musl be connected with nerve-cells somewhere on their course. The lumbar fibres which run outward to the inferior mesenteric ganglia are for the most part connected with the cells of these ganglia. A lesser number is con- 1 Langley and Anderson : Journal of Physiology, 1894, xvi. p. 420. CIRCULATION. 209 nected with small ganglia lying as a rule near the organs to which the nerves are distributed. The remaining division of lumbar fibres running downward in the sympathetic chain, and including the majority of the nerve-fibres to the external generative organs are connected with nerve-cells in the sacral gan- glia of the sympathetic. The sacral group of nerves enter ganglion-cells scattered on their course, most of the nerve-cells for any one organ being in ganglia near that organ. Bladder. — Neither lumbar nor sacral nerves send vaso-motor fibres to the vessels of the bladder. Portal System. — It has already been said that vaso-constrictor fibres for the portal vein were discovered by Mall in the splanchnic nerve. Constrictor fibres have been found by Bayliss and Starling 1 in the nerve-roots from the third to the eleventh dorsal inclusive. Most of the constrictor nerves pass out from the fifth to the ninth dorsal. Back. — The dorsal branches of the lumbar and intercostal arteries, issuing from the dorsal muscles to supply the skin of the back, 2 can be seen to con- tract when the gray ramus of the corresponding sympathetic ganglia are stimulated. Limbs. 3 — The vaso-motor nerves of the limbs in the dog leave the spinal cord from the second dorsal to the third lumbar nerves. The area for the hind limb, according to Bayliss and Bradford, is less extensive than that for the fore limb, the former receiving constrictor fibres from nine roots, namely the third to the eleventh dorsal, the latter from six roots, the eleventh dorsal to third lumbar. Langley finds that the sympathetic constrictor and dilator fibres for the fore foot are connected with nerve-cells in the ganglion stella- tum ; while those for the hind foot are connected with nerve-cells in the sixth and seventh lumbar, and the first, and possibly the second, sacral ganglia. Thompson and Bancroft have studied the nerves to the superficial veins of the hind limb. The latter finds that in general the arrangement of the vaso-motor nerves corresponds to that of the arterial vaso-motor nerves and the sweat fibres. The fibres to the superficial veins originate from the lower end (first to fourth lumbar nerves) of the region of the spinal cord supplying all the vaso-motor nerves for the hind limbs. Tail. 4 — Stimulation of any part of the sympathetic from about the third lumbar ganglion downward almost completely stops the flow of blood from wounds in the tail. The vaso-motor fibres for the tail leave the cord chiefly in the third and fourth lumbar nerves. Their stimulation may cause primary dilatation followed by constriction. Muscles. — According to Gaskell, the section of the nerve belonging to 1 Bayliss and Starling: Journal of Physiology, 1894, xvii. p. 125. 2 Langley : Journal of Physiology, 1894, xvii. |>. 314. :1 Thompson : Archiv fur Physiohgie, 1893, p. 104; Wertheinier : Archives de Physiologic 1894, p. 724; Bancroft: American Journal of Physiology, 1898, i. p. 477 ; Bayliss and Bradford: Journal of Physiology, 1894, xvi. p. 16; Langley: Journal of Physiology, 1894, xvii. p. 307; Piotrowski : Archiv fur die ycsmnmfe Physiologic, 1893, lv. p. 268. 4 Langley : Journal of Physiology, 1894, xvii. p. 311. Vol. I.— 14 210 Ay AMERICAN TEXT-BOOK OF PHYSIOLOGY. any particular muscle or group of muscles causes a temporary increase in the amount of blood which flows from the muscle vein. The stimulation of the peripheral end of the nerve also increases the rate of flow through the muscle. The same increase is seen on stimulation of the nerve when the muscle is kept from contracting by curare, provided the drug is not used in amounts sufficient to paralyze the vaso-dilator nerves. Mechanical stimulation by crimping the peripheral end of the nerve gives also an increase. The existence of vaso- dilator nerves to muscles must therefore be conceded. The presence of vaso-con- strictor fibres is shown by the diminution in outflow from the left femoral vein which followed Gaskell's stimulation of the peripheral end of the abdominal sympathetic in a thoroughly curarized dog, but the supply of constrictor fibres is comparatively small. In curarized animals reflex dilatation apparently follows the stimulation of the nerves the excitation of which would have caused the contraction of the muscles observed, had not the occurrence of actual contrac- tion been prevented by the curare. The stimulation of the central end of nerves not capable of calling forth reflex contractions in the muscles observed — for example, the vagus — seems to cause constriction of the muscle- vessels. IV. SECRETION. A. General Considerations. The term secretion is meant ordinarily to apply to the liquid or semi- liquid products formed by glandular organs. On careful consideration it becomes evideut that the term gland itself is widely applied to a variety of structures differing greatly in their anatomical organization — so much so, in fact, that a general definition of the term covering all cases becomes very indefinite, and as a consequence the conception of what is meant by a secretion becomes correspondingly extended. Considered from the most general standpoint we might define a gland as a structure composed of one or more gland-cells, epithelial in character, which forms a product, the secretion, that is discharged either upon a free epithelial surface such as the skin or mucous membrane, or upon the closed epithelial surface of the blood- and lymph-cavities. In the former case — that is, when the secretion appears upon a free epithelial surface communi- cating with the exterior, the product forms what is ordinarily known as a secretion; for the sake of contrast it might be called an external secretion. In the latter case the secretion according to modern nomenclature is designated as an internal secretion. The best-known organs furnishing internal secretions are the liver, the thyroid, and the pancreas. It remains possible, however, that any organ, even those not possessing an epithelial structure, such as the muscles, may give off substances to the blood comparable to the internal secretions — a possibility that indicates how indefinite the distinction between the processes of secretion and of general cell-metabolism may become if the analysis is carried sufficiently far. If we consider only the external secret ion- definition and generalization become much easier, for in these cases the secret- iDg surface is always an epithelial structure which, when it possesses a certain organization, is designated as a gland. The type upon which '♦/•rOW* / • /•) •T^T^M^7^p]^*7^R^iM rXi. these secretingsurfaecs arecon- ~~DQ£ structed is illustrated in Figure 46. The type consists of an epithelium placed upon a basement membrane, while upon the other side of the membrane are blood-capillaries and lymph-spaces. The secretion is derived ultimately from the blood and is discharged upon the free epithelial surface, which is supposed to communicate with the exterior. The mucous membrane of the alimentary canal from stomach to rectum may be considered, ■j 1 1 46,— Plan (if a Becretlne membrane. 212 AN AMERICAN TEXT- HOOK OF PHYSIOLOGY. if we neglect the existence of the villi and crypts, as representing a secreting surface constructed on this type. If we suppose such a membrane to become amBEEB3E33£BS sciw§~a Fig. 47.— To illustrate the Bimplest form of a tubular and a racemose or acinous gland. invaginated to form a tube or a sac possessing a definite lumen (see Fig. 47), we have then what may be designated technically as a gland. It is obvious that in this case the gland may be a simple pouch, tubular or saccular in shape (Fig. 48), or it may attain a varying degree of complexity by the elongation of the involuted portion and the development of side branches lir.. is.- simple alveolar gland of the amphibian skin (after Flemming). Fig. 49.— Schematic representation of a lobe of a compound tubular gland (after Flemming). ( Fig. 49). The more complex structures of this character are known sometimes as compound glands, and are further described as tubular, or racemose (saccular), or tubulo-racemose, according as the terminations of the invaginations are tubular, or saccular, or intermediate in shape. 1 As a matter of fact we find the greatest variety in the structure of the glands imbedded in the cutaneous aud mucous surfaces, a variety extending from the simplest form of crypts or tubes to very complicated organs possessing an anatomical independence and definite vascular and nerve-supplies as in the case of the salivary glands or the kidney. In compound glands it is generally assumed that the terminal portions of the tubes alone form the secretions, and these are designated as the the acini or alveoli, while the tubes connecting the alveoli with the exterior are known as the ducts, and it is supposed that their lining epithelium is devoid of secretory activity. The mentions formed by these glands are as varied in composition as the glands are in structure. If we neglect the case of the so-called reproductive 1 Flemming has called attention to the fact that most of the so-called compound racemose glands, salivary glands, pancreas, etc., do not contain terminal sacs or acini at the ends of the system of ducts; on the contrary, the final secreting portions are cylindrical tubes, and such glands are better designated as compound tubular glands. SECRETION. 213 glands, the ovary and testis, whose right to the designation of glands is doubt- ful, we may say that the secretions in the mammalian body are liquid or semi- liquid in character and are composed of water, inorganic salts, and various organic compounds. With regard to the last-mentioned constituent the secre- tions differ greatly. In some cases the organic substances present are not found in the blood, and furthermore they may be specific to a particular secretion, so that we must suppose that these constituents at least are produced in the gland itself. In other cases the organic elements may be present in the blood, ami are merely eliminated from it by the gland, as in the case of the urea found in the urine. Johannes Miiller long ago made this distinction, and spoke of secre- tions of the latter kind as excretions, a term which we still use and which car- ries to our minds also the implication that the substances so named are waste products whose retention would be injurious to the economy. Excretion as above defined is not a term, however, that is capable of exact application to any secretion as a whole. Urine, for example, contains some constituents that are probably formed within the kidney itself, e. g., hippuric acid ; while, on the other hand, in most secretions the water and inorganic salts are derived directly from the blood or lymph. So, too, some secretions — for example, the bile — carry off waste products that may be regarded as mere excretions, and at the same time contain constituents (the bile salts) that are of immediate value to the whole organism. Excretion is therefore a name that we may apply conveniently to the process of removal of waste products from the body, or to particular constituents of certain secretions, but no fundamental distinc- tion can be made between the method of their elimination and that of the formation of secreted products in general. Owing to the diversity in com- position of the various external secretions and the obvious difference in the extent to which the glandular epithelium participates in the process in different glands, a general theory of secretion cannot be formulated. • The kinds of activity seem to be as varied as i.s the metabolism of the tissues in general. It was formerly believed that the formation of the secretions was de- pendent mainly if not entirely upon the physical processes of filtration, osmosis, and diffusion. The basement membrane with its lining epithelium was supposed to constitute a membrane through which various products of the blood or lymph passed by filtration and diffusion, and the variation in com- position of the secretions was referred t<> differences in structure and chemical properties of the dialyzing membrane. flic significant point about this view- is that the epithelial cells were supposed t<» play a passive pari in the process; the metabolic processes within the cytoplasm of the cells were not believed to affect the composition of the secreted product. A.S compared with this view the striking peculiarity of modern ideas of secretion is, perhaps, the import- ance attributed to the living structure and properties of the epithelial cells. It is believed generally now that the glandular epithelium take- ;i direct part in the production of some at least of the constituents of the secretions. The reasons for this view will be brought out in detail further on in describing the secreting processes of the separate glands. Some of the general facts, how- 214 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. ever, which influenced physiologists in coming to this conclusion are as follows : Microscopic examination has demonstrated clearly that in many cases parts of the epithelial cell-substance can be followed into the secretion. In the sebaceous secretion the cells seem to break clown completely to form the mate- rial of the secretion ; in the formation of mucus by the goblet cells of the mucous membrane of the stomach and intestines a portion of the cytoplasm after undergoing a mucoid degeneration is extruded bodily from the cell to form the secretion ; in the mammary glands a portion of the substance of the epithelial cells is likewise broken off and disintegrated in the act of secretion, while in other glands the material of the secretion is deposited within the cell in the form of visible granules which during the act of secretion may be observed to disappear, apparently by dissolution in the stream of water passing through the cell. Facts like these show that some at least of the products of secretion arise from the substance of the gland-cells, and may be considered as representing the results of a metabolism within the cell-substance. From this standpoint, therefore, we may explain the variations in the organic constituents of the secretions by referring them to the different kinds of metabolism existing in the different gland-cells. The existence of distinct secretory nerves to many of the glands is also a fact favoring the view of an active participation of the gland-cells in the formation of the secretion. The first discovery of this class of nerve-fibres we owe to Ludwig, who (in 1851) showed that stimulation of the chorda tympani nerve causes a strong secretion from the submaxillary gland. Later investigations have demon- strated the existence of similar nerve-fibres to many other glands — for example, the lachrymal glands, the sweat-glands, the gastric glands, the pancreas. Recent microscopic work indicates that the secretory fibres end in a fine plexus between and around the epithelial cells, and we may infer from this that the action of the nerve-iinpulses conducted by these fibres is exerted directly upon the gland-cells. The formation of the water and inorganic salts present in the various secretions offers a problem the general nature of which may be referred to appropriately in this connection, although detailed statements must be reserved until the several secretions are specially described. The problem involves, indeed, not only the well-recognized secretions, but also the lymph itself as well as the various normal and pathological exudations. Formerly the occur- rence of these substances was explained by the action of the physical processes of filtration, diffusion, and osmosis through membranes. With the blood under a considerable pressure and with a certain concentration in salts on one side of the basement membrane, and on the other a Liquid under low pressure and differing in chemical composition, it would seem inevitable that water should filter through the membrane and that processes of osmosis and diffusion should be set up, further changing the nature of the secretion. Upon this theory the water and salts in all secretions were regarded merely as transudatory prod- ucts, and so far as they were concerned the epithelium was supposed to act SECRET I OX. 215 simply as a passive membrane. This theory has not proved entirely acceptable for various reasons. It has been shown that living membranes offer consider- able resistance to filtration even when the liquid pressure on one side is much greater than on the other. Tigerstedt 1 and Santessen, for instance, found that a lung taken from a frog just killed gave no filtrate when its cavity was distended by liquid under a pressure of 18 to 20 centimeters, provided the liquid used was one that did not injure the tissue. If, however, the lung- tissue was killed by heat or otherwise, filtration occurred readily under the same pressure. In some glands, also, the formation of the water and salts, as has been said, is obviously under the control of nerve-fibres, and this fact is difficult to reconcile with the idea that the epithelial cells are merely pas- sive filters. In glands like the kidney, and in other glands as well, it lias not, as yet, been shown conclusively that the amount of water and salts increases in proportion to the rise of blood-pressure within the capillaries, as should happen if filtration were the sole agent at work ; and furthermore, certain chemical substances when injected into the blood may increase the flow of urine to an extent that it is difficult to explain by the use of the filtration and diffusion theory alone. While, therefore, it cannot be denied that the anatomical conditions pre- vailing in the glands are favorable to the processes of filtration and osmosis, and while w r e are justified in assuming that these processes do actually occur and serve to account in part for the appearance of the water and inorganic salts, it seems to be clear that in the present condition of our knowledge theories based on these factors alone do not suffice to explain all the phe- nomena connected with the secretion of water and salts. Until the contrary is definitively proved we may suppose that the epithelial cells are actively con- cerned in the process. The way in which they act is not known ; various hypotheses have been advanced, but none of them meets all the facts to be explained, and at present it is customary to refer the matter to the vital properties of the cells — that is, to the peculiar physical or chemical properties connected with their living structure. We may now pass to a consideration of the facts known witli regard to the physiology of the different glands considered merely as secretory organs. The functional value of the secretions will be found described in the sections on Digestion and Nutrition. B. Mucous and Albuminous ( Serous ) Types of Glands ; Salivary Glands. Mucous and Albuminous Glands. — Heidenhain recognized two types of glands, the mucous and the albuminous, basing his distinction upon the character of the secretion and upon the histological appearance of the secreting cells. The classification as originally made was applied only to the salivary glands and to similar glands found in the mucous membranes of the mouth 1 Mittheil. mm physiol. Lab. des Octroi, med.-chir. Tnsliliiis in Storkholm, lSSo. 216 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. and oesophagus, the air-passages, conjunctiva, etc. The chemical difference in the secretions of the two types consists in the fact that the secretion of the albuminous (or serous) glands is thin and watery, containing in addition to possible enzymes only water, inorganic salts, and small quantities of albumin ; while that of the mucous glands is stringy and viscid owing to the presence of mucin. As examples of the albuminous glands we have the parotid in man and the mammalia generally, the submaxillary in some animals (rabbit), -Mine of the glands of the mucous membrane of the month and nasal cavities, and tin.' lachrymal glands. As examples of the mucous glands, the submaxil- lary in man and most mammals, the sublingual, the orbital, and some of the glands of the mucous membrane of the mouth-cavity, oesophagus, and air- passages. The histological appearance of the secretory cells in the albuminous glands is in typical cases markedly different from that of the cells in the mucous glands. In the albuminous glands the cells are small and densely filled with granular material, so that the cell outlines, in preparations from the fresh gland, cannot be distinguished (see Figs. 53 and 55). In the mucous glands, on the contrary, the cells are larger and much clearer (see Fig. 56). In microscopic preparations of the fresh gland the cells, to use Langley's expression, present the appearance of ground glass, and granules are only indistinctly seen. Treatment with proper reagents brings out the granules, which are, however, larger and less densely packed than in the albuminous glands, and are imbedded in a clear homogeneous substance. Histological examination shows, moreover, that in some glands, e. g. the submaxillary gland, cells of both types occur. Such a gland is usually spoken of as a mucous gland, since its secretion contains mucin, but histologically it is a mixed gland. The terms mucous and albuminous or serous, as applied to the entire gland, are not in fact perfectly satisfactory, since not only do the mucous gland- usually contain some secretory cells of the albuminous type, but albu- minous glands, such as the parotid, may also contain cells belonging to the mucous type. The distinction is more satisfactory when it is applied to the individual cells, since the formation of muciu within a secreting cell seems to present a definite histological picture, and we can recognize microscopically a mucous cell from an albuminous cell although the two may occur together in a single alveolus. Goblet Cells. — The goblet cell- found in the epithelium of the intestine afford an interesting example of mucous cells. The epithelium of the intes- tine i> a simple columnar epithelium. Scattered among tin columnar cells are found cell- containing mucin. These cells are originally columnar in shape like the neighboring cells, but their protoplasm undergoes a chemical change of such a character that mucin is produced, causing the cell to become swollen at its i'vfr extremity, whence the name of goblet cell. It has been shown that the mucin is formed within the substance of the protoplasm as distinct granules of a large size, and that the amount of mucin increases gradually, forcing the nucleus and a small part of the unchanged protoplasm toward the base of the SECRETION. 21 cell. Eventually the mucin is extruded bodily into the lumen of the intestine, leaving behind a partially empty cell with the nucleus and a small remnant of protoplasm (see Fig. 50). The complete life-history of these cells is imper- I i'. "n.— Formation of secretion of mucus in the goblet cells: A, cell containing mucin; B, escape of the mucin ; C, after escape of the mucin (after Paneth). fectly known. According to Bizzozero 1 they are a distinct variety of cell and are not genetically related to the ordinary granular epithelial cells by which they are surrounded. According to others, any of the columnar epithelial cells may become a goblet cell by the formation of mucin within its interior, and after the mucin is extruded the cell regenerates its protoplasm and becomes again an ordinary epithelial cell. However this may be, the interesting fad from a physiological standpoint is that these goblet cells are genuine unicellular mucous glands. Moreover, the deposition of the mucin in the form of definite granules within the protoplasm gives histological proof that this material is produced by a metabolism of the cell-substance itself. It will be found that the mucin cells in the secreting tubules of the salivary glands exhibit similar appearances. So far as is known, the goblet cells do not possess secretory nerves. Salivary Glands. Anatomical Relations. — The salivary glands in man are three in num- ber on each side — the parotid, the submaxillary, and the sublingual. The parotid gland communicates witli the mouth by a large duel (Stenson's duet) which opens upon the inner surface of the cheek opposite the second molar tooth of the upper jaw. The submaxillary gland lies below the lower jaw. and its duct (Wharton's duct) opens into the mouth-cavity at the side of the frsenum of the tongue. The sublingual gland lies in the floor of the mouth to the side of the frsenum and opens into the mouth-cavity by a Dumber (8 to 20) of small duets, known as the duets of Kivinus. One larger duet that runs parallel with the duct of Wharton and opens separately into the mouth- cavity is sometimes present in man. It is known as the duel of Bartholin and occurs normally in the dog. In addition to these three pairs of large glands a number of small glands belonging both to the albuminous and the mucous types arc found imbedded in the mucous membrane of the mouth and 1 Archiv fur mikroakopische ■ I notomte, 1893, Bd. 42. S. 82. 218 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. tongue. The secretions of these glands contribute to the formation of the saliva. The course of the nerve-fibres supplying the large salivary glands is interest- ing in view of the physiological results of their stimulation. The description here given applies especially to their arrangement in the dog. The parotid gland receive- its fibres from two sources — first, cerebral fibres that originate in the glosso-pharyngeal or ninth cranial nerve, pass into a branch of this nerve known as the tympanic branch or nerve of Jacobsou, thence to the small superficial petrosal nerve, through which they reach the otic ganglion. From this gan- glion they pass by way of the auriculotemporal branch of the inferior max- Inferior maxillary - branch of fifth Glossopharyngeal nerve Petro ganglion Fig. 51.— Schematic representation of the course of the cerebral fibres to the parotid gland. illary division of the fifth cranial nerve to the parotid gland. (A schematic diagram showing the course of these fibres is giveu in Figure 51.) A second Facial Inferior maxillary branch of fifth flinches Jto tongue Branches to submaxiU- , lary and sublingual ganglion Fig. 52.— Schematic representation of the course of the chorda tympani nerve to the submaxillary gland. supply of nerve-fibres is obtained from the cervical sympathetic nerve, the fibres reaching the gland ultimately in the coats of the blood-vessels. The submaxillary (and the sublingual) glands receive their nerve-fibres also from SECRETION. 219 two sources. The cerebral fibres arise from the brain in the facial nerve and pass out in the chorda tympani branch (Fig. 52). This latter nerve, after emerging from the tympanic cavity through the Glaserian fissure, joins the lingual nerve. After running; with this nerve for a short distance, the secre- tory (and vaso-dilator) nerve-fibres destined for the submaxillary and sublin- gual glands branch off and pass to the glands, following the course of the ducts. Where the chorda tympani fibres leave the lingual there is a small ganglion which has received the name of submaxillary ganglion. The nerve- fibres to the glands pass close to this ganglion, but Langley has shown that only those destined for the sublingual gland really connect with the nerve- cells of the ganglion, and he suggests therefore that it should be called the sublingual instead of the submaxillary ganglion. The nerve-fibres for the submaxillary gland make connections with nerve-cells mainly within the hilus of the gland itself. The submaxillary and sublingual glands receive also sympathetic nerve-fibres, which after leaving the superior cervical gan- glion pass to the glands in the coats of the blood-vessels. Histological Structure. — The salivary glands belong to the type of com- pound tubular glands, as Flemming has pointed out. That is, the secreting portions are tubular in shape, although in cross sections these tubes may present various outlines according as the plane of the section passes through them. The parotid is described usually as a typical serous or albuminous gland. Its secreting epithelium is composed of cells which in the fresh con- dition as well as in preserved specimens contain numerous fine granules (see Figs. 53 and 55, A). Heidenhain states that in exceptional cases (in the dog) some of the secreting cells may belong to the mucous type. The base- ment membrane is composed of flattened branched connective-tissue cells, the interstices between which are filled by a thin membrane. The submaxillary gland differs in histology in different animals. In some, as the dog or cat, all the secretory tubes are composed chiefly or exclusively of epithelial cells of the mucous type (Fig. 56). In man the gland is of a mixed type, the secretory tubes containing both mucous and albuminous cells. The sublingual gland in man also contains both varieties of cells, although the mucous cells predominate. It follows from these histological characteristics that the secre- tion from the submaxillary and sublingual glands is thick and mucilaginous as compared with that from the parotid. In the mucous glands another variety of cells, the so-called demilunes or crescent cells, is frequently met with ; and the physiological significance of these cells has been the subject of much discussion. The demilunes are cres- cent-shaped granular cells lying between the mucous cells and the basement membrane, and not in contact, therefore, with the central lumen of the tube (see Fig. 56). According to Heidenhain these demilunes are for the purpose of replacing the mucous cells. In consequence of long-continued activity the mucous cells may disintegrate and disappear, and the demilunes then develop into new mucous cells. The most probable view at present is that the demi- lunes represent distinct secretory cells of the albuminous type. 220 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. The secreting tubules of the salivary glands possess distinct lumens round which the cells are arranged. In addition a number of recent observers, making use of* the Grolgi method of staining, have apparently demonstrated thai in the albuminous glands the Lumen is continued as fine capillary spaces running between the secreting cells. 1 The statement is also made that 1'rom these secretion capillaries small side-branches are given off that penetrate into the substance of the cell, making an intracellular origin of the system of duets ; this point, however, needs confirmation. In the mucous glands similar secretion capillaries an' found only in connection with the demilunes. This latter fact supports the view that the demilunes are not simply inactive forms of mucous cells, hut cells with a specific functional activity. It is an nu- ll. ml)ted fact that the salivary glands possess definite secretory nerves which when stimulated start the formation of secretion. This fact indicates that there must be a direct contact of some kind between the gland-cells and the terminations of the secretory fibres. The nature of this connection has been the subject of numerous investigations, the results of which were for a long time negative or untrustworthy. More recently, however, the application of the useful Gol«;i method has led to satisfactorv results. The ending of the nerve- fibres in the submaxillary and sublingual glands has been described by a num- ber of observers. 2 The accounts differ somewhat as to details of the finer anatomv, but it seems to be clearly established that the secretory fibres from the chorda tympani end first round the intrinsic nerve-ganglion cells of the glands, and from these latter cells axis-cylinders are distributed to the secreting cells, passing to these cells along the ducts. The nerve-fibres termi- nate in a plexus upon the membrana propria of the alveoli, and from this plexus fine fibrils pass inward to end on and between the secreting cells. It would seem from these observations that the nerve-fibrils do not penetrate or fuse with the gland-cells, as was formerly supposed, but form a terminal network in contact with the cells, following thus the general schema for the connection between nerve-fibres and peripheral tissues. Composition of the Secretion. — The saliva as it is found in the; mouth is a mixed secretion from the large salivary elands and the numerous smaller glands scattered over the mucous membrane of the mouth. It is a colorless or opalescent, turbid, and mucilaginous liquid of weakly alkaline re- action and a specific gravity of about 1003. It may contain numerous flat c,ll~ derived from the epithelium of the mouth, and the peculiar spherical cell- known as salivary corpuscles, which seem to be altered leucocytes. The im- portant constituents of the secretion are mucin, a diastatic enzyme known as ptvalin, traces of albumin and of potassium sulphocyanide, and inorganic salts such a- potassium and -odium chloride, potassium sulphate, sodium carbonate, and calcium carbonate and phosphate. The average proportions of these con- stituent- is given in the following analysis by Hammerbacher : 1 Laserstein: Pfliiger'a Archiv fur die gesammte Physiologie, 1893, Bd. ■">•">, S. 417. • Huber : Journal of Efi>rrhncnt. "J*l. SECRETION. 221 Water, 99-1.203 Solids : Mucin and epithelial cells, 2.202 Ptyalin and albumin, 1.390 Inorganic salts, 2.205 5.797 1.000.000 (Potassium sulphocyanide, 0.041.) Of the organic constituents of the saliva the proteid exists in small and varia- ble quantities, and its exact nature is not determined. The mucin gives to the saliva its ropy, mucilaginous character. This substance belongs to the group of combined proteids, glyco-proteids (see section on Chemistry), consisting of a proteid combined with a carbohydrate group. The physiological value of this constituent seems to lie in its physical properties, as described in the section on Digestion. The most interesting constituent of the mixed saliva is the pty- alin. This body belongs to the group of enzymes or unorganized ferments, whose general and specific properties are described in the section on Digestion. It suffices here to say only that ptyalin belongs to the diastatic group of enzymes, whose specific action consists in a conversion of the starches into sugar by a proc- ess of hydrolysis. In some animals (dog) ptyalin seems to be normally absent from the fresh saliva. An interesting fact with reference to the saliva is the large quantity of gases, particularly 0O 2 , which may be obtained from it when freshly secreted. In an analysis by Pfliiger of the saliva from the submaxil- lary gland the following figures were obtained: C0 2 , 65 per cent., of which 42.5 per cent, was in the form of carbonates; N, 0.8 per cent. ; O, 0.6 per cent. For the parotid secretion Kiilz reports: CG 2 , 66.7 per cent., (if which 62 per cent, was in combination as carbonate; N, 3.8 per cent. ; O, 1.46 per cent. The secretions of the parotid and submaxillary glands can be obtained easily by inserting a cannula into the openings of the duets in the mouth. The secre- tion of the sublingual can only be obtained in sufficient quantities for analysis from the lower animals. Examination of the separate secretions shows that the main difference lies in the fact that the parotid saliva contains no mucin, while that of the submaxillary and especially of the sublingual gland is rich in mucin. The parotid saliva of man seems to be particularly rich in ptyalin as compared with that of the submaxillary, while the secretion of the latter and that of the sublingual gland give a stronger alkaline reaction than the parotid saliva. The Secretory Nerves. — The existence of secretory nerves was discovered by Ludwig in 1851. He found that stimulation of the chorda tympani nerve caused a How of saliva from the submaxillary gland. He established also several important facts with regard to the pressure and composition of the secretion which will be referred to presently. It was afterward shown that, the salivary glands receive a double nerve-supply, in pari by way of the cervical sympathetic and in part through cerebral nerves, as briefly described on p. 218. It was discovered also that not only arc secretory fibres carried 222 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. to the glands by these paths, but that the vaso-motor fibres are contained in tli'' same nerves, and the arrangement of these latter fibres is such that the cerebral nerves contain vaso-dilator fibres that cause a dilatation of the small arteries in the glands and an accelerated blood-flow, while the sympathetic carries vaso-constrictor fibres whose stimulation causes a constriction of the small arteries and a diminished blood-flow. The effect upon the secretion of stimulating these two sets of fibres is found to vary somewhat in different animals. For purposes of description we may confine ourselves to the effects observed on dogs, since much of our fundamental knowledge upon the subject is derived from Heidenhain's 1 experiments upon this animal. If the chorda tympani nerve is stimulated by weak induction shocks, the gland begins to secrete promptly, and the secretion, by proper regulation of the stimuli, may be kept up for hours. The secretion thus obtained is thin and watery, flows freely, is abundant in amount, and contains not more than 1 or 2 per cent, of total solids. At the same time there is an increased flow of blood through tin gland. The whole gland takes on a redder hue, the veins are distended, and if cut the blood that flows from them is of a redder color than in the resting gland, and may show a distinct pulse — all of which points to a dilata- tion of the small arteries. If now the sympathetic fibres are stimulated, quite different results are obtained. The secretion is relatively small in amount, Hows slowly, is thick and turbid, and may contain as much as 6 per cent, of total solids. At the same time the gland becomes pale, and if the veins be cut the flow from them is slower than in the resting gland, thus indicating that a vaso-constrietion has occurred. The increased vascular supply to the gland accompanying the abundant flow of "chorda saliva" and the diminished flow of blood during the scanty secretion of "sympathetic saliva" suggest naturally the idea that the whole process of secretion may be at bottom a vaso-motor phenomenon, the amount of secretion depending only on the quantity and pressure of the blood flowing through the gland. It has been shown conclusively that this idea is erro- neous and that definite secretory fibres exist. The following facts may be quoted in support of this statement: (1) Ludwig showed that if a mercury manometer is connected with the duct of the submaxillary gland and the chorda is then stimulated for a certain time, the pressure in the duct may become greater than the blood-pressure in the gland. This fact shows that the secretiou is not derived entirely by processes of filtration from the blood. (2) If the blood-How be shu toll' completely from the gland, stimulation of the chorda will still give a secretion for a short time. (3) If atropin is injected into the gland, stimulation of the chorda will cause vascular dilata- tion but no secretion. This may be explained by supposing that the atropin paralyzes the secretory but not the dilator fibres. (4) Hydrochlorate of qui- nine injected into the gland gives vascular dilatation but no secretiou. In 1 Pjlii'irr's Arrhir fiir die r/extniDiilr I'lii/sin/in/ir, 1878, Bd. xvii. S. 1 ; also in Hermann's Hand- buck der Physiologic, 1SSI], Bel. v. Tli. 1. SECRETIOX. 223 this case the secretory fibres are still irritable, since stimulation of the chorda gives the usual secretion. A still more marked difference between the effect of stimulation of the cerebral and the sympathetic fibres may be observed in the case of the parotid gland in the dog. Stimulation of the cerebral fibres alone in any part of their course (see Fig. 51) gives an abundant thin and watery saliva, poor in solid constituents. Stimulation of the sympathetic fibres alone (provided the cerebral fibres have not been stimulated shortly before (Laugley) and the tym- panic nerve has been cut to prevent a reflex effect) gives usually no perceptible secretion at all. But in this last stimulation a marked effect is produced upon the gland, in spite of the absence of a visible secretion ; this is shown by the fact that subsequent or simultaneous stimulation of the cerebral fibres gives a secretion very unlike that given by the cerebral fibres alone, in that it is very rich indeed in organic constituents. The amount of organic matter in the secretion may be tenfold that of the saliva obtained by stimulation of the cerebral fibres alone. Another important and suggestive set of facts with regard to the action of the secretorv nerves is obtained from a study of the differences in composition of the secretion following upon variations in the strength of stimulation of the nerves. Relation of the Composition of the Secretion to the Strength of Stimula- tion. — If the stimulus to the chorda is gradually increased in strength, care being taken not to fatigue the gland, the chemical composition of the secretion is found to change with regard to the relative amounts of the water, the salts, and the organic material. The water and the salts increase in amount with the increased strength of stimulus up to a certain maximal limit, which for the salts is about 0.77 per cent. It is important to observe that this effect may be obtained from a perfectly fresh gland as well as from a gland which had previously been secreting actively. With regard to the organic constituents the precise result obtained depends on the con- dition of the gland, li' previous to the stimulation the gland was in a resting condition and unf'atigued, then increased strength of stimulation i- followed at first by a rise in the percentage of organic constituents, and this rise in the beginning is more marked than in the case of the salts. lint with continued stimulation the increase in organic material soon ceases, and finally the amount begins actually to diminish, and may fall to a low point in spite of the stronger stimulation. On the other hand, if the gland in the beginning of the experiment had been previously worked to a considerable extent, then an increase in the stimulating current, while it increases the amount of water and salts, may have either no effect at all upon the organic constituents or cause only a temporary increase, quickly followed by a fall. Similar results may be obtained from stimulation of the cerebral nerves of the parotid gland. The above facts led Heidenhain to believe that the con- ditions determining the secretion of the organic material are different from 224 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. those controlling the water and salts, and he gave a rational explanation of the differences observed, in his theory of trophic and secretory fibres. Theory of Trophic and Secretory Nerve-fibres. — This theory supposes that two physiological varieties of nerve-fibres are distributed to the salivary glands. One of these varieties controls the secretion of the water and inor- ganic -alts and it> fibres may be called secretory fibres proper, while the other, to which the name trophic is given, causes the formation of the organic con- stituents of the secretion, probably by a direct influence on the metabolism in the cell. Were the trophic fibres to act alone, the organic products would be formed within the cell but there would be no visible secretion, and this is the hypothesis which Ileidenhain uses to explain the results of the experi- ment described above upon stimulation of the sympathetic fibres to the parotid of the dog. In this animal, apparently, the sympathetic branches to the parotid contain exclusively or almost exclusively trophic fibres, while in the cerebral branches both trophic and secretory fibres proper are present. The results of stimulation of the cerebral and sympathetic branches to the submaxillary gland of the same animal may be explained in terms of this theory by supposing that in the latter nerve trophic fibres preponderate, and in the former the secretory fibres proper. 1 1 is obvious that this anatomical separation of the two sets of fibres along the cerebral and sympathetic paths may be open to individual variations, and that dogs may be found in which the sympathetic branches to the parotid glands contain secretory fibres proper, and therefore give some flow of secretion on stimulation. These variations might also be expected to be more marked when animals of different groups are compared. Thus Langley 1 finds that in cats the sympathetic saliva from the submaxillary gland is less viscid than the chorda saliva, just the reverse of what occurs in the dog. To apply Heidenhain's theory to this case it is necessary to assume that in the cat the trophic fibres run chiefly in the chorda. An interesting fact with reference to the secretion of the parotid in dogs has been noted by Langley and is of special interest, since, although it may be reconciled with the theory of trophic and secretory fibres, it is at the same time suggestive of an incompleteness in this theory. As has been said, stimulation of the sympathetic in the dog causes usually no secretion from the parotid. Langley 2 finds, however, that if the tympanic nerve is stimulated just previously, stimulation of the sympathetic causes an abundant but brief flow from the parotid. One may explain this in terms of the theory by assuming that the sympathetic does contain a few se- cretory fibre- proper, but that ordinarily their action is too feeble to start the flow of water. Previous stimulation of the tympanic nerve, however, haves the gland-cells in a more irritable condition, so that the few secretory fibres proper in the sympathetic branches are now effective in producing a flow of water. 1 Journal of Physiology, 1878, vol. i. p. 96. 'Ibid., 1889, vol. x. p. 291. SECRETION. 225 Theories of the Action of Trophic and Secretory Fibres. — The way in which the trophic fibres act has been briefly indicated. They may be sup- posed to set up metabolic changes in the protoplasm of the cells, leading to the formation of certain definite products, such as mucin or ptyalin. That sucli changes do occur is abundantly shown by microscopic examination of the rest- ing and the active gland, the details of which will be given presently. In general these changes may be supposed to be katabolic in nature; that is, to consist in a disassociation or breaking down of the complex living material with the formation of the simpler and more stable organic constituents of the secretion. There is evidence to show that these gland-cells during activity form fresh material from the nourishment supplied by the blood; that is, that anabolic or building-up processes occur along with the katabolic changes. The latter are the more obvious and are the changes which are usually associated with the action of the trophic nerve-fibres. It is possible, also, that the anabolic or growth changes may be under the control of separate fibres for which the name anabolic fibres would be appropriate. Satisfactory proof of the existence of a separate set of anabolic fibres has not yet been furnished. The method of action of the secretory fibres proper is difficult to under- stand. At present the theories suggested are very speculative, and a detailed account of them is scarcely appropriate in this place. Heidenhain's own view may be mentioned, but it should be borne in mind that it is only an hy- pothesis, the truth of which is far from being demonstrated. The theory starts from the fact that no more water leaves the blood-capillaries than afterward appears in the secretion ; that is, no matter how long the secretion continues, the gland does not become ©edematous nor does the velocity of the lymph- stream in the lymphatics of the gland increase. This being the case, we must suppose that the stream of water is regulated by the secretion, that is, by the activity of the gland-cells. If we suppose that some constituent of these cells has an attraction for water, or, to use the modern expression, exerts a high osmotic pressure, then, while the gland is in the resting state, water will diffuse from the basement membrane; this in turn supplies its loss from the surrounding lymph, and the lymph obtains the same amount of water from the blood. As the amount of water in the cell increases a point is reached at which an equilibrium is established, and the osmotic stream from blood to cells comes to a standstill. The water in the cells does not escape into the lumen of the tubule or of the secretion capillaries, because the periphery of the cell is modified to form a layer offering considerable resistance to filtra- tion. The action of the secretory fibres proper consists in so altering the structure of this limiting layer of the cells that it oilers less resistance to filtra- tion ; consequently the water under tension in the cells escapes into the lumen, and the osmotic pressure of its substance again starts up a stream of water from capillaries to cells, which continues as long as the Qerve-stim illation is effective. Vol. I.— 15 226 AN AMERICAN TEXT- BOOK OF PHYSIOLOGY. Recent work by Ranvier, Drasch, Biedermann, and others has called atten- tion to an interesting phenomenon occurring in gland-cells during secretion which when better known will possibly throw light upon the formation of the water stream under the influence of nerve-stimulation. Ranvier 1 describes in both serous and mucous cells the formation of vacuoles within the proto- plasmic substance. These vacuoles are particularly abundant after nerve- stimulation. They seem to contain water, and if they behave as they do in the protozoa — and this is indicated by the observations of Drasch 2 upon the glands in the nictitating membrane in the frog — they would seem to form a mechanism sufficient to force water from the cells into the lumen. Histological Changes during Activity. — The cells of both the albu- minous and mucous glands undergo distinct histological changes in conse- quence of prolonged activity, and these changes may be recognized both in preparations from the fresh gland and in preserved specimens. In the parotid gland Heidenhain studied the changes in stained sections after hardening in alcohol. In the resting gland (Fig. 53) the cells are compactly filled with Fig. 53.— Parotid of the rabbit, in the resting condition (after Heidenhain). granules that stain readily and are imbedded in a clear ground substance thai does not stain. The nucleus is small and more or less irregular in out- line. After stimulation of the tympanic nerve the cells show but little altera- tion, but stimulation of the sympathetic produces a marked change (Fig. 54). The cells become Bmaller, the nuclei more rounded, and the granules more closely packed. This last appearance seems, however, to be due to the hard- ening reagents used. A truer picture of what occurs may be obtained from a Mu.lv of sections of the fresh -land. Langley, 3 who first used this method, 1 Comptes rendus, cxviii., 1, p. K'> s . 2 Archivfiir AnatomU wnd 1'lojsiologie, 1889, S. 96. 8 Journal of Physiology, 1879, vol. ii. p. 260. SECRETION. 227 describes his results as follows : When the animal is in a fasting condition the cells have a granular appearance throughout their substance, the outlines of Wt^m^. ^i.ftSs^jj 5k; Fig. 54.— Parotid of the rabbit, after stimulation of the sympathetic (after Heidenhain). the different cells being faintly marked by light lines (Fig. 55, A). When the gland is made to secrete by giving the animal food, by injecting pilocarpin, or by stimulating the sympathetic nerves, the granules begin to disappear from ^Sftfe-* C D Fig. 55.— Parotid gland of the rabbit in a fresh state, showing portions of the secreting tubules : .1. in a resting condition ; /;, after secretion caused by pilocarpin ; ( '. after stronger Becretion, pilocarpin and stimulation of sympathetic ; D, after Long-continued stimulation of Bympathel Ic (after Langley). the outer borders of the cells (Fig. - r )' r ), />), so that each cell now shows an outer clear border and an inner granular one. If the stimulation is continued the granules become fewer in number and are collected near the Lumen and the mar- 228 AN AMERICAN TEXT- BOOK OF PHYSIOLOGY. gins of the cells, the clear zone increases in extent and the cells become smaller (Fig. 55, C, D). Evidently the granular material is used up in some way to make the organic material of the secretion. Since the ptyalin is a conspicuous organic constituent of the secretion, it is assumed that the granules in the rest- ing gland contain the ptyalin, or rather a preliminary material from which the ptyalin is constructed during the act of secretion. On this latter assumption the granules are frequently spoken of as zymogen granules. During the act of secretion two distinct processes seem to be going on in the cell, leaving out of consideration for the moment the formation of the water and the salts. In the first place the zymogen granules undergo a change such that they are forced or dissolved out of the cell, and, second, a constructive metabolism or an- abolism is set up, leading to the formation of new protoplasmic material from the substances contained in the blood and lymph. The new material thus formed is the clear, non-granular substance, which appears first toward the basal sides of the cells. We may suppose that the clear substance during the resting periods undergoes metabolic changes, whether of a katabolic or anabolic character cannot be safely asserted, leading to the formation of new granules, and the cells are again ready to form a secretion of normal composition. It should be borne in mind that in these experiments the glands were stimulated beyond normal limits. Under ordinary conditions the cells are probably never depleted of their granular material to the extent represented in the figures. In the cells of the mucous glands changes equally marked may be observed after prolonged activity. In stained sections of the resting gland, according to Heidenhain, the cells are large and clear (Fig. 56), with flattened nuclei Fk;. 56.— Mucous gland : submaxillary of dog ; rest- Fio. 57.— Mucous jdaud: submaxillary of dog ing stage. after eight hours' stimulation of the chorda tym- pani. placed well toward the base of the cell. When the gland is made to secrete the nuclei become more spherical and lie more toward the middle of the cell, and the cells themselves become distinctly smaller. After prolonged secretion the changes become more marked (Fig. 57) and, according to Heidenhain, some of the mucous cells may break down completely. According to most of the later observers, however, the mucous cells do not actually disintegrate, but SECRETIOX. 229 form again new material during the period of rest as was described for the goblet cells of the intestine. In the mucous as in the albuminous cells ob- servations upon pieces of the fresh gland seem to give more reliable results than those upon preserved specimens. Langley x has shown that in the fresh mucous cells of the submaxillary gland numerous large granules may be discovered, about 125 to 250 to a cell. These granules are comparable to those found in the goblet cells, and may be interpreted as consisting of mucin or some preparatory material from which mucin is formed. The granules are sensitive to reagents ; addition of water causes them to swell up and disappear. It may be assumed that this happens during secretion, the gran- ules becoming converted to a mucin-mass which is extruded from the cell. Action of Atropin, Pilocarpin, and Nicotin upon the Secretory- Nerves. — The action of drugs upon the salivary glands and their secretions belongs properly to pharmacology, but the effects of the three drugs men- tioned are so decided that they have a peculiar physiological interest. Atro- pin in small doses injected either into the blood or into the gland-duct prevents the action of the cerebral fibres (tympanic nerve or chorda tympani) upon the glands. This effect may be explained by assuming that the atropin paralyzes the endings of the cerebral fibres in the glands. That it does not act directly upon the gland-cells themselves seems to be assured by the inter- esting fact that with doses sufficient to throw out entirely the secreting action of the cerebral fibres, the sympathetic fibres are still effective when stimulated. Pilocarpin has directly the opposite effect to atropin. In minimal doses it sets up a continuous secretion of saliva, which may be explained upon the supposition that it stimulates the endings of the secretory fibres in the gland. Within certain limits these drugs antagonize each other — that is, the effect of pilocarpin may be removed by the subsequent application of atropin and vice versa. Nicotin, according to the experiments of Langley, 2 prevents the action of the secretory nerves, not by action on the gland-cells or the endings of the nerve-fibres round them, but by paralyzing the connections between the nerve- fibres and the ganglion cells through which the fibres pass on their way to the gland. If, for example, the superior cervical ganglion is painted with a solu- tion of nicotin, stimulation of the cervical sympathetic below the gland will give no secretion; stimulation, however, of the fibres in the ganglion or between the ganglion and gland will give the usual effect. By the use of this drug Langley is led to believe that the cells of the so-called submaxillary ganglion are really intercalated in the course of the fibres to the sublingual gland, while the nerve-cells with which the submaxillary fibres make con- nection are found chiefly in the hilus of the gland itself. Paralytic Secretion. — A remarkable phenomenon in connection with the salivary glands is the so-called paralytic secretion. It has been known for a long time that if the chorda tympani is cut the submaxillary gland after a cer- tain time, one to three days, begins t<> secrete slowly and the secretion contin- 1 Journal of Physiology, 1889, vol. x. p. -133. 2 Proceedings of (he Royal Society, London, 1889, vol. xlvi. j>. 123. 230 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. ues uninterruptedly for a long period — as long, perhaps, as several weeks — and eventually the gland itself undergoes atrophy. Langley l states that section of the chorda on one side is followed by a continuous secretion from the glands on botli sides ; the secretion from the gland of the opposite side he designates :i- tin' antiparalytic or antilytic secretion. After section of the chorda the iurve-fibres peripheral to the section degenerate, the process being com- pleted within a few days. These fibres, however, do not run directly to the gland-cell ; they terminate in end-arborizations round sympathetic nerve-cells placed somewhere along their course, in the sub-lingual ganglion, for instance, or within the gland substance itself. It is the axons from these second nerve units that end round the secreting cells. Langley 2 has accumulated some facts to show that within the period of continuance of the paralytic secretion (5 to 6 weeks) the fibres of the sympathetic cells are still irritable to stimula- tion. He is inclined to believe therefore that the continuous secretion is due to a continuous excitation, from some cause, of the local nervous mechanism in the gland. On the other hand, it is possible that the mere cessation of the normal action of the chorda fibres is followed by an altered metabolism in the gland cells of such a nature as to cause a continuous feeble secretion. Normal Mechanism of Salivary Secretion. — Under normal conditions the flow of saliva from the salivary glands is the result of a reflex stimulation of the secretorv nerves. The sensory fibres concerned in this reflex must be chiefly fibres of the glosso-pharyngeal and lingual nerves supplying the mouth and tongue. Sapid bodies and various other chemical or mechanical stimuli applied to the tongue or mucous membrane of the mouth will produce a flow mi' saliva. The normal flow during mastication must be effected by a reflex of this kind, the sensory impulse being carried to a centre and thence trans- mitted through the efferent nerves to the glands. It is found that section of the chorda prevents the reflex, in spite of the fact that the sympathetic fibres are still intact. No satisfactory explanation of the normal functions of the secretorv fibres in the sympathetic has yet been given. Various authors have suggested that possibly the three large salivary glands respond normally to different stimuli. This view has lately been supported by Pawlow, who reports that in the dog at least the parotid and the submaxillary may react quite differently. When fistulas were made of the ducts of these glands it was found that the submaxillary responded readily to a great number of stimuli, such as the sight of food, chewing of meats, acids, etc. The parotid, on the contrary, seemed to react only when dry food, dry powdered meat, or bread was placed in the mouth. Dryness in this case seemed to be the efficient stimulus. Since the How of saliva is normally a definite reflex, we should expect a distinct salivary secretion centre. This centre has been located by physiological means in the medulla oblongata ; its exact position is not clearly defined, but possibly it is represented by the nuclei of origin of 1 Proceedings of the Royal Society, London, 1885, No. 236. 1 Text-book of Physiology, edited by Scbafer, 1898. SECRETION. 231 the secretory fibres which leave the medulla by way of the facial and glosso- pharyngeal nerves. Owing to the wide connections of nerve-cells in the central nervous system we should expect this centre to be affected by stimuli from various sources. As a matter of fact, it is known that the centre and through it the glands may be called into activity by stimulation of the sensory fibres of the sciatic, splanchnic, and particularly the vagus nerves. So, too, various psychical acts, such as the thought of savory food and the feeling of nausea preceding vomiting, may be accompanied by a flow of saliva, the effect in this case being due probably to stimulation of the secretion centre by nervous impulses descending from the higher nerve-centres. Lastly, the medullary centre may be inhibited as well as stimulated. The well-known effect of fear, embarrassment, or anxiety in producing a parched throat may be supposed to arise in this way by the inhibitory action of nerve-impulses arising in the cerebral centres. Electrical Changes in the Gland during Activity. — It has been shown that the salivary as well as other glands suffer certain changes iu electric potential during activity which are comparable in a general way to the " action currents " observed in muscles and nerves (see section on Muscle and Nerve). The theories bearing upon the causes of these electrical changes are too intricate and speculative to enter upon here. The reader is referred to an account given by Biedcrmann l for further details. C. Pancreas ; Glands of the Stomach and Intestines. Anatomical Relations of the Pancreas. — The pancreas in man lies in the abdominal cavity behiud the stomach. It is a long, narrow gland, its head lying against the curvature of the duodenum and its narrow extremity or tail reaching to the spleen. The chief duct of the gland (duct of Wirsung) usually opens into the duodenum, together with the common bile-duet, about eight to ten centimeters below the pylorus. In some cases, at least, a smaller duct may enter the duodenum separately somewhat lower down. The points at which the ducts of the pancreas open into the duodenum vary considerably in different animals. For instance, in the dog there are two ducts, the larger of which enters the duodenum separately about six to seven centimeters below the pylorus, while in the rabbit the main duct opens into the duodenum over thirty centimeters below the pylorus. The nerves of the pancreas are derived from. the solar plexus, but physiological experiments which will be described presently show that the gland receives fibres from at least two sources, through the vagus nerve and through the sympathetic system. Histological Characters. — The pancreas, like the salivary glands, belongs to the compound tubular type. The cells in the secreting portions of the tubules, the so-called alveoli, belong to the serous or albuminous type, and are usually characterized by the fad that the outer portion of each cell, that is, the pari toward the basement membrane, is composed of a clear non-glandular 1 Eleklrophysiologie, Jena, 1895. 232 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. substance that takes stains readily, while the inner portion tnrned toward the lumen is rilled with conspicuous granules. In addition to this type of cell, which is the characteristic secreting element of the organ, the pancreas contains a number of irregular masses of cells of a different character (bodies of Langerhans). These latter cells are clear and small, frequently have ill- defined cell-bodies, but contain nuclei which stain readily with ordinary reagents. By some these eel Is are supposed to be immature secreting cells of the ordinary pancreatic type. By others it is thought that they are a separate type of cell and take some special part in the secretory functions of the pan- creas. Nothing definite, however, is known as to their physiological import- ance. Composition of the Pancreatic Secretion. — The pancreatic secretion is a clear alkaline liquid which in some animals (dog) is thick and mucilaginous. Its phvsical characters seem to vary greatly, even in the same animal, accord- ing to the duration of the secretion or the time siuce the establishment of the fistula by which it is obtained (see p. 300). In a newly made fistula in the dog the secretion is thick, but in a permanent fistula it becomes much thinner and more watery. The main constituents of the secretion are three enzymes, a large percentage of proteid material the exact nature of which is not known, some fats, soaps, a slight amount of lecithin, and inorganic salts. The strongly alkaline nature seems to be due chiefly to sodium carbonate, which may be present in amounts equal to 0.2 to 0.4 per ceut. The three enyzmes are known respectively as trypsin, a proteolytic ferment ; amylopsin, a diastatic ferment, and steapsin, a fat-splitiug ferment. The action of these enzymes in digestion is described in the section on Digestion. Action of the Nerves on the Secretion of the Pancreas. — In animals like the dog, in which the process of digestion is not continuous, the secretion of the pancreas is also supposed to be intermittent. A study of the flow of secretion as observed in cases of pancreatic fistula indicates that it is connected with the beginning of digestion in the stomach, and is therefore probably a reflex act. Until recently, however, little direct evidence had been obtained of the existence of secretory nerves. Stimulation of the medulla was known to increase the flow of pancreatic juice and to alter its composition as regards the organic constituents, but direct stimulation of the vagus and the sympa- thetic nerves gave only negative results. Lately, however, Pawlow 1 and some of his students have been able to overcome the technical difficulties in the way, and have given what seems to be perfectly satisfactory proof of the existence of distinct secretory fibres comparable in their nature to those described for the salivary glands. The results that they have obtained may be stated briefly as follow- : Stimulation of either the vagus nerve or the sympathetic causes, after a considerable latent period, a marked flow of pancreatic secretion. The failure of other experimenters to ^{ this result was due apparently to the sensitive- ness of the gland to variations in its blood-supply. Either direct or reflex 'Paw-Lav : /'» Bois-Reymond 's Archiv fur Physiologie, 1893, Suppl. Bd.; Mett: Ibid., 1894; Kudrewetsky: Ibid., 1894 ; Pawlow: Die Arbeit der Verdauungsdriisen, Wiesbaden, 1898. SECRETION. 233 vasoconstriction of the pancreas prevents the action of the secretory nerves upon it. Thus stimulation of the sympathetic gives usually no effect upon the secretion, because vaso-constrictor fibres are stimulated at the same time, but if the sympathetic nerve is cut five or six days previously, so as to give the vaso-constrictor fibres time to degenerate, stimulation will cause, after a long latent period, a distinct secretion of the pancreatic juice. A similar result may be obtained from stimulating the undegenerated nerve if mechani- cal stimulation is substituted for the electrical. The long lateut period elapsing between the time of stimulation and the effect upon the flow is not easily understood. The authors quoted do not give an entirely satisfactory explanation of this curious fact, but suggest that it may be due to the presence of definite inhibitory fibres to the gland, which are stimulated simultaneously with the secretory fibres and thus hold the secretion in check for a time. The existence of inhibitory fibres is rendered probable by several interesting experiments, for an account of which the original sources must be consulted. 1 Histological Changes during Activity. — The morphological changes in the pancreatic cells have long been known and have been studied satisfac- torily in the fresh gland as well as in preserved specimens. The general nature of the chauges is the same as that described for the salivary gland, and is illustrated in Figures 58, 59, and 60. If the gland is removed from a dog which has been fasting for about twenty-four hours and is hardened in alcohol and sectioned and stained, it will be found that the cells are filled with granules except for a narrow zone toward the basal end, which is marked off more clearly because it stains more deeply than the granular portion (Fig. 58). If, on the contrary, the gland is taken from a dog which had been fed Fig. 58.— Pancreas of the dog during hungei : preserved in alcohol and stained in carmine (after Heidcnlmin). six to ten hours previously, the non-staining granular zone is much reduced in size, while the clearer non-granular zone is enlarged (Fig. 59). The increase in size of the non-gran uiar zone does not, however, entirely compensate for 1 Pawlow: Die Arbeit der Venlaiuiv/jxiiriisen, p. 78, Wiesbaden, 1898. 2:U AN AMERICAN TEXT-BOOK OF PHYSIOLOGY the loss of the granular material, so that the cell as a whole is smaller in size than in the gland from the fasting animal. It seems evident that during the hours immediately following a meal — that is, at the time when we know Fig. 59.— Pancreas of dog during first stage of digestion ; alcohol, carmine (after Heidenhain). that the gland is discharging its secretion, the granular material is being used up. After the cessation of active secretion — that is, during the tenth to the twentieth hour after a meal in the case of a dog fed once in twenty-four Fig. 60.— Pancreas of dog during second stage of digestion; alcohol, carmine (after Heidenhain). hours — the gland-cells return t<> their resting condition (Fig. 60). New gran- ules are formed, and finally, if the gland is left unstimulated they fill the entire cell except for a narrow margin at the basal end. Similar results are reported by Kiiline 1 and Lea from observation^ made upon the pancreas cells in a living rabbit. In the inactive gland the outlines 1 Untertuchungen aua dem phyriologischen Institut des Universitats Heidelberg, 1882, Bd. ii. SECRETION. 235 of the individual cells are not clearly distinguishable, but it can be seen that there are two zones, one clear and homogeneous on the side toward the basement membrane, and one granular on the side toward the lumen. During activity the secretory tubules show a notched appearance corresponding to the positions of the cells, the outlines of the cells become more distinct, the granular zone becomes smaller, and the homogeneous zone increases in width. It should be stated also that in this latter condition the basal zone of the cells shows a dis- tinct striation. From these appearances we must believe that, as in the case of the salivary gland, a part at least of the organic material of the secretion is formed from the granules of the inner zone, and that the granules in turn are formed within the cells from the homogenous material of the outer zone. Enzyme and Zymogen. — The observations just described indicate that the enzymes of the pancreatic secretion are derived from the granules in the cells, but other facts show that the granules do not contain the enzymes as such, but a preparatory material or mother-substance to which the name zymogen (enzyme-maker) is given. This belief rests upon facts of the following kind : If a pancreas is removed from a dog that has fasted for twenty-four hours, when, as we have seen, the cells are heavily loaded with granules, and a glycerin extract is made, very little active enzyme will be found in it. If, however, the gland is allowed to stand for twenty-four hours in a warm spot before the extract is made, or if it is first treated with dilute acetic acid, the glycerin ex- tract will show very active tryptic or amylolytic properties. Moreover, if an inactive glycerin extract of the perfectly fresh gland is treated by various methods, such as dilution with water or shaking with finely divided platinum- black, it becomes converted to an active extract capable of digesting proteid material. These results are readily explained upon the hypothesis that the granules contain only zymogen material, which during the act of secretion, or by means of the methods mentioned, may be converted into the corresponding enzymes. As the three enzymes of the pancreatic secretion seem to be distinct substances, one may suppose that each has it own zymogen to which a distinc- tive name might be given. The zymogen that is converted into trypsin is frequently spoken of as trypsinogen. Normal Mechanism of Pancreatic Secretion. — Alter the establishment of a pancreatic fistula it is possible to study the flow of secretion in its rela- tions to the ingestion of food. Experiments of this kind have Ween made. They show that in animals like the dog, in which sufficient food may be taken in a single meal to last for a day, the flow of secretion is intimately connected with the reception of food into the stomach and its subsequent digestiv changes. The time relations of the secretion to the ingestion of food are shown in the accompanying chart (Fig. 61). The secretion begins immedi- ately after the food enters the stomach, and increases in velocity up to a cer- tain maximum which is reached some time between the first and the third hour after the meal. The velocity then diminishes rapidly to the fifth or sixth hour, after which there may be a second smaller increase reaching its maxi- mum about the ninth to the eleventh hour. From this point the secretion •j:;.; AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. diminishes in quantity to the sixteenth or seventeenth hour, when it has practically reached the zero point. In man, in whom the meals normally occur at intervals of five to six hours, this curve of course would have a dif- ferent form. The interesting fact, however, that the secretion starts very soon 1.H 13 i-Z II 10 03 Ob 07 0.6 as a* a 02. 0, 1 „ --' v if 1 1 \\ 1 J \\ 1 1 \ A 7 / / \ / / \ \ / t V O i % 3 * $ 6 > B 9 TO tl IZ IS i* 15 7b // 18 Fig. 61.— < iirvi- of the secretion of pancreatic juice during digestion. The figures along the abscissa represent hours after the beginning of digestion ; the figures along the ordinate represent the quantity of this secretion in cubic centimeters. Curves of two experiments are given (after Heidenhain). after the beginning of gastric digestion is probably true for human beings, and gives strong indication that the secretion is a reflex act. Recently a number of experiments have been reported which strengthen the view that the normal secretion of the pancreas is reflexly excited by stimuli acting upon the mucous membrane of the stomach or duodenum. Dolinsky, 1 working upon dogs by Pawlow's methods, finds that acids are particularly effective in arousing the pancreatic flow ; on the contrary, alkalies in the stomach diminish the pancreatic secretion. Dolinsky believes that the normal acidity of the gastric secretion is perhaps the most effective stimulus to the pancreatic gland, and that in this way the flow of gastric juice in ordinary digestion starts the pancreatic gland into activity. Whether the acid acts after absorption into the blood, or stimulates the sensory fibres of the mucous membrane, and thus reflexly affects the pancreas through its secretory nerves, is not definitely known, but the probabilities arc in favor of the latter view. It is probable also that the acid acts upon the sensory fibres of the mucous membrane of the duodenum rather than upon the gastric membrane. In addition to acids, it has been found that oils and water introduced into the stomach also cause a flow of pancreatic juice, the stimulation occurring prob- 1 Archives des Sciences biologiques, St. Petersburg, 1895, t. iii.'p. 399. SECRETION. 237 ably after these substances have reached the duodenum. Moreover, Pawlow has given proof that the secretion of the pancreas varies in both quantity and quality with the nature of the food. Indeed, there seem to be indications of a specific relationship between the food and the composition of the secretion, albuminous food giving a secretion with a greater digestive action on pro- teids; oily foods, a secretion with a larger amount of fat-splitting enzymes, and so on. If this relationship is shown to exist, it forms an adaptation whose mechanism is very obscure.' Glands of the Stomach. Histological Characteristics. — The glands of the gastric mucous mem- brane belong practically to the type of simple tubular glands ; for, although two or more of the simple tubes may possess a common opening or mouth, there is no system of ducts such as prevails in the compound glands, and the divergence from the simplest form of tubular gland is very slight. Each of these glands possesses a relatively wide mouth, lined with the columnar epi- thelium found on the free surface of the gastric membrane, and a longer, nar- rower secreting part, which penetrates the thickness of the mucosa and is lined by cuboidal cells. The glands in the pyloric end of the stomach differ in gen- eral appearance from those in the fundic end, and are especially characterized by the fact that they possess only one kind of secretory cell, while the fundic glands contain two apparently distinct types of cells (Fig. 64). The lumen in the latter glands is lined by a continuous layer of short cylindrical cells to which Heidenhain gave the name of chief-cells. These cells are apparently concerned in the formation of pepsin, the proteolytic enzyme contained in the gastric secre- tion. In addition there are present a number of cells of an oval or triangular shape which are placed close to the basement membrane and do not extend quite to the main lumen of the gland. These cells are not found in the pyloric glands ; they are known by various names, such as border-cells, parietal cells, oxyntic cells, etc. The last-mentioned name has been given to them because of their supposed connection with the formation of the acid of the gastric secretion. The nature and function of these border-cells have been the subject of much discus- sion. From the histological side they have been interpreted as representing either immature forms of the chief-cell, or else the active modificatioD of this cell. Recent work, however, seems to have demonstrated that they form a specific type of cell, and probably therefore have a specific function. An interesting histological fact in connection with the parietal cells is that, in the human stomach at least, they frequently contain several nuclei, five or six, and some of these seem to be derived from ingested leucocytes. They are interesting also is the fact that they contain distinct vacuoles that seem to appear some time after digestion has begun, reach a maximum size, and then gradually grow smaller and finally disappear. Like the similar phenomenon 1 For other interesting facts bearing upon the mechanism of pancreatic secretion, see Walter : Archives des Sciences biologiques, 1899, t. vii. p. 1. 238 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. described for other gland-cells (p. 226), this appearance is possibly connected with the formation of the secretion. The duct of a gastric gland was formerly supposed to be a simple tube extending the length of the gland. A number of recent observers, however, have shown, by the use of the Golgi stain, that this view is not entirely correct, at least not for the glands in the fundus in which border-cells are present. In these glands the central lumen sends offside channels that pass to the border-cells and there form a net- work of small capillaries lying either in or round the cell. 1 An illustration of the duct-system of a fundic gland is given in Figure 62. If this work i- correct it would seem that the chief-cells com- fig. 62.— Ducts and secretion muiiicate directly with the central lumen, but that capillars '" ! ' ari ," ,al ,"';*• the border-cells have a system of secretion capillaries Oland from the fundus of cat s _ J l Btomach (after Langendorff of their own, resembling in this respect the demi- lunes of the mucous salivary glands (p. 220). This fact tends to corroborate the statement previously made, that the border-cells form a distinct type of cell whose function is probably different from that of the chief-cells. Composition of the Secretion of the Gastric Mucous Membrane. — The secretion as it is poured out on the surface of the mucous membrane is composed of the true secretion of the gastric glands together with more or less mucus, which is added by the columnar cells lining the surface of the mem- brane and the mouths of the glands. In addition to the mucus, water, and inorganic salts, the secretion contains as its characteristic constituents hydro- chloric acid and two enzymes — namely, pepsin which acts upon proteids, and renuin which has a specific coagulating effect upon the casein of milk. For an analysis of the gastric secretion of the dog see p. 288. According to Heiden- hain, 2 the secretion from the pyloric end of the stomach is characterized by the absence of hydrochloric acid, although it still contains pepsin. This statement pests upon careful experiments in which the pyloric end was entirely resected and made into a blind pouch which was then sutured to the abdominal wall to form a fistula. In this way the secretion of the pyloric end could be obtained free from mixture with the secretion of any other part of the alimentary canal. By this means Heidenhain found that the pyloric secretion is an alkaline liquid containing pepsin. Tin- fad forms the strongest evidence for Heidenhain's hypothesis that the HC1 of the normal gastric secretion is produced by the " border-cells" of the fundic glands and the pepsin by the "chief-cells," since HC1 is formed only in part- of the stomach containing border-cells, whereas the pepsin is produced in the pyloric end. where only chief-cells are present. Evidence of this character is naturally not very convincing, and the hypoth- 1 Laii^endorfi' and Laserstein : Pfluger's Archiv filr die gesammU Physiologic, 1894, Bd. lv. S. 578. 2 Archiv fur die gesammti Physiologic, l s 7s. Bd, xviii. S. 169, also Bd. xix. SECRETION. 239 esis, especially that part connecting the border-cells with the formation of HO, can only be accepted provisionally until further investigation confirms or disproves it. It should be stated that the alkalinity of the secretion obtained from the pyloric glands by Heideuhain's method has been attributed by some authors to the abnormal conditions prevailing, especially to the section of the vagus fibres that necessarily results from the operation. Contejean l asserts that the reaction of the pyloric membrane under normal conditions is acid in spite of the absence of border-cells. Influence of the Nerves upon the Gastric Secretion. — It has been very difficult to obtain direct evidence of the existence of extrinsic secretory nerves to the gastric glands. In the hands of most experimenters, stimulation of the vagi and of the sympathetics has given negative results, and, on the other hand, section of these nerves does not seem to prevent entirely the formation of the gastric secretion. There are on record, however, a number of observations that point to a direct influence of the central nervous system on the secre- tion. Thus Bidder and Schmidt found that in a hungry dog with a gastric fistula (page 288) the mere sight of food caused a flow of gastric juice ; and Richet reports a case of a man in whom the oesophagus was completely oc- cluded and in whom a gastric fistula was established by surgical operation. It was then found that savory foods chewed in the mouth produced a marked flow of gastric juice. There would seem to be no clear way of explaining the secretions in these cases except upon the supposition that they were caused bv a reflex stimulation of the gastric mucous membrane through the central nervous system. These cases are strongly supported by some recent experimental work on dogs by Pawlow 2 and Schumowa-Simanowskaja. These observers used dogs in which a gastric fistula had been established, and in which, more- over, the oesophagus had been divided in the neck and the upper and lower cut surfaces brought to the skin and sutured so as to make two fistulous openings. In these animals, therefore, food taken into the mouth and subse- quently swallowed escaped to the exterior through the upper (esophageal fistula, without entering the stomach. Nevertheless this "fictitious meal," as the authors designate it, brought about a secretion of gastric juice. If in such animals the two vagi were cut, the "fictitious meal" no longer caused a secretion of the gastric juice, and this fact may be considered as showing that the secretion obtained when the vagi were intact -was due to a reflex stimulation of the stomach through these nerves. In later experiments 8 from the same laboratory the secretion caused in this way bv the act of eating is designated as a " psychical secretion," on the assumption, for which consider- able evidence is given, that the reflex must involve psychical factors such as the sensations accompanying the provocation and gratification of the appetite. In favorable cases the fictitious feeding was continued for as long as five to six hours, with the production of a secretion of about 700 c.e. of pure gastric 1 Archives de Physiologie, 1S9'J, p. 554. * Du Bois-Reymond! & Archivjur Physiologic, 1895, S. 53. 1 Die Arbeit der Verdauungsdriisen, Wiesbaden, 1898. 240 AN AMERICAN TEXT- HOOK OF PHYSIOLOGY. juice. Finally, these observers were able to show that direct stimulation of the vagi under proper conditions causes, after a long latent period (four and a half to ten minutes), a marked secretion of gastric juice. The long latent period is attributed to the simultaneous stimulation of inhibitory fibres. Taking these results together, we must believe that the vagi send secretory fibres to the gastric glands, and that these fibres may be stimulated reflexly through the sensory nerves of the mouth, and probably also by psychical states. Normal Mechanism of Secretion of the Gastric Juice. — Our knowl- edge of the means by which the flow of gastric secretion is caused during normal digestion, and of the varying conditions which influence the flow, is as vet quite incomplete. The notable experiments recently made by Pawlow ' and his pupils, together with older experiments by Heidenhain, 2 have, however, thrown some light upon this difficult problem, and have, moreover, opened the way for further experimental study of the matter. Heidenhain cut out a part of the fundus of the stomach, converted it into a blind sac, and brought one end of the sac to the abdominal wall so as to form a fistulous opening to the exterior. The continuity of the stomach was established by suturing the cut cnd>, but the fundic sac was completely separated from the rest of the alimentary canal. This operation has since been modified by Pawlow in such a way that the isolated fundic sac retains its normal nerve supply. Heiden- hain found that under these conditions the ingestion of ordinary food caused a secretion in the isolated and empty fundic sac, the secretion beginning fifteen to thirty minutes after the food was taken, and continuing until the stomach was empty. The ingestion of water caused a temporary secretion in the fundus, while indigestible material such as ligamentum nucha? gave no secretion at all. Heidenhain's interpretation of these experiments as applied to normal secretion was that in ordinary digestion we must distinguish between a primary and a secondary secretion. The primary secretion depends upon the mechanical stimulus of the ingested food, and is confined to the spots directly stimulated ; the secondary secretion begins after absorption from the stomach is in progress, and involves the whole secreting surface. The first part of this theory is in accord with a belief which heretofore has been very generally held by physiologists, namely, that the gastric glands may be made to secrete by direct mechanical excitation. Pawlow has shown, however, by what seem to be most convincing experiments, that this belief is erroneous. Mechanical stimulation, strong or weak, circumscribed or general, seems to be totally without effect in arousing a secretion. Pawlow has been led by his interesting experiments to give a different explanation of the normal mechan- ism of secretion. The first effect of eating is the production of the " psychical secretion," before referred to. This secretion is effected through the action of secretory fibres in the vagus, and possibly also in the sympathetic nerve. It begins usually within five minutes, is, in a general way, proportional in amount 1 Archives des Sciences biologiques, St. Petersburg, 1895, t. iii. p. 461 ; t. v. p. 425. 'Hermann's Handbuch der Physiologie, 1883, Bd. v. S. 114. SECRETION. 241 to the intensity of the appetite or enjoyment of the food, and may last for several hours even though the aetnal period of eating has been short (five min- utes). It is this secretion that first acts upon the food received into the stomach. Later its action is supplemented by an augmented secretion, caused by stimuli of a chemical nature originating in the food ingested. Some foods contain substances ready formed that are capable of acting in this way. Investigation of various articles of diet showed that meat extracts, juices, and soups contain these substances in largest amounts. Milk and aqueous solutions of gelatin act in the same way, although less powerfully. Water also, if in sufficient quantity, acts as a direct stimu- lant. Other common articles of food, such as bread or white of egg, do not contain these stimulating substances. Food of the latter character, when introduced directly into a dog's stomach through a fistula, pro- vokes not a drop of secretion and undergoes no digestion, if it has been introduced in such a way as to avoid arous- ing the psychical secretion, as, for instance, at times when the animal is dozing. If, how- ever, this latter class of foods undergo digestion, as would happen in normal feeding in consequence of the action of the " psychical secretion," sub- stances capable of stimulating the stomach to secretion are developed, and their action keeps up the flow of secretion after the effect of the psychical factor has become weakened. The nature of these chemical stimuli remains entirely undetermined. Pawlow's first statement that pep- tone constituted at least one member of this group lie now finds is erroneous. It is assumed that these substances act through the secretory nerves, and it has been shown also that other substances may have the contrary effeel of retarding or inhibiting the gastric secretion. This has been proved tor fats at least. Oils of various kinds decrease the secretion of gastric juice, while they augment the pancreatic secretion. Another mosl suggestive result of Pawlow's work is the proof that the quantity and characteristics of the secre- tion vary with the food. Apparently the quantity of the secretion varies, other Vol. I.— 16 f* •S'l 2-2 a> ■stive ver in timet lity in cent. Milk, Meat, Bread, 600 c.c. 100 gr. 100 gr. Ml o '" |& 10 8 6 4 2 0.576 0.528 0.480 0.432 0.384 0.336 0.288 0.240 0.192 0.144 0.096 0.048 18 16 14 12 10 8 6 4 2 \ • ' ' ; \ i i \ ; \ 1 \ f ! ' T \ i ; I \ s J i ~" 1 ■ 1 V t Z34S6Y8? Mini Quantity of secretioi i. ; . ~y/ ' Ig ■ 1 Fig. 63.— Diagram showing the variation in quantity of gastric secretion in the dog after a mixed meal: also the variations In acidity and In digestive power (after Ehigine). 242 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. conditions being the same, with the amount of the food to be digested. By some means the apparatus is adjusted in this respect to work economically. Different kinds of food produce secretions varying not only as regards quan- tity, but also in their acidity and digestive action. The secretion produced by bread, though less in quantity than that caused by meat, possesses a greater digestive action. On a given diet the secretion will assume certain charac- teristics, and Pawlow is convinced that further work will disclose the fact that the secretion of the stomach is not caused normally by general stimuli all affecting it alike, but by specific stimuli contained in the food or produced during digestion, whose action is of such a kind as to produce the secretion best adapted for the food ingested. One of the curves showing the effect of a mixed diet (milk, GOO cubic centimeters ; meat, 100 grams ; bread, 100 grams) upon the gastric secretion, as determined by Pawlow's method, is reproduced in Fig. 68. It will be noticed that the secretion began shortly after the ingestion of the food (seven minutes), and increased rapidly to a maximum that was reached in two hours. After the second hour the flow decreased rapidly and. nearly uniformly to about the tenth hour. The acidity rose slightly between the first and second hours, and then fell gradually. The digestive power showed an increase between the second and third hours. Histological Changes in the Gastric Glands during- Secretion. — The cells of the gastric glands, especially the so-called chief-cells, show distinct changes as the result of prolonged activity. Upon preserved specimens taken from dogs fed at intervals of twenty-four hours, Heidenhain found that in the fasting condition the chief-cells were large and clear, that during the first six hours of digestion the chief-cells as well as the border-cells increased in size, but that in a second period extending from the sixth to the fifteenth hour, the chief-cells became gradually smaller, while the border-cells remained large or even increased in size. After the fifteenth hour the chief-cells increased in size, gradually passing back to the fasting condition (see Fig. 6*4). Langley ' has succeeded in following the changes in a more satisfactory way by observations made directly upon the living gland. He finds that the chief-cells in the fasting stage are charged with granules, and that during digestion the granules are used up, disappearing first from the base of the cell, which then becomes filled with a non-granular material. Observations similar to those made upon the pancreas demonstrate that these granules represent in all probability a preliminary material from which the gastric enzymes are made during the act of secretion. The granules, therefore, as in the other glands, may be spoken of as zymogen granules, the preliminary material of the pepsin being known as pepsinogen and that of the rennin sometimes as pexinogen. Glands of the Intestine. — At the very beginning of the intestine in the immediate neighborhood of the pylorus is found a small area of mucous mem- brane containing distinct tubular glands, known usually as the glands of 1 Journal <>j Physiology, 1880, vol. iii. p. 269. SECRETION. 243 Brunner. These glands resemble closely in arrangement those of the pyloric end of the stomach, with the exception that the tubular duct is more branched. The secreting cells are similar to those of the pyloric glands of the stomach. Little is known of their secretion. According to some authors it contains pepsin. The amount of secretion furnished by these glands would seem to be too small to be of great importance in digestion. Throughout the length Fig. 64.— Glands of the fundus (dog) : A and A 1 , during hunger, resting condition ; />, during the tir-t stage of digestion : ''and />, the second stage of digestion, showing the diminution in the Bize of the "chief" or central cells (after Heidenhain). of the small and large intestine the well-known crypts of Lieberkiihn are found. These structures resemble the gastric glands in general appear- ance, but not in the character of the epithelium. The epithelium lining the crypts is of t\\<> varieties — the goblet cells, whose function h to form mucus, and columnar cells with a characteristic striated border. The changes in the goblet cells during secretion and the probability of a relationship between them and the neighboring epithelial cells has been discussed (see p. 216). Whether or not the crypts form a definite secretion has Ween much debated. Physiologists are accustomed to speak of an intestinal juice, " succus entericus," as being formed by the glands of Lieberkiihn, but practically uothing is known as to the mechanism of the secretion. The succus entericus itself, however it may be formed, can be collected by isolating small loops of the intestine and 244 AN AMERICAN TEXT-ROOK OF PHYSIOLOGY. bringing the ends to the abdominal wall to form fistulous openings. The secretion thus obtained contains diastatie and also inverting ferments, the action of which is described on p. 308. Histologically, the cells in the bottom of the crypts do not possess the general characteristics of secreting cells. D. Liver ; Kidney. The liver is a gland belonging to the compound tubular type. The hepatic cells represent the secretory cells and the bile-ducts carry off the external secretion, which is designated as bile. In addition it is known that the liver-cells occasion important changes in the material brought to them in the blood, and that two important compounds, namely, glycogen and urea, are formed under the influence of these cells and afterward are given off to the blood-stream. The liver, then, furnishes a conspicuous example of a gland that forms simultaneously an external and an internal secretion. In this section we have to consider only certain facts in relation to the external secretion, the bile. Histological Structure. — The general histological relations of the hepatic lobules need not be repeated in detail. It will be remembered that in each lobule the hepatic cells arc arranged in columns radiating from the central vein, and that the intralobular capillaries are so arranged with reference to these columns that each cell is practically brought into contact with a mixed blood derived in part from the portal vein and in part from the hepatic artery. As a gland making an external secretion, the relations of the liver-cells to the ducts and to the nervous system are important points to be determined. The bile-ducts can be traced without difficulty to the fine interlobular branches running round the periphery of the lobules, but the finer branches or bile- capillaries springing from the interlobular ducts and penetrating into the in- terior of the lobules have been difficult to follow with exactness, especially as to their connection with the interlobular ducts on the one hand, aud with the liver-cells on the other. The bile-capillaries have long been known to pene- trate the columns of cells in the lobule in such a way that each cell is in con- tacl with a bile-capillary at one pointofits periphery, and with a blood-capil- lary at another, the bile- and blood-capillaries being separated from each other by a portion of the cell-snbstance. But whether or not intracellular blanches from these capillaries actually penetrate into the substance of the liver-cells ha- been a matter in dispute. Knppfer contended that delicate ducts arising from the capillaries enter into the cells and end in a small intracellular vesicle. As this appearance was obtained by forcible injections through the bile-duets, it was thought by many to be an artificial product; but recent observations with staining reagents tend to substantiate the accuracy of Kuppfer's # obser- vations and confirm the belief that normally the system of bile-duct- begins within the liver-oil- in minute channels that connect directly with the bile- capillaries. Two questions with reference to the bile-ducts have given rise to considerable SECRETION. 245 discussion and investigation : first, the relationship existing between the liver- cells and the lining epithelium of the bile-duets ; second, the presence or ab- sence of a distinct membranous wall for the bile-capillaries. Different opin- ions are still held upon these points, but the balance of evidence seems to show that the bile-capillaries have no proper wall. They are simply minute tubular spaces penetrating between the liver-cells and corresponding to the alveolar lu- men in other glands. Where the capillaries join the interlobular ducts the liver- cells pass gradually or abruptly, according to the class of vertebrates examined, into the lining epithelium of the ducts. From this standpoint, then, the liver- cells are homologous to the secreting cells of other glands in their relations to the general lining epithelium. Several observers (MaCallum, 1 Berkley, 2 and Korolkow 3 ) have claimed that they are able to trace nerve-fibres to the liver-cells, thus furnishing histological evidence that the complex processes oc- curring in these cells are under the regulating control of the central nervous system. According to the latest observers (Berkeley, Korolkow) the terminal nerve-fibrils end between the liver-cells, but do not actually penetrate the sub- stance of the cells, as was described in some earlier papers. If these observa- tions prove to be entirely correct they would demonstrate the direct effect of the nervous system on some at least of the manifold activities of the liver- cells. So far as the formation of the bile is concerned we have no satisfactory phvsiological evidence that it is under the control of the nervous system. Composition of the Secretion. — The bile is a colored secretion. In most carnivorous animals it is golden red, while in the herbivora it is green, the difference depending on the character and quantity of the pigments. In man the bile is usually stated to follow the carnivorous type, showing a red- dish or brownish color, although in some cases apparently the green predomi- nates. The characteristic constituents of the bileare the pigments, bilirubin in carnivorous bile and bilivcrdin in herbivorous bile, and the bile acids or bile- salts, the sodium salts of glycocholic or taurocholic acid, the relative proportions of the two acids varying in different animals. In addition there is present a considerable quantity of a mucoid nucleo-albumin, a constituent which is QOl formed in the liver-cells, but is added to the secretion by the mucous membrane of the bile-ducts and gall-bladder ; and small quantities of cholesterin, lecithin, fats, and soaps. The inorganic constituents comprise the usual salts — chlorides, phosphates, carbonates and sulphates of the alkalies or alkaline earths. Iron is found in small quantities, combined probably as a phosphate. The secre- tion contains also a considerable though variable quantity <>f CO a gas, held in such loose combination that it can be extracted with the gas-pump without the addition of acid. The presence of this constituent serves a- an indication of the extensive metabolic changes occurring in the liver-cells. Quantitative analyses of the bile show that it varies greatly in composition even in the same species of animal. Examples of this variability are given in the analyses 1 MaCallum : Quarterly Journal of the Microscopical Sciences, 1887, vol, x.wii. p. 189. ■■* Berkley : Anatomischer Aruseiger, 1893, Bd. viii. 8. 769. Korolkow: Ibid., 8. 750. 240 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. quoted in the section on Digestion (p. 322), where a brief account will also be found of the origin and physiological significance of the different constituents. The Quantity of Bile Secreted. — Owing to the fact that a fistula of the common bile-duet or gall-bladder may be established upon the living animal and the entire quantity of bile be drained to the exterior without serious detri- ment t<> the animal's lite, we possess numerous statistics as tothedailv quantity of the secretion formed. Surgical operations upon human beings (see p. 321 for references), made necessary by occlusion of the bile-passages, have furnished similar data for man. In round numbers the quantity in man varies from 500 to 800 euliie centimeters per day, or, taking into account the weight of the individuals concerned, about 8 to 16 cubic centimeters for each kilogram of body-weight. Observations upon the lower animals indicate that the secretion is proportionally greater in smaller animals. This fact is clearly shown in the following table, compiled by Heidenhain ' for three herbivorous animals: Sheep. Rabbit. Guinea-pig. Eatio of bile-weight for 24 hours to body-weight . . - 1 : 37.5 1 : 8.2 1 : 5.6 Ratio of bile-weight for 24 hours to liver-weight . . . 1.507 : 1 4.0(54 : 1 4.467 : 1 There seems to be no doubt that the bile is a continuous secretion, although in animals possessing a gall-bladder the secretion may be stored in this reser- voir and ejected into the duodenum only at certain intervals connected with the processes of digestion. The movement of the bile-stream within the system of bile-ducts — that is, its actual ejection from the liver, is also probably intermittent. The observations of Copeman and Winston on a human patient with a biliary fistula showed that the secretion was ejected in spirts, owing doubtless to contraction- of the muscular walls of the larger bile-ducts. But though continuously formed within the liver-cells, the flow of bile is subject to considerable variations. According to most observers the activity of secre- tion is definitely connected with the period of digestion. Somewhere from the third to the fifth hour after the beginning of digestion there is a very marked acceleration of the flow, and a second maximum at a later period, ninth to tenth hour (Hoppe-Seyler), has been observed in dogs. The mechanism con- trolling the accelerated How during the third to the fifth hour is not perfectly understood. It would seem to be correlated with the digestive changes occur- ring in the intestine, but whether the relationship is of the nature of a reflex nervous act, or whether it depends on increased blood-flow through the organ or upon some action of the absorbed products of secretion remains to be deter- mined. It has been shown that the presence of bile in the blood acts as a stimulus to the liver-cells, and it is highly probable that the absorption of bile from the intestine which occurs during digestion serves to accelerate the secre- tion ; but this circumstance obviously does not account for the marked increase observed in animals with biliary fistulas, since in these cases the bile does not reach the intestine at all. Therapeutically various substances have been stated by different authors to act as true cholagogues — that is, to stimulate the 1 Hermann's Handbuch der Physiologic, Bd. v. Thl. I, S. 253. SECRETION. 'JIT secretion of bile. Of these substances the < >m- whose action is most undoubted is bile itself or the bile acids. When given as dried bile, in the form of pills, a marked increase in the flow is observed.' Relation of the Secretion of Bile to the Blood-flow in the Liver. — Numerous experiments have shown that the quantity of bile formed by the liver varies more or less directly with the quantity of blood flowing through the organ. The liver-cells receive blood from two sources, the portal vein and the hepatic artery. The supply from both these sources is probably essen- tial to the perfectly normal activity of the cells, but it has been shown that bile continues to be formed, for a time at least, when either the portal or the arterial supply is occluded. However, there can be little doubt that the material actually utilized by the liver-cells in the formation of their external and internal secre- tions is brought to them mainly by the portal vein, and that variations in the quantity of this supply influences directly the amount of bile produced. Thus, occlusion of some of the branches of the portal vein diminishes the secretion; stimulation of the spinal cord diminishes the secretion, since, owing to the large vascular constriction produced thereby in the abdominal viscera, the quantity of blood in the portal circulation is reduced ; section of the spinal cord also dimin- ishes the flow of bile or may even stop it altogether, since the result of such an operation is a general paralysis of vascular tone and a general fall of blood- pressure and velocity ; stimulation of the cut splanchnic nerves diminishes the secretion because of the strong constriction of the blood-vessels of the abdom- inal viscera and the resulting diminution of the quantity of the blood in the portal circulation ; section of the splanchnics alone, however, is said to increase the quantity of bile, in dogs, since in this case the paralysis of vascular tone is localized in the abdominal viscera. The effect of such a local dilatation of the blood-vessels would be to diminish the resistance alono- the intestinal paths, and thus lead to a greater flow of blood to that area and the portal circulation. In all these cases one might suppose that the greater or less quantity of bile formed depended only on the blood-pressure in the capillaries of the liver lobules — that so far at least as the water of the bile is concerned it is produced by a process of filtration and rises and falls with the blood-pressure. That this simple mechanical explanation is not sufficient seems to be proved by the fact that the pressure of bile within the bile-ducts, although comparatively low, may exceed that of the blood in the portal vein. The Existence of Secretory Nerves to the Liver. — The numerous experiments that have been made to ascertain whether or not the secretion of bile is under the direct control of secretory nerves have given unsatisfactory results. The experiments are difficult, since stimulation of the nerves supply- ing the liver, such as the splanchnic, is accompanied by vaso-motor changes which alter the blood-flow to the organ and thus introduce a factor that in itself influences the amount of the secretion. So far as our actual knowledge goes, the physiological evidence is against the existence of secretory ncrve- 1 Journal of Experimented Medicine, 1897, vol. ii. p. 4'.'. 248 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. fibres controlling the formation of bile. On the other hand, there are some experiments, 1 although they are not perfectly conclusive, which indicate that the glycogen formation within the liver-cells is influenced by a special set of glyco-seerehory nerve-fibres. This fact, however, does not bear directly upon the formation of bile. Motor Nerves of the Bile-vessels. — Doyon 2 has recently shown that the gall-bladder as well as the bile-ducts is innervated by a set of nerve-fibres comparable in their general action to the vaso-constrictor and vaso-dilator fibres of the blood-vessels. According to this author, stimulation of the peripheral end of the cut splanchnics causes a contraction of the bile-ducts and gall-bladder, while stimulation of the central end of the same nerve, on the contrary, brings about a reflex dilatation. Stimulation of the central end of the vagus nerve causes a contraction of the gall-bladder and at the same time an inhibition of the sphincter muscle closing the opening of the common bile-duct into the duodenum. These facts need confirmation, perhaps, on the pari of other observers, although they are in accord with what is known of the actual movement of the bile-stream. The ejection of bile from the gall- bladder into the duodenum is produced by a contraction of the gall-bladder, and it is usually believed that this contraction is brought about reflexly from some sensory stimulation of the mucous membrane of the duodenum or stomach. The result of the experiments made by Doyon would indicate that the afferent fibres of this reflex pass upward in the vagus, while the efferent fibres to the gall-bladder run in the splanchnics and reach the liver through the semilunar plexus. Normal Mechanism of the Bile-secretion. — Bearing in mind the tact that our knowledge of the secretion of bile is in many respects incomplete, and that any description of the act is therefore partly conjectural, wc might picture the processes concerned in the secretion and ejection of bile as follows : The bile is steadily formed by the liver-cells and turned out into the bile-capil- laries ; its quantity varies with the quantity and composition of the blood flowing through the liver, but the formation of the secretion depends upon the activities taking place in the liver-cells, and these activities are independ- ent of direct nervous control. During the act of digestion the formation of bile is increased, owing probably to a greater blood-flow through the organ and to the generally increased metabolic activity of the liver-cells occasioned by the inflow of the absorbed products of digestion. The bile after it gets into the bile-ducts is moved onward partly by the accumulation of new bile from behind, the secretory force of the cells, and partly by the contractions of the walls of the bile-vessels. It is stored in the gall-bladder, and at inter- vals during digestion is forced into the duodenum by a contraction of the muscular walls of the bladder, the process being aided by the simultaneous relaxation of a sphincter-like layer of muscle that normally occludes the bile-duct :it it- opening into the intestine; both these last acts are under the control of a nervous reflex mechanism. 1 Morat iiinl Dufonrt: Archives de Physiologie, 1 s 04, p. 371. 2 Archives de Physiologic, 1894, p. 19 ; see also Oddi : Arch. tied, de Biologie, t. xxii., cvi. SECRETION. 249 In a very interesting research by Bruno 1 it has been shown that the actual passage of bile into the intestine is occasioned, reflexly no <1< ml >t , by the passage of the chyme from stomach to intestine. As long as the stomach is empty no bile flows into the duodenum ; the flow commences when the stomach begins to empty its contents into the intestine, and ceases as soon as this process is completed. The author endeavored to ascertain the substances in the chyme that serve as the stimulus in this reaction. As far as his experi- ments go, they show that fats and the digested products of proteids (peptones and proteoses) are the most efficient stimuli. Acids, alkalies, and starch or the substances formed from it during salivary digestion are ineffective. Pre- sumably the fats and the products of proteid digestion act on the sensory fibres of the duodenal membrane. Effect of Complete Occlusion of the Bile-duct. — It is an interesting fact that when the flow of bile is completely prevented by ligation of the bile- duct, the stagnant liquid is not reabsorbed by the blood directly, but by the lymphatics of the liver. The bile-pigments and bile-acids in such cases may be detected in the lymph as it flows from the thoracic duct. In this way they get into the blood, producing a jaundiced condition. The way in which the bile gets from the bile-ducts into the hepatic lymphatics is not definitelv known, but possibly it is due to a rupture, caused by the increased pressure, at some point in the course of the delicate bile-capillaries. Kidney. Histology. — The kidney is a compound tubular gland. The constituent uriniferous tubules composing it may be roughly separated into a secreting part comprising the capsule, convoluted tubes, and loop of Henle, and a col- lecting part, the so-called straight collecting-tube, the epithelium of which is assumed not to have any secretory function. Within the secreting part the epithelium differs greatly in character in different regions; its peculiarities may be referred to briefly here so far as they seem to have a physiological bearing, although for a complete description reference must he made to some work on Histology. The arrangement of the glandular epithelium in the capsule with reference to the blood-vessels of the glomerulus is worthy of special attention. It will be remembered that each Malpighian corpuscle consists of two principal parts, a tuft of blood-vessels, the glomerulus, and an enveloping expansion of the uriniferous tubule, the capsule. The glomerulus is a remarkable structure (set- Fig. 65, ^1). It consists of a small afferent artery which after entering the glomerulus breaks up into a number of capillaries, which, though twisted together, do not anastomose. These capillaries unite to form a single efferent vein of a smaller diameter than the afferent artery. The whole structure, therefore, is not an ordinary capillary area, but a rete mirabile, and the phys- ical factors are such that within the capillaries of the rete there must he a greatly diminished velocity of the blood-stream, owing to the great increase 1 Archives des sciences biologiques, 18'J9, t. vii. p. 87. I'.-.u AN AMERICAN TEXT-BOOK OF PHYSIO/A OG V. in the width of the stream-bed, and a high blood-pressure as compared with ordinary capillaries. Surrounding; this glomerulus is the double- walled capsule. < me wall of the capsule is closely adherent to the capillaries of the glomerulus; it not only covers the structure closely, but dips into the interior between the small lobules into which the glomerulus is divided. This layer of the capsule is composed of flattened endothelial-like cells, the glomerular epithelium, to which great importance is new attached in the formation of the secretion. It will benoticed that between the interior of the blood-vessels of the glomerulus and Fig. 65.— Portions of the various divisions of the uriniferous tubules drawn from sections of human kidney: .1, Malpighian body ; x, squamous epithelium lining the capsule and reflected over the glomer- ulus ; //, e, a Hi rent and efferent vessels of the tuft; e, nuclei of capillaries; n, constricted neck marking passage of capsule into convoluted tubule ; B, proximal convoluted tubule : C, irregular tubule; D and F, spiral tubules ; E, ascending limb of Henle's loop; G, straight collecting tubule (Piersol). the cavity of the capsule, which is the beginning; of the uriniferous tubule, there are interposed only two very thin layers, namely, the epithelium of the capil- lary wall and the glomerular epithelium. The apparatus would seem to afford most favorable conditions for filtration of the liquid parts of the blood. The epithelium clothing the convoluted portion- of the tubule, including under this designation the so-called irregular and spiral portions and the loop of Henle, is of a character quite different from that of the glomerular epithelium (Fig. 65, B, C, D, E, F, G). The cells, speaking generally, are cuboidal or cylindrical, proto- plasmic, and granular in appearance; on the side toward the basement mem- brane they often show a peculiar >t nation, while on the lumen side the extreme periphery presents a compact border which in some cases shows a cilia-like itriation. These cells have the general appearance of active secretory struc- tures, and recent theories of urinary secretion attribute this importance to them. Composition of Urine. — The chemical composition of the urine is very complex, as we should expect it to be when we remember that it contains most of the end-products of the varied metabolism of the body, its importance in this respect being greater than the other excretory organs such as the lungs, skin, and intestine. The secretion is a yellowish liquid which in carnivorous ani- mal- and in man has normally an acid reaction, owing to the presence of acid SECRETION. 251 salts (acid sodium and acid calcium phosphate), and an average specific gravity of 1017 to 1020. The quantity formed in twenty-four hours is about 1200 to 1700 cubic centimeters. In the very young the amount of urine formed is proportionately much greater than in the adult. The normal urine contains about 3.4 to 4 per cent, of solid matter, of which over half is organic mate- rial. Among the important organic constituents of the urine are the follow- ing : urea, uric acid, hippuric acid, xanthin, hypoxanthin, guanin, creatinin and aromatic oxy- acids (para-oxyphenyl propionic acid and para-oxyphenyl acetic acid, as simple salts or combined with sulphuric acid) ; phenol, paracre- sol, pyrocatechin and hydrochinon, these four substances being combined with sulphuric or glycuronic acid; iudican or indoxyl sulphuric acid; skatol sul- phuric acid ; oxalic acid ; sulphocyanides, etc. These and other organic con- stituents occurring under certain conditions of health or disease in various animals, are of the greatest importance in enabling us to follow the metab- olism of the body. Something as to their origin and significance will be found in the section on Nutrition, while their purely chemical relations are described in the section on Chemistry. Among the inorganic constituents of the urine may be mentioned sodium chloride, sulphates, phosphates of the alkalies and alkaline earths, nitrates, and carbon dioxide gas partly in solution and partly as carbonate. In this sect inn we are concerned only with the general mechanism of the secretion of urine, and in this connection have to consider mainly the water and soluble inorganic salts and the typical nitrogenous excreta, namely, urea and uric acid. The Secretion of Urine. — The kidueys receive a rich supply of nerve- fibres, but most histologists have been unable to trace any connection between these fibres and the epithelial cells of the kidney tubules. Berkley ' has, how- ever, described nerve-fibres passing through the basement membrane and ending between the secretory cells. The majority of purely physiological experiments upon direct stimulation of the nerves going to the kidney are adverse to the theory of secretory fibres, the marked effects obtained in these experiments being all explicable by the changes produced in the blood-flow through the organ. Two general theories of urinary secretion have been proposed. Ludwig held that the urine is formed by the simple phvsical processes of filtration and diffusion. In the glomeruli the conditions are most favorable to filtration, and he supposed that in these struc- tures water filtered through from the blood, carrying with it not only the in- organic salts, but also the specific elements (urea) of the secretion. There was thus formed at the beginning of the uriniferous tubules a complete bul diluted urine, and m the subsequent passage of this Liquid along the convoluted tubes it became concentrated by diffusion with the lymph surrounding the outside of the tubules. S<> far as the latter part of this theory is concerned it has not been supported by actual experiments; recent histological work (see below) seems to indicate that the epithelial cells of the convoluted tubules have a 1 The Johns Hopkins Hospital Bulletin, vol. iv., No. 28, p. 1. 252 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. distinct secretory function, and that tiny give material to the secretion rather than take from it. Bowman's theory of urinary secretion, which has since been vigorously supported and extended by Heidenhain, was based apparently mainly on his- tological grounds. It assumes that in the glomeruli water and inorganic salts are produced, while the urea and related bodies are eliminated through the activity of the epithelial cells in the convoluted tubes. Elimination <>/ Urea ' /' UniversiU de Oand, 1892. 2 Referate und Beiirdge zur Analomie and Entvrickdungsgesehichte (anatomische Hefte), Merkel and Bonnet, 1893. 3 Archives Ualiennes de liiologie, 1898, t. 30, p. 426. sec i urn ox. 253 tion is emptied from the cells by filtration. Van der Stricht believes that the vesicles rupture and thus empty into the lumen. In longitudinal sections various stages in the process may be seen scattered along the length of a single tubule. Secretion of the Water and Salts. — There seems to be no question that the elimination of water together with inorganic salts, and probably still other soluble constituents, takes place chiefly through the glomerular epithelium. This supposition is made in both the general theories that have been men- tioned. It has, however, long been a matter of controversy, in this as in other glands, whether the water is produced by simple filtration or whether the glomerular epithelium takes an active part of some character in setting up the stream of water. The problem is perhaps simpler in this case than in the salivary glands, since the direct participation of secretory nerves in the process is excluded. Ou the filtration theory the quantity of urine should vary directly with the blood-pressure in the glomerulus. This relationship has been accepted as a crucial test of the validity of the filtration theory, and numerous experiments have been made to ascertain whether it invariably exists. Speaking broadly, any general rise of blood-pressure in the aorta will occasion a greater blood-flow and greater pressure in the glomerular vessels provided the kidney arteries themselves are not simultaneously constricted to a sufficient extent to counteract this favorable influence ; whereas a general fall of pressure should have the opposite influence both on pressure and velocity of flow. It has been shown experimentally that if the general arterial pressure falls below 40 or 50 millimeters of mercury, as may happen after section of the spinal cord in the cervical region, the secretion of the urine will be greatly slowed, or suspended completely. Constriction of the small arteries in the kidney, whether effected through its proper vaso-constrictor nerves or by par- tially clamping its arteries, causes a diminution in the secretion and at the same time in all probability a fall of pressure within the glomeruli and a diminution in the total flow of blood. On the other hand, dilatation of the arteries of the kidney, whether produced through its vaso-dilator fibres or by section or inhibition of its constrictor fibres, augments the flow of urine and at the same time probably increases the pressure within the glomerular capil- laries, and also the total quantity of blood flowing through them in a unit of time. From these and other experimental facts it is evident that the amount of secretion and the amount of pressure within the glomerular vessels do often vary together, and this relationship has been used to prove that the water of the secretion is obtained by filtration from the blood-plasma. lint it will be observed that the quantity of secretion varies not only with the pressure of the blood within tin; glomeruli, but also with the quantity of blood (lowing through them. Ileidenhain has insisted that it is this latter factor and not the intracapillary pressure which determines the quantity of water secreted. He believes that the glomerular epithelial cells possess the property of actively secreting water, and that they are not simply passive fillers; that the forma- tion, in other words, is not a simple mechanical process, bin a more complex 254 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. one depending upon the living structure and properties of the epithelial cells. In support of this view he quotes the fact that partial compression of the renal veins quickly slows or stops altogether the flow of urine. Compression of the veins should raise the pressure within the vessels of the glomeruli, and upon the filtration hypothesis should increase rather than diminish the secre- tion. It has been shown also that if the renal artery is compressed for a short time so as to completely shut off the blood-flow to the kidney the secretion is not only suspended during the closure of the arteries but for a long lime after the circulation is re-established. According to Tiegerstedt, if the renal artery is ligated for only half a minute the activity of the kidney is suspended for three-quarters of an hour. This fact is difficult to understand if the glomerular epithelium is regarded simply as a filtering mem- brane, but it is explicable upon the hypothesis that the epithelial cells are actively concerned in the production of the water. The uncertainty as to the mechanism of production of the water and salts renders it difficult to give a theoretical explanation of the action of diuretics. V T arious -aline substances, such as NaCl and KXO s , increase the flow of urine. According to Starling, 1 these substances increase the bulk of water in the blood by drawing water from the tissues. A condition of hydraemic plethora. ensues, causing a greater volume of blood in the kidney capillaries and a rise of capillary pressure, conditions that favor greater filtration and account in part for the increased amount of urine. Experiments seem to show, however, that the condition of hydraemic plethora passes off before the increased secre- tion of urine ceases, so that the diuretic action of the salts is not due to this factor alone. The adherents of the filtration theory assume that in addition the -alts cause a vaso-dilatation in the kidney, and thus produce a rise in blood-pressure in the glomeruli. According to the other point of view, these substances may be considered as having a specific stimulating effect upon the glomerular epithelium. So the action of caffein may be referred either to a specific action- on the secreting cells or possibly to an indirect effect exerted through the circulation of the kidney. It seems clear that at present we arc not justified in asserting more than that the glomeruli control in some way the production of the water and salts of the secretion. The extent of the activity seems to be correlated with the quantity of blood flowing through the glomeruli. It must be borne in mind, however, that some water and probably also some of the inorganic salts are secreted at other part- of the tubule along with the nitrogenous wastes. It is of interest to add that the most important of the abnormal constituents of the urine under pathological conditions, such as the albumin in albuminuria, the haemoglobin in haemoglobinuria, and the sugar in glycosuria, seem likewise to escape from the blood into the kidney tubule- through the glomerular epithelium. 1 Journal of Physiology, 1899, vol. 24, i>. :!17. Von Schr ler : Archiv. fur exper. Pathologie and Pharmakol ., Bd. xxiv. S. 85; and Dreser, Ibid., 1892, Bd. xxix. S. 303. SECRETION. 255 The- normal stimulus to the epithelial cells of the convoluted tubules, using the term convoluted to include the actively secreting part-, seems to be the presence of urea and related substances in the blood (lymph). That the elimination of the urea is not a simple act of diffusion seems to be clearly shown by the fact that its percentage in the blood is much less than in the urine. In some way the urea is selected from the blood and passed into the lumen of the tubule, and although we have microscopic evidence that tins process involves active changes in the substance of the cells, there is no ade- quate theory of the nature of the force which attracts the urea from the sur- rounding lymph. The whole process must be rapidly effected by the cell, since there is normally no heaping up of urea in the kidney-cells ; the material is eliminated into the tubules as quickly as it is received from the blood. The rate of elimination increases normally with the increase in the urea in the blood, as would be expected upon the assumption that the urea itself acts as the physiological stimulus to the epithelial cells. The Blood-flow through the Kidneys. — It will be seen from the dis- cussion above that, other conditions remaining the same, the secretion of the kidney varies with the quantity of blood flowing through it. It is therefore important at this point to refer briefly to the nature and especially the regula- tion of the blood-flow through this organ, although the same subject is referred to in connection with the general description of vaso-motor regulation (see Circulation). It has been shown by Landergren 1 and Tiegerstedt that the kidney is a very vascular organ, at least when it is in strong functional activ- ity such as may be produced by the action of diuretics. They estimate that in a minute's time, under the action of diuretics, an amount of blond flows through the kidney equal to the weight of the organ; this is an amount from four to nineteen times as great as occurs in the average supply of the other organs in the systemic circulation. Taking both kidneys into account, their figures show that (in strong diuresis) 5.6 per ceut. of the total quantity of blood sent out of the left heart in a minute may pass through the kidneys, although the combined weight of these organs makes only 0.56 per cent, of that of the body. The nature of the supply of vaso-motor nerves to the kidney and the con- ditions which bring then) into activity are fairly well known, owing to the use- ful invention of the oncometer by Roy. 2 This instrument is in principle a plethysmograph especially modified for use upon the kidney of the living animal. It is a kidney-shaped box of thin brass made in two parts, biuged at the back, and with a clasp in front to hold them together. In the interior of the box thin peritoneal membrane is so fastened to each half that a layer of olive oil may be placed between it ami the brass walls. There is thus formed in each half a soft pad of oil upon which the kidney rests. When the kidney. freed as far as possible from fat and surrounding connective tissue, but with the blood-vessels and nerves entering at the hilus entirely uninjured, is laid in 1 Skamdinavisekes Arehvufiir Physiologie, 1892, Bd. iv. 8. 241. 2 See Cohnheim and Roy: Virchou/s Arehiv, 1883, Bd. scii. S. -1-4. 256 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. one-half of the oncometer, and the other half is shut down upon it and tightly fastened, the organ is .surrounded by oil in a box which is liquid-tight at every point except one, where a tube is led off to some suitable recorder such as a tambour. Under these conditions every increase in the volume of the kidney will cause a proportional outflow of oil from the oncometer, which will be measured by the recorder, and every diminution in volume will be accompa- nied by a reverse change. At the same time the flow of urine during these changes can be determined by inserting a cannula into the ureter and measur- ing directly the outflow of urine. By this and other means it has been shown that the kidney receives a rich supply of vaso-constrictor nerve-fibres that reach it between and round the entering blood-vessels. These fibres emerge from the spinal cord chiefly in the lower thoracic spinal nerves (tenth to thir- teenth in the dog), pass through the sympathetic system, and reach the organ as non-medu Hated fibres. Stimulation of these nerves causes a contraction of the small arteries of the kidney, a shrinkage in volume of the whole organ as measured by the oncometer, and a diminished secretion of urine. When, on the other hand, these constrictor fibres are cut as they enter the hilus of the kidney, the arteries are dilated on account of the removal of the tonic action of the constrictor fibres, the organ enlarges, and a greater quantity of blood passes through it, since the resistance to the blood-flow is diminished while the general arterial pressure in the aorta remains practically the same. Along with this greater flow of blood there is a marked increase in the secretion of urine. Under normal conditions we must suppose that these fibres are brought into play to a greater or less extent by reflex stimulation, and thus serve to control the blood-flow through the kidney and thereby influence its functional activity. It has been shown, too, that the kidney receives vaso-dilator nerve- fibres, that is, fibres which when stimulated directly or reflexly cause a dilata- tion of the arteries, and therefore a greater flow of blood through the organ. According to Bradford, 1 these fibres emerge from the spinal cord mainly in the anterior roots of the eleventh, twelfth, and thirteenth spinal nerves. Under normal conditions these fibres are probably thrown into action by reflex stimula- tion and lead to an increased functional activity. It will be seen, therefore, that the kidneys possess a local nervous mechanism through which their secretory activity may be increased or diminished by corresponding alterations in the blood-supply. So far as is known, this is the only way in which the secretion in the kidneys can be directly affected by the central nervous system. It should be borne in mind, also, that the blood-flow through the kidneys, and therefore their secretory activity, may be affected by conditions influ- encing general arterial pressure. Conditions such as asphyxia, strychnin- poisoning, or painful stimulation of sensorv nerves, which cause a general vaso- constriction, influence the kidney in the same way, and tend, therefore, to diminish the flow of blood through it; while conditions which lower general arterial pressure, such as general vascular dilatation of the skin 1 Journal of Physiology, 1889, vol. x. p. 358. SECRETION. 257 vessels, may also depress the secretory action of the kidney by diminishing the amount of blood flowing through it. In what way any given change in the vascular conditions of the body will influence the secretion of the kidney depends upon a number of factors, and their relations to one another ; but any change which will increase the differ- ence in pressure between the blood in the renal artery and the renal vein will tend to augment the flow of blood unless it is antagonized by a simultaneous constriction in the small arteries of the kidney itself. On the contrary, any vascular dilatation of the vessels in the kiduey will tend to increase the blood- flow through it unless there is at the same time such a general fall of blood- pressure as is sufficient to lower the pressure in the renal artery and reduce the driving force of the blood to an extent that more than counteracts the favora- ble influence of diminished resistance in the small arteries. Movements of the Ureter and the Bladder. — (See Micturition, p. 389.) E. Cutaneous Glands ; Internal Secretions. The sebaceous glands, sweat-glands, and mammary glands are all true epider- mal structures, and may therefore be conveniently treated together. Sebaceous Secretion. — The sebaceous glands are simple or compound alveolar glands found over the cutaneous surface usually in association with the hairs, although in some cases they occur separately, as, for instance, on the pre- puce and glans penis, and on the lips. When they occur with the hairs the short duet opens into the hair-follicle, so that the secretion is passed out upon the hair near the point where it projects from the skin. The alveoli are filled with cuboidal or polygonal epithelial cells, which are arranged in several lay- ers. Those nearest the lumen of the gland are filled with fatty material. These cells are supposed to be cast off bodily, their detritus going to form the secretion. New cells are formed from the layer nearest the basement mem- brane, and thus the glands continue to produce a slow but continuous secretion. The sebaceous secretion, or sebum, is an oily semi-liquid material that sets upon exposure to the air to a cheesy mass, as is seen in the comedones or pim- ples which so frequently occur upon the skin from occlusion of the opening of the ducts. The exact composition of the secretion is not known. It contains fats and soaps, some cholesterin, albuminous material, pari of which is a nucleo-albumin often described as a casein, remnants of epithelial cells. and inorganic salts. The cholesterin occurs in combination with a fatty acid and is found in especially large quantities in sheep's wool, from which it is extracted and used commercially under the name of lanolin. 'The sebaceous secretion from different places, or in different animals, is probably somewhal variable in composition as well as in quantity. The secretion of the prepuce is known as the smegma prcepvMi; that of the external auditory meatus, mixed with the secretion of the neighboring sweat-glands or ceruminous glands, forms the well-known ear-wax or cerumen. The secretion in this place con- tains a reddish pigment of a bitterish-sweet taste, the composition of which has not been investigated. Upon the skin of the newly-born the sel»a< us ma- Vol. I.— 17 258 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. terial is accumulated to form the remix caseosa. The well-known u ropy gal gland of birds is homologous with the mammalian sebaceous glands, and its secretion lias been obtained in sufficient quantities for chemical analysis. Physiologically it is believed that the .sebaceous secretion affords a protection to the skin and hairs. Its oily character doubtless serves to protect the hairs from becoming too brittle, or, on the other hand, from being too easily satu- rated with external moisture. In this way it probably aids in making the hairy coat a more perfect protection against the effect of external changes of temperature. Upon the surface of the skin also it forms a thin protective layer that tends to prevent undue loss of heat from evaporation, and possi- bly is important in other ways in maintaining the physiological integrity of the external surface. Sweat. — The sweat or perspiration is a secretion of the sweat-glands. These latter structures are found over the entire cutaneous surface except in the deeper portions of the external auditory meatus. They are particularly abundant upon the palms of the hands and the soles of the feet. Krause estimates that their total number for the whole cutaneous surface is about two millions. In man they are formed on the type of simple tubular glands, the terminal portion contains the secretory cells, and at this part the tube is usually coiled to make a more or less compact knot, thus increasing the extent of the secreting surface. The larger ducts have a thin muscular coat of invol- untary tissue that may possibly be concerned in the ejection of the secretion. The secretory cells in the terminal portion are columnar in shape, they possess a granular cytoplasm and are arranged in a single layer. The amount of secretion formed by these glands varies greatly, being influenced by the con- dition of the atmosphere as regards temperature and moisture, as well as by various physical and psychical states, such as exercise and emotions. The average quantity for twenty-four hours is said to vary between TOO and 900 grams, although this amount may be doubled under certain conditions. According to an interesting paper by Schierbeck, 1 the average quantity of sweat in twenty-four hours may amount to 2 to 3 liters in a person clothed, and therefore with an average temperature of 32° C. surrounding the skin. This author states that the amount of sweat given off from the skin in the form of insensible perspiration increases proportionately with the tempera- ture until a certain critical point is reached (about 33° C. in the person investigated), when there is a marked increase in the water eliminated, the increase being simultaneous with the formation of visible sweat. At the same time there is a more marked and sudden increase in the CO., eliminated from the skin, from 8 grams to 20 grams in twenty-four hours. It is possible that the sudden increase in (X )., is an indication of greater metabolism in the sweat- glands in connection with the formation of visible sweat. Composition oftht Secretion. — The precise chemical composition of sweat is difficull to determine, owing to the fact that as usually obtained it is liable 1 Archivfur Anatomieund Physiologie (Physiol. Abtheil), 1893, S. llfi. SECRETION. 259 to be mixed with the sebaceous secretion. Normally it is a very thin secre- tion of low specific gravity (1004) and an alkaline reaction, although when first secreted the reaction may be acid owing to admixture with the sebaceous material. The larger part of the inorganic salts consists of sodium chloride. Small quantities of the alkaline sulphates and phosphates arc also present. The organic constituents, though present in mere traces, are quite varied in num- ber. Urea, uric acid, creatinin, aromatic oxy- acids, ethereal sulphates of phenol and skatol, and albumin, are said to occur when the sweating is pro- fuse. Argutinsky has shown that after the action of vapor-baths, and as the result of muscular work, the amount of urea eliminated in this secretion may be considerable (see p. 360). Under pathological conditions involving a diminished elimination of urea through the kidneys it has been observed that the amount found in the sweat is markedly increased, so that crystals of it may be deposited upon the skin. Under perfectly normal conditions, how- ever, it is obvious that the organic constituents are of minor importance. The main fact to be considered in the secretion of sweat is the formation of water. Secretory Fibres to the Sweat-glands. — Definite experimental proof of the existence of sweat-nerves was first obtained by Goltz l in some experiments upou stimulation of the sciatic nerve in cats. In the cat and dog, in which sweat-glands occur on the balls of the feet, the presence of sweat-nerves may be demonstrated with great ease. Electrical stimulation of the peripheral end of the divided sciatic nerve, if sufficiently strong, will cause visible drops of sweat to form on the hairless skin of the balls of the feet. When the elec- trodes are kept at the same spot on the nerve and the stimulation is maintained the secretion soon ceases, but this effect seems to be due to a temporary injury of some kind to the nerve-fibres at the point of stimulation, and not to a genuiue fatigue of the sweat-glands or the sweat-fibres, since moving the elec- trodes to a new point on the nerve farther toward the periphery calls forth a new secretion. The secretion so formed is thin and limpid, and has a marked alkaline reaction. The anatomical course of these fibres has been worked out in the cat with great care by Langley. 2 He finds that for the hind feet they leave the spinal cord chiefly in the first and second lumbar nerves, enter the sympathetic chain, and emerge from this as non-medullated fibres in the gray rami proceeding from the sixth lumbar to the second sacral ganglion, but chiefly in the seventh lumbar and first sacral, and then join the nerves of the sciatic plexus. For the fore feet the fibres leave the spinal cord in the fourth to the tenth thoracic nerves, enter the sympathetic chain, pass upward to the first thoracic ganglion, whence they are continued as non-medullated fibres thai pass out of this ganglion by the gray rami communicating with the nerves forming the brachial plexus. The action of the nerve-fibres upon the sweat-glands cannot be explained as an indirect effect — for instance, as a result of a variation in the blood-flow. Experiments have repeatedly shown that, in the cat, stimulation of the sciatic still calls forth a secretion after the 1 Archiv fur die gesammte Physiologic, 1875, Bd. \i. B. 71. 2 Journal of Physiology, 1891, vol. xii. p. 347. 260 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. blood has been shut off from the leg by ligation of the aorta, or indeed after the leg has beeu amputated for as long as twenty minutes. So in human beings it is known that profuse sweating may often accompany a pallid skin, as in terror or nausea, while on the other hand the Hushed skin of fever is characterized by the absence of perspiration. There seems to be no doubt at all that the sweat-nerve- are genuine secretory fibres, causing a secretion in consequence of a direct action on the cells of the sweat-glands. In accord- ance with this physiological fact histological work has demonstrated that special nerve-fibres are supplied to the glandular epithelium. According to Arnstein ' the terminal fibres form a small branching varicose ending in con- tact with the epithelial cells. The sweat-gland may be made to secrete in many ways other than by direct artificial excitation of the sweat-fibres; for example, by external heat, dyspnoea, muscular exercise, strong emotions, and by the action of various drugs such as pilocarpin, muscarin, strychnin, nicotin, picrotoxin, and physostigmin. In all such cases the effect is supposed to result from an action on the sweat-fibres, either directly on their terminations, or indirectly upon their cells of origin in the central nervous system. In ordinary life the usual cause of profuse sweating is a high external temper- ature or muscular exercise. With regard to the former it is known that the high temperature does not excite the sweat-glands immediately, but through the intervention of the central nervous system. If the nerves going to a limb be cut, exposure of that limb to a high temperature does not cause a secretion, showing that the temperature change aloue is not sufficient to excite the gland or its terminal nerve-fibres. AVe must suppose, therefore, that the high temperature acts upon the sensory cutaneous nerves, possibly the heat-fibres, and reflexly stimulates the sweat-fibres. Although external temperature does not directly excite the glands, it should be stated that it affects their irritability either by direct action on the gland-cells or upon the terminal nerve-fibres. At a sufficiently low temperature the cat's paw does not secrete at all, and the irritability of the glands is increased by a rise of temperature up to about 45° C. Dyspnoea, muscular exercise, emotions, and many drugs affect the secretion, probably by action on the nerve-centres. Pilocarpin, on the contrary, is known to stimulate the endings of the nerve-fibres in the glands, while atropin has the opposite effect, completely paralyzing the secretory fibres. Sweat-centres in the Central Nervous System. — The fact that secretion of sweat may be occasioned by stimulation of afferent nerves or by direct action upon the central nervous system, as in the case of dyspnoea, implies the exi-t- ence of physiological centres controlling the secretory fibres. The precise loca- tion of the sweat-centre or centres has not, however, been satisfactorily deter- mined. Histologically and anatomically the arrangement of the sweat-fibres resembles that of the vaso-constrictor fibres, and, reasoning from analogy, one might suppose the existence of a general sweat-centre in the medulla compara- ble to the vaso-constrictor centre, but positive evidence of the existence of such 1 Anatomischer Anzcujer, 1895, Bd. x. SECRETION. 261 an arrangement is lacking. It has been shown than when the medulla is separated from the cord by a section in the cervical or thoracic region the action of dyspnoea, or of various sudorific drugs supposed to act on the cen- tral nervous system, may still cause a secretion. On the evidence of results of this character it is assumed that there are spinal sweat-centres, but whether these are few in number or represent simply the various nuclei of origin of the fibres to different regions is not definitely known. It is possible that in addi- tion to these spinal centres there is a general regulating centre in the medulla. Mammary Glands. The mammary glands are undoubtedly epidermal structures comparable in development to the sweat- or the sebaceous glands. Whether they are to be homologized with the sweat- or with the sebaceous glands is not clearly deter- mined. In most animals they are compound alveolar glands, and their acinous structure and the rich albuminous and fatty constituents of their secretion would seem to suggest a relationship to the sebaceous glands. But the histo- logical structure of the alveolus with its single layer of epithelium points rather to a connection with the sweat-glands. Whatever may have been their exact origin in the primitive mammalia, there seems to be no question that they were derived in the first place from some of the ordinary skin-glands which at first simply opened, without a distinct mamma or nipple, on a defi- nite area of the skin, as is seen now in the case of the monotremes. Later in the phylogenetic history of the gland the separate ducts united to form one or more larger ones, and these opened to the exterior upon the protrusion of the skin known as the nipple. The number and position of the glands vary much in the different mammalia. In man they are found in the thoracic region and are normally two in number. The milk-ducts do not unite to form a single canal, but form a group of fifteen to twenty separate systems, each of which opens separately upon the surface of the nipple. Before preg- nancy the secreting alveoli are incompletely formed, but during pregnancy and at the time lactation begins the formation of the alveoli is greatly acceler- ated by proliferation of the epithelial cells. Composition of the Secretion. — The general appearance and composi- tion of the milk are well known. Microscopically milk consists of a liquid portion, or plasma, in which float an innumerable multitude of fine fat-drop- lets. The latter elements contain the milk-fat, which consists chiefly of neutral fats, stearin, palmitin, and olein, but contains also a small amount of the fata of butyric and caproic acid as well as slight traces of other fatty acid emu- pounds and small amounts of lecithin, cholesterin, and a yellow pigment. Upon standing, a portion of these elements rises to the surface to form the cream. The milk-plasma holds in solution important proteid and carbohydrate compounds as well as the necessary inorganic salts. The proteids are casein, belonging to the group of nucleo-albumins ; lactalbumin, which closely resembles thesenun- albumin of blood, and lacto-globulin, which is similar to the paraglobulin of blood : the two latter proteids occur in much smaller quantities than the casein. 262 AN AMERICA X TEXT-BOOK OF PHYSIOLOGY. The chief rail )« >liydrate in milk is the milk-sugar or lactose. Hammarsten x has succeeded in isolating from the mammary gland a nucleo-proteid contain- ing a reducing group. He designates this substance as nucleo-glyco-proteid. It -cciiis possible that a compound of this character might serve as the parent substance for both the casein and the lactose of the secretion. The mineral constituents are varied and, considered quantitatively, show an interesting rela- tionship to the mineral composition of the body of the suckling (see p. 867). The fact that the inorganic salts of the milk vary so widely in quantitative composition from those of the blood has been used to show that they are not derived from the blood by the simple mechanical processes of filtration and diffusion, but are secreted by the epithelial cells of the glands. Traces of nitrogeneous excreta, such as urea, creatin, and creatinin, are also found in tin milk-plasma, together with some lecithin and cholesterin and a small amount of citric acid occurring as citrate of calcium. Histological Changes during Secretion. — The simple fact that sub- stances are found in the milk which do not occur in the blood or lymph is sufficient proof that the epithelial cells are actively concerned in the process of secretion. Histological examination of the gland during lactation confirms fully this a 'priori deduction, and enables us to understand the probable origin of some of the important constituents. 2 In the resting gland during the period of gestation, or in certain alveoli during lactation, the alveoli are lined by a single layer of flattened or cuboidal cells, which have only a single nucleus, present a granular appearance, and have few or no fat-globules in them (Fig. QQ). When such alveoli enter into the active formation of milk the epithelial cells increase in height, projecting in toward the lumen, the nuclei divide, and as a Fig. 66.— Suction through the middle of two alveoli of the mammary gland of the dog; con- dition of re.^t i alter Ileidenhain). A B Fig. 67.— Mammary gland of dog, showing the formation of the secretion: A, medium condition of gn fwth of the epithelial cells ; B, a later condition (after Heidenhain). rule (Steinhaus 3 ) each cell contains two nuclei (Fig. 67). Fat-droplets de- velop in the cytoplasm, especially in the free end of the cell, and according to 1 Zeitechrift fur physiologisehe Cltemie, 1894, Bd. xix. S. 19. 2 See Heidenhain: Hermann's Handbuch der Physiologie, 1883, Bd. v. S. 381. 3 Du Bois-Reymond's Arehiv fur Physiologic, 1892, Suppl. I'>d., 8. 54. SECRETION. 263 Steinhaus the nucleus nearest the lumen undergoes a fattv metamorphosis. According to the same author the granular material in the cytoplasm also undergoes a visible change; the granules, which in the resting cell are spherical, elongate during the stage of activity to threads thai take on a spirochaeta-like form. The acme of this phase of development is reached by the solution or disintegration of a portion of the end of the cell, the frag- ments being discharged into the lumen of the alveolus. The debris of this disintegrated portion of the cell helps to form the secretion ; part of it goes into solution to form, probably, the albuminous and carbohydrate constituents, while the fat-droplets are set free to form the milk-fat. Apparently the basal portion of the cell regenerates its cytoplasm and thus continues to form oew material for the secretion. In some cases, however, the whole cell seems to undergo dissolution, and its place is taken by a new cell formed by karvo- kinetic division of one of the neighboring epithelial cells. The origin of the peculiar colostrum corpuscles found in the milk during the first few days of its secretion has been explained differently by different observers. Heid- enhain traces them to certain epithelial cells of the alveoli which at this time become rounded, develop numerous fat-droplets, and are finally dis- charged bodily into the lumen, although he was not able to actually trace the intermediate steps in the process. Steinhaus, on the contrary, thinks that these corpuscles are derived from the wandering cells of the connective tissue (Mastzellen) which at the beginning of lactation are very numerous, but seem to undergo fatty degeneration and elimination in the secretion of the newly active gland. Control of the Secretion by the Nervous System. — There are indica- tions that the secretion of the mammary glands is under the control, to some extent at least, of the central nervous system. For instance, in women during the period of lactation cases have been recorded in which the secretion was altered or perhaps entirely suppressed by strong emotions, by an epileptic attack, etc. This indication has not received satisfactory confirmation from the side of experimental physiology. Eckhard 1 found that section of the main nerve- trunk supplying the gland in goats, the external spermatic, caused no dif- ference in the quantity or quality of the secretion. Rohrig 2 obtained more positive results, inasmuch as he found that some of the branches of the exter- nal spermatic supply vaso-motor fibres to the blood-vessels of the gland and influence the secretion of milk by controlling the local blood-How in the gland. Section of the inferior branch of this nerve, for example, gave in- creased secretion, while stimulation caused diminished secretion, as in the case of the vaso-constrictor fibres to the kidney. These results have qoI been confirmed by others — in fact, they have been subjected to adverse criticism — and they cannot, therefore, be accepted unhesitatingly. Mironow 1 reports a Dumber of interesting experiments made upon goats. 1 See Heidenhain : Hermawnfs Handbuch der Physiologic, Bd. v. Thl. 1. 8. 392. 2 Virr/imi-'s Archir fur pathologiache Anatomie, etc., 1876, Bd. 67, 8. 119. 3 Archives 90, Bd. xxvi. S. 371. See also Minkow- ski, Ibid., 1S93, Bd. xxxi. S. 85, for a more complete account. 'See IIe\lon : Diab&te pancriatique, Travaux de Physiologie Universite de MontpeUier, 1898. SECRETION. 207 tially or completely by grafting a portion of the pancreas elsewhere in the abdominal cavity or even under the skin. The duets of the gland may be completely occluded by ligature or by injection of paraffin without causing a condition of permanent glycosuria. The condition of glycosuria produced by removal of the pancreas is desig- nated frequently as pancreatic diabetes and offers many analogies to the similar pathological condition in man known as diabetes mellitus. The cause of the glycosuria is obscure. It has been shown that in severe cases sugar appears in the urine even when the animal is deprived of food, although the quantity is increased by feeding and especially by carbohydrate food. Examination of the blood shows that the percentage of sugar in it is increased above the normal, from 0.15 per cent, to 0.3 or 0.5 per cent. In the liver, on the con- trary, the supply of glycogen disappears. Carbohydrate foods when fed cause no deposition of glycogen in the liver, and apparently escape consumption in the body, being eliminated in the urine. It is said, however, that one form of sugar, levulose, offers an exception to this general rule, since it causes a formation of liver glycogen and seemingly is consumed in the body. We may believe from these experiments that the pancreas produces a substance of some kind that is given off to the blood or lymph, and is either necessary for the normal consumption of sugar in the body, or else, as is held by some, 1 normally restrains the output of sugar from the liver and other sugar-producing tissues of the body. What this material is and how it acts has not yet been determined satisfactorily. The most plausible theory suggested is that the internal secretion produced contains a special enzyme, glycolytic enzyme (Lepine), whose presence in the blood is necessary for the consumption of the sugar. Such an enzyme may be obtained from blood (p. 354), but it is not proved whether it is a normal constituent or whether it is produced after the blood is shed by the disintegration of some of its cor- puscular elements. This theory therefore cannot be considered as more than a possibility. It is interesting and suggestive to state in this connection that post-mortem examination in cases of diabetes mellitus in the human being has shown that this disease is associated in some instances with obvious alterations in the structure of the pancreas. The Thyroid Body. — The thyroids are glandular structures found in all the vertebrates. In the mammalia they lie on either side of the trachea at its junction with the larynx. In man they are united across the front oi the trachea by a narrow band or isthmus, and hence are sometimes spoken of as one structure, the thyroid body. In some of the lower mammals (e. g. dog) the isthmus is often absent, The thyroids in man are small bodies measuring about 50 millimeters in length by 30 millimeters in width ; they have a distinct glandular structure but possess no ducts. Histological examination shows that they are composed of a number of closed vesicles vary- ing in size. Each vesicle is lined by a single layer of cuboidal epithelium, while its interior is filled by a homogeneous glairy liquid, tin' colloid substance 1 See Kaufmann: Archives de Physiologie normah ft pathologique, 1895, p. 210. 2(38 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. which is found also in the tissue between the vesicles lying in the lymph- spaces. This colloid substance is regarded as a secretion from the epithelial cells of the vesicles, and Biondi, 1 Langendorff, 2 and Hurthle 3 claim to have followed the development of the secretion in the epithelial cells by micro- chemical reactions. While the interpretation of the microscopical appearances given by these authors is not the same, they agree in believing that the colloid material is formed within some or all of the epithelial cells, and is eliminated into the lumen with or without a disintegration of the cell-substance. More- over. Langendorff and Biondi believe that the colloid material is finallv dis- charged into the lymphatics by the rupture of the vesicles. The composition of the colloid is incompletely known. Parathyroids. — The parathyroids are small bodies, two on each side, lying lateral or posterior to the thyroids. One of them may be enclosed within the substance of the thyroid, and is then known as the internal parathyroid, the other being the external parathyroid. They are quite unlike the thyroids in structure, consisting of solid masses or columns of epithelial-like cells which are not arranged to form acinous vesicles. According to Schaper, 4 these bodies are not always paired, but may have a multiple origin extending along the common carotid in the neighborhood of the thyroids. Accessory Thyroids. — In addition to the parathyroids, a variable number of accessory thyroids have been described by different observers, occurring in the neck or even as far down as the heart. These bodies possess the structure of the thyroid, and presumably have the same function. After removal of the thyroids they may suffice to prevent a fatal result. Funct ions of the Thyroids and Parathyroids. — Very great interest has been excited within recent years with regard to the functions of the thyroids. In 185b' Schiff showed that in dogs complete extirpation of the two thyroids i- followed by the death of the animal ; and within the last few years similar results have been obtained by numerous observers. Death is preceded by a number of characteristic symptoms, such as muscular tremors, which may pass into spasms and convulsions, cachexia, emaciation, and a more or less marked condition of apathy. The muscular phenomena seem to proceed from the central nervous system, since section of the motor nerves protects the muscles from the irritation. The metabolic changes may also be due primarily to an alteration in the condition of the cord and brain. Similar results have been obtained in cats. Among the herbivorous animals it was at first stated that removal of the thyroids does not cause death; but so far as the rabbit is concerned Gley 5 has shown that if care be taken to remove the parathyroids also, death is as certain and rapid as in the case of the carnivora; a similar result has been obtained upon rats by Chris- tiani. Cases have been reported in which dogs recovered after complete 1 Berliner klinisehe Woehensehrift, 1S88. 2 Archivfiir Physiologic, 18S9, Suppl. Bd. 5 Pilii'i' r'.< Archivfiir 08. 270 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Two views prevail as to the general nature of their function. 1 According to some, the office of these bodies is to remove some toxic substance or sub- stances which normally accumulate in the blood as the result of the body- metabolism. If the thyroids or parathyroids are extirpated, the correspond- ing substance then increases in quantity and produces the observed symptoms by a process of auto-intoxication. In support of this view there are numerous observations to show that the blood, or urine, or muscle-juice of thyroid- ectomized animals has a toxic effect upon sound animals. These latter results, however, do not appear to be marked or invariable, and in the hands of some experimenters have failed altogether. The second view is that the thyroids and parathyroids secrete each a material, a true internal secretion, which after getting into the blood plays an important and indeed essential part in the metabolic changes of some or all of the organs of the body, but especially the central nervous system. In support of this view we have such facts as these: Injections of properly prepared thyroid extracts have a beneficial and not an injurious influence ; there is microscopic evidence to show that the epithelial cells participate actively in the formation of the colloid secretion, and that this secretion eventually reaches the blood by way of the lymph-vessels; the beneficial material in the thyroid extracts may be obtained from the gland by methods which prove that it is a distinct and stable substance formed in the gland, as we might suppose would be the case if it formed part of a definite secretion. This latter fact, indeed, amounts to a proof that the important function of the thyroids is connected with a material secreted within its substance ; but it may still be questioned, per- haps, whether this material acts by antagonizing toxic substances produced elsewhere in the bodv or by directly influencing the body metabolism. For a more specific theory of the functional value of the thyroids proposed by ('von'-' reference must be made to original sources. Much work has been done to isolate the beneficial material of the thyroid, particularly in relation to the therapeutic use of the gland in myxoedema and goitre. The mere fact that feeding the gland acts as well as injecting its extracts shows the resistant nature of the substance, since it is evidently not injured by the digestive secretions. It has been shown also by Baumann 3 that the gland material may be boiled for a long period with 10 per cent, sulphuric acid without destroying the beneficial substance. This observer has succeeded in isolating from the gland a substance to which the name iodothyrin is given, which is characterized by containing a relatively large percentage (!'.."> per cent, of the dry weight) of iodine, and which preserves in large measure the beneficial influence of thyroid extracts in cases of myxoedema and parenchymatous goitre. In the parathyroid tissue the same material is contained in relatively larger quantities. This notable discovery shows that thyroid tissue has the 1 See Schaefer: "Address on Physiology," annual meeting of the British Medical Associa- tion, London, July-August, IS').". : Archives de Phyaiologie, 1898, p. 618. 8 Zeitschrift fur physwlogische Chemie, l x '.'t'., Bd. xxi. >S. 319. SECRETION. 271 power of forming a specific organic compound of iodine, and it is possible that its influence upon body-metabolism may be connected with this feet Baumann and Koos ' state that the iodothyrin is contained within the gland mainly in a state of combination with proteid bodies, from which it may be separated by digestion with gastric juice or by boiling with acids. Most of 'the substance is combined with an albuminous proteid, while a smaller part is united with a globulin-like proteid. There can be little doubt that the authors have succeeded in isolating at least one of the really effective substances of thyroid extracts. If the distinction made between the functions of the thyroids and parathyroids proves to be correct, and if each of these glands exercises its functions by means of an internal secretion, we may hope that future work will be able to isolate the distinctive substance or Hill- stances characteristic of each gland. Adrenal Bodies. — The adrenal bodies — or, as they are frequently called in human anatomy, the suprarenal capsules — belong to the group of ductless glands. Their histology as well as their physiology is incompletely known. It was shown first by Brown-Sequard (1856) that removal of these bodies is followed rapidly by death. This result has been confirmed by many experi- menters, and so far as the observations go the effect of complete removal is the same in all animals. The fatal effect is more rapid than in the case of removal of the thyroids, death following the operation usually in two to three days, or, according to some accounts, within a few hours. The symptoms preceding death are great prostration, muscular weakness, and marked dimi- nution in vascular tone. These symptoms are said to resemble those occurring in Addison's disease in man, a disease which clinical evidence has shown to be associated with pathological lesions in the suprarenal capsules. It has been expected, therefore, that the results obtained for thyroid treatment of myx- cederna might be repeated in cases of Addison's disease by the use of adrenal extracts. These expectations seem to have been realized in part, but complete and satisfactory reports are yet lacking. The physiology of the adreuals has usually been explained upon the auto-intoxication theory. The death that comes after their removal has been accounted for upon the supposition that during life they remove or destroy a toxic substance produced elsewhere in the body, possibly in the muscular system. Oliver 2 and Sehaefer, and, about the same time, Cybulski and Szymonowicz, 8 have given reasons for believing that this organ forms a peculiar substance that has a very definite physiological action especially upon the circulatory system. They find that aqueous extracts of the medulla of the gland when injected into the blood of ;i living animal have a remarkable influence upon the heart and blood-vessels. If the vagi are intact, the adrenal extracts cause a very marked slowing of the heart-beat together with a rise of blood-pressure. When the inhibiting fibres of the vagus arc thrown out of action by section or by the use of atropin the beart- 1 Zeitschrift fur physiologisehe Chemie, L896, Bd, xxi. S. 481, * Journal of Physiology, 1895, vol. xviii. |>. 'J.'lu. 3 Archir fiir die geeammte Physiologic, L896, Bd. Ixiv. S. !)7. 272 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. rate is accelerated, while the blood-pressure is increased sometimes to an extraordinary extent. These facts are obtained with very small doses of the extracts. Schaefer states that as little as 51 milligrams of the dried gland may produce a maximal effect upon a dog weighing 10 kilograms. The effects produced by such extracts arc quite temporary in character. In the course of a few minutes the blood-pressure returns to normal, as also the heart-beat, showing that the substance has been destroyed in some way in the body, although where or how this destruction occurs is not known. Accord- ing to Schaefer, the kidneys and the adrenals themselves are not responsible tor this prompt elimination or destruction of the injurious substance. The constriction of the blood-vessels seems to be due to a direct effect on the muscles in the walls of the vessels, in part at least, since it is present after de- struction of the vaso-motor centre and most or, indeed, all of the spinal cord. Several observers 1 have shown satisfactorily that the material producing this effect is present in perceptible quantities in the blood of the adrenal vein, so that there can be but little doubt that it is a distinct internal secretion of the adrenal. Dreyer has shown, moreover, that the amount of this substance in the adrenal blood is increased, judging from the physiological effects of its injection, by stimulation of the splanchnic nerve. Since this result was obtained independently of the amount of blood-flow through the gland, Dreyer makes the justifiable assumption that the adrenals possess secretory nerve fibres. Abel 2 has succeeded in isolating the substance that produces the effect on blood-pressure and heart-rate, and proposes for it the name epinephrin. He assigns to it the formula C 17 H 15 N0 4 , and describes it as a peculiar unstable basic body. Salts of epinephrin were obtained which when injected into the circulation caused the typical effects produced by injection of extracts of the gland. It is possible that the substance in question may be continually secreted under normal conditions by the adrenal bodies and play a very important part with reference to the functional activity of the muscular tissues. Pituitary Body. — This body is usually described as consisting of two parts, a large anterior lobe of distinct glandular structure, and a much smaller posterior lobe, whose structure is not clearly known, although it contains nerve-cells and also apparently some glandular cells. Embryologically the t\v«> lobe- arc entirely distinct. The anterior lobe, which it is preferable to call the hypophysis cerebri, arises from the epithelium of the mouth, while the posterior lobe, or the infundibular body, develops as an outgrowth from the infundibulum of the brain, and in the adult remains connected with this portion of the brain by a long stalk. Howell 3 and others have shown that extracts of the hypophysis when injected intravenously have little or no physiological effect, while extracts of the infundibular body, on the contrary, 1 American Journal of Physiology, 1899, vol. ii. p. 203. ' Zeitsehrtft fur phystologisehe Chemie, 1899, Bd. xxviii. S. 318. • Journal of Experimental Medicine, 1898, vol. iii. p. 245; also Schaefer and Vincent : Journal of Physiology, 1899, vol. xxv. p. 87. SECRETION. 273 cause a marked rise of blood-pressure and slowing of the heart-beat. These effects resemble in general those obtained from adrenal extracts, but differ in some details. They seem to warrant the conclusion that the infundibular body is not a mere rudimentary organ, as has been generally assumed, but produces a peculiar substance, an internal secretion, that may have a distinct physiological value. A number of observers, especially Vassale and Sacchi, have succeeded in removing the entire pituitary body. They report that the operation results eventually in the death of the animal with a certain group of symptoms, such as muscular tremors and spasms, apathy and dyspnoea, that resemble the results of thyroidectomy. It has been suggested therefore that the pituitary body may be related in function to the thyroids and maybe able to assume vicariously the functions of the latter after thyroidectomy. There is no satisfactory evidence, however, in support of this view. On the pathological side it has been shown that usually lesions of the pituitary body, particularly of the hypophysis, are associated with a peculiar disease known as acromegaly, the most prominent symptom of which is a marked hyper- trophy of the bones of the extremities and of the face. The conclusion some- times drawn from this fact that acromegaly is caused by a disturbance of the functions of the pituitary body is, however, very uncertain, and is not sup- ported by any definite clinical or experimental facts. Testis and Ovary. — Some of the earliest work upon the effect of the internal secretions of the glands was done upon the reproductive glands, especially the testis, by Brown-Sequard. 1 According to this observer, extracts of the fresh testis when injected under the skin or into the blood may have a remarkable influence upon the nervous system. The general mental and physical vigor, and especially the activity of the spinal centres, are greatly improved, not only in cases of general prostration and neurasthenia, but also in the case of the aged. Brown-Sequard maintained that this general dvnamo- genic effect is due to some unknown substance formed in the testis and sub- sequently passed into the blood, although he admitted that some of the same substance may be found in the external secretion of the testis — i. c, the spermatic liquid. More recently Poehl 2 asserts that he has prepared a sub- stance, spermin, to which he gives the formula C 5 H U N 2 , which has a very beneficial effect upon the metabolism of the body. He believes that this spermin is the substance that gives to the testicular extracts prepared by Brown-Sequard their stimulating effect. He claims for this substance an extraordinary action as a physiological tonic. The precise scientific value of the results of experiments with the testicular extracts cannot be estimated at present, in spite of the large literature upon the subject ; we must wait for more detailed and exact experiments, which doubtless will SOOD be made. Zoth '' and also Pregel 'seem to have obtained exact objective proof, by means 1 Archives de Plii/^inlni/i, normale et pathologique, 1889 '.>-. 2 Zeitschriflfiir klini&che Wedicin, 1894, Bd. xxvi. S. 133. 3 Pjiiiger's Archiv fiir die gesammte Physiologic, 189(>, Bd. Ixii. S. 335; also 1897, Bd. lxix. S. 386. ' 4 Ihid., S. 379. Vol. I.— 18 274 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. of ergographic records, of the stimulating action of the testicular extracts upon the neuro-muscular apparatus in num. They find that injections of the testicular extracts cause not only a diminution in the muscular and nervous fatigue resulting from muscular work, but also lessen the subjective fatigue sensations. The fact that the internal secretion of the testis, if it exists at all, is not absolutely essential to the life of the body as a whole, as in the case «>t' the thyroids, adrenals, and pancreas, naturally makes the satisfactory determination of its existence and action a more difficult task. Similar ideas in general prevail as to the possibility of the ovaries furnish- ing an internal secretion that plays an important part in general nutrition. In gynecological practice it has been observed that complete ovariotomy with its resulting premature menopause is often followed by distressing symptoms, mental and physical. In such cases many observers have reported that these symptoms may be alleviated by the use of ovarian extracts. So also in the natural, as well as in the premature menopause following opera- tions, it is a frequent, though not invariable, result for the individual to gain noticeably in weight. The probability of an effect of the ovaries on general nutrition is indicated also by the interesting fact that in eases of osteomalacia, a disease characterized by softening of the bones, removal of the ovaries may exert a very favorable influence upon the course of the disease. These indi- cations have found some experimental verification recently in a research by Loewy and Richter 1 made upon dogs. These observers found that complete removal of the ovaries, although at first apparently without effect, resulted in the course of two to three months in a marked diminution in the consump- tion of oxygen by the animal, measured per kilo, of body-weight. If now the animal in this condition was given ovarian extracts (oophorin tablets) the amount of oxygen consumed was not only brought to its former normal, but considerably increased beyond it. A similar result was obtained when the extracts were used upon castrated males. The authors believe that their experiments show that the ovaries form a specific substance which is capable of increasing the oxidation of the body. Kidney. — Tiegerstedt and Bergman 2 state that a substance may be extracted from the kidneys of rabbits which when injected into the body of a living animal causes a rise of blood-pressure. They get the same effect from the blood of the renal vein. They conclude, therefore, that a substance, for which they suggest the name " rennin," is normally secreted by the kidney into the renal blood, and that this substance causes a vaso-constriction. l Archivfiir Physiologie, 1899, Buppl. Bd. S. 174. 2 Skandinavisehes Archiv far Physiologie, 1898, Bd. viii. S. 223; see also Bradford: Proceedings of the Royal Society, 1892. V. CHEMISTRY OF DIGESTION AND NUTRITION. A. Definition and Composition of Foods ; Nature of Enzymes. Speaking broadly, what we eat and drink for the purpose of nourish- ing the body constitutes our food. A person in adult life who has reached his maximum growth, and whose weight remains practically constant from year to year, must eat and digest a certain average quantity of food daily to keep himself in a condition of health and to prevent loss of weight. In such a case we may say that the food is utilized to repair the wastes of the body — that is, the destruction of body-material which goes on at all times, even during sleep, but which is increased by the physical and psychical activities of the waking hours — and in addition it serves as the source of heat, mechanical work, and other forms of energy liberated in the body. In a person who is growing — one who is, as we say, laying on flesh or increasing in stature — a certain portion of the food is used to furnish the energy and to cover the wastes of the body, while a part is converted into the new tissues formed during growth. The material that we eat or drink as food is for the most part in an insoluble form, or has a composition differing very widely from that of the tissues which it is intended to form or to repair. The object of the processes of digestion carried on in the alimentary tract is to change this food so that it may be absorbed into the blood, and at the same time so to alter its com- position that it can be utilized by the tissues of the body. For we shall find, later on, that certain foods — eggs, for example — which are very nutritious when taken into the alimentary canal and digested cannot be used at nil by the tissues if injected at once, unchanged, into the blood. The food of man- kind is most varied iu character. At different times of the year and in different parts of the world the diet is changed to suit the necessities of the environment. When, however, we come to analyze the various animal and vegetable foods made use of by mankind it is found that they arc all com- posed of one or more of five or six different classes of substances to which the name food -.stuff's or alimentary principles has been given. To ascertain the nutritive value of any food, it must he analyzed and the percentage amounts of the different food-stuffs contained in it must be determined. The classi- fication of food-stuffs usually given is as follows: 276 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Water ; [norganic salts; Proteids (or proteid-containing bodies); Food-stuffs. { Albuminoids (a group of bodies resembling proteids, but having in some respects a different nutritive value) ; Carbohydrates ; Fats. The main facts with regard to the specific nutritive value of each of these substances will be given later on, after the processes of digestion have been described. A few general remarks, however, at this place will serve to give the proper standpoint from which to begin the study of the chemistry of digestion and nutrition. Wafer and Salts. — Water and salts we do not commonly consider as foods, but the results of scientific investigation, as well as the experience of life, show that these substances are absolutely necessary to the body. The tissues must maintain a certain composition in water and salts in order to function normally, and, since there is a continual loss of these substances in the various excreta, they must continually be replaced in some way in the food. It is to be borne in mind in this connection that water and salts constitute a part of all our solid foods, so that the body gets a partial supply at least of these substances in everything we eat. Proteids. — The composition and different classes of proteids are described from a chemical standpoint in the section ou The Chemistry of the Body. Different varieties of proteids are found in animal as well as in vegetable foods. The chemical composition in all cases, however, is approximately the same. Physiologically, they are supposed to have equal nutritive values out- side of differences in digestibility, a detail that will be given later. The essential use of the proteids to the body is that they supply the material from which the new proteid tissue is made or the old protcid tissue is repaired, although, as we shall find when we come to discuss the subject more thor- oughly (p. 345), proteids are also extremely valuable as sources of energy to the body. Inasmuch as the most important constituent of living matter is the proteid part of its molecule, it will be seen at once that proteid food is an absolute necessity. Proteids contain nitrogen, and they arc frequently spoken of as the nitrogenous foods; carbohydrates and fats, on the contrary, do not contain nitrogen. It follows immediately from this fact that fats and carbo- hydrates alone could not suffice to make new protoplasm. If our diet con- tained no proteids, the tissue s of the body would gradually waste away and death from starvation would result. All the food-stuffs are necessary in one way or another to the preservation of perfect health, but proteids, together with a certain proportion of water and inorganic salts, are absolutely necessary for the bare maintenance of animal life — that is, for the formation and preservation of living protoplasm. Whatever else is contained in our food, proteid of some kind must form a part of our diet. The use of CHEMISTRY OF DIGESTION AND NUTRITION. 277 the other food-stuffs is, as we shall see, more or less accessory. It may be worth while to recall here the familiar fact that in respect to the nutritive importance of proteids there is a wide difference between animal and vegetable life. What is said above applies, of course, only to animals. Plants can, and for the most part do, build up their living protoplasm upon diets con- taining no proteid. With some exceptions that need not be mentioned here, the food-stuffs of the great group of chlorophyll-containing plants, outside of oxygen, consist of water, C0 2 , and salts, the nitrogen being found in the last- mentioned constituent. Albuminoids. — Gelatin, such as is found in soups or is used in the form of table-gelatin, is a familiar example of the albuminoids. They are not found to any important extent in our raw foods, and they do not therefore usually appear in the analyses given of the composition of foods. An examination of the composition and properties of these bodies (see section on The Chemistry of the Body) shows that they resemble closely the proteids. Unlike the fats and carbohydrates, they contain nitrogen, and they are evidently of complex structure. Nevertheless, they cannot be used in place of proteids to build protoplasm. They are important foods without doubt, but their value is similar in a general way to that of the non-nitrogenous foods, fats and carbohydrates, rather than to the so-called " nitrogenous foods," the proteids. Carbohydrates. — We include among carbohydrates the starches, sugars, gums, and the like (see Chemical section) ; they contain no nitrogen. Their physiological value lies in the fact that they are destroyed in the body and a certain amount of energy is thereby liberated. The energy of muscular work and of the heat of the body comes largely from the destruction or oxidation of carbohydrates. Inasmuch as we are continually giving off energy from the body, chiefly in the form of muscular work and heat, it follows that material for the production of this energy must be taken in the food. Carbo- hydrates form perhaps the easiest and cheapest source of this energy. They constitute the bulk of our ordinary diet. Fats. — In the group of fats we include not only what is ordinarily under- stood by the term, but also the oils, animal and vegetable, that form such a common part of our food. Fats contain no nitrogen (see Chemical section). Their use in the body is substantially the same as that of the carbohydrates. Weight for weight, they arc more valuable than the carbohydrates as sources of energy, but the latter are cheaper, more completely digested when i'vd in quantity, and more easily destroyed in the body. For these reasons we find that under most conditions fats are a subsidiary article of food as compared with the carbohydrates. From the standpoint of the physiologist, fats arc of special interest because the animal body stores up its reserve of food material mainly in that form. The history of the origin of the fats of the body is one of the most interesting parts of the subject of nutrition, and it will be discussed at some length in its proper place. As has been said, our ordinary foods are mixtures of some or all of the food-stuffs, together with such things as flavors or condiments, whose nutritive 278 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. value is of a special character. Careful analyses have been made of the different articles of food, mostly of the raw or uncooked foods. As might be expected, the analyses on record differ more or less in the percentages assigned to the various constituents, but almost any of the tables published give a just idea of the fundamental nutritive value of the common foods. For details of separate analyses reference may be made to some of the larger works upon the composition of foods. 1 The subjoined table is one compiled by Munk from the analyses given by Konig: Composition of Foods. In 100 parts. Meat Egfrs ( beese , Cow's milk . . . , Human milk . . , Wheat Hour . . . Wheat bread . . , Rye flour . . . , Bye bread . . . . Rice Corn , Macaroni . . . . Peas, beans, lentils Potatoes Carrots ( labbages Mushrooms . . . Fruit 76.7 73.7 36-GO 87.7 89.7 13.3 35.6 13.7 42.3 13.1 13.1 10.1 12-15 75.5 87.1 90 73-91 84 Proteid. Fat. 20.8 12.6 25-33 3.4 2.0 10.2 7.1 11.5 6.1 7.0 9.9 9.0 23-26 2.0 1.0 2-3 4-8 0.5 1.5 12.1 7-30 3.2 3.1 0.9 0.2 2.1 0.4 0.9 4.6 0.3 l|-2 0.2 0.2 0.5 0.5 Carbohydrate. Digestible. Cellulose 0.3 3-7 4.8 5.0 74.8 55.5 69.7 49.2 77.4 68.4 79.0 49-54 20.6 9.3 4-6 3-12 10 0.3 0.3 1.6 0.5 0.6 2.5 0.3 4-7 0.7 1.4 1-2 1-5 4 Ash. 1.3 1.1 3-4 0.7 0.2 0.5 1.1 1.4 1.5 1.0 1.5 0.5 2-3 1.0 0.9 1.3 1.2 0.5 An examination of this table will show that the animal foods, particularly the meats, are characterized by their small percentage in carbohydrate and by a relatively large amount of proteid or of proteid and fat. With regard to the last two food-stuffs, meats differ very much among themselves. Some idea of the limits of variation may be obtained from the following table, taken chiefly from Konig's analyses: Beef, moderately fat Veal, fat Mutton, moderately fat J'ork, lean I [am, salted Pork (bacon), very fat 2 M.nkerel 2 Water. Proteid. Fat. 73.03 20.96 5.41 7-J.:;i 18.88 7.41 75.99 17.11 5.77 72.57 20.05 6.81 62.58 22.32 s c,s 10.00 3.00 80.50 Tl.li 18.8 8.2 Carbohydrate. 0.46 0.07 Ash. 1.14 1.33 1.33 1.10 6.42 6.5 1.4 The vegetable foods are distinguished, as a rule, by their large percentage in carbohydrates and the relatively small amounts of proteids and fats, as seen, for example, in the composition of rice, corn, wheat, and potatoes. Neverthe- 1 Konig, Die Menscfdichen Nahrunga wnd Gemmmittel, 3d ed., 1889; Parke's Manual of Prac- tical Hygiene, section on Food. '-' At water: The Chemistry of Foods ami Nutrition, 1887. CHE3IISTBY OF DIGESTION AND NUTRITION. 279 less, it will be noticed that the proportion of proteid in some of the vegetables is not at all insignificant. They are characterized by their excess in carbohy- drates rather than by a deficiency in proteids. The composition of peas and other leguminous foods is remarkable for the large percentage of proteid, which exceeds that found in moats. Analyses such as arc given here are indispensable in determining the true nutritive value of foods. Nevertheless, it must be borne in mind that the chemical composition of a food is not alone sufficient to determine its precise value in nutrition. It is obviously true that it is not what we eat, but what we digest and absorb, that is nutritious to the body, so that, in addition to determining the proportion of food-stuffs in any given food, it is necessary to determine to what extent the several constitu- ents are digested. This factor can be obtained only by actual experi- ments. It may be said here, however, that in general the proteids of animal foods are more completely digested than are those of vegetables, and with them, therefore, chemical analysis comes nearer to expressing directly the nutritive value. The physiology of digestion consists chiefly in the study of the chemical changes that the food undergoes during its passage through the alimentary canal. It happens that these chemical changes are of a peculiar character. The peculiarity is due to the fact that the changes of digestion are effected through the agency of a group of bodies known as enzymes, or unorganized ferments, whose chemical action is more obscure than that of the ordinary reagents with which we have to deal. It will save useless repetition to give here certain general facts that are known with reference to these bodies, reserving for future treatment the details of the action of the specific enzymes found in the different digestive secretions. Enzymes. — Enzymes, or unorganized ferments, or unformed ferments, is the name given to a group of bodies produced in animals and plants, but not themselves endowed with the structure of living matter. The term u/norganisu d or unformed ferment was formerly used to emphasize the distinction between these bodies and living ferments, such as the yeast-plant or the bacteria. " Enzyme," however, is a better name, and is coming into general use. Enzymes are to be regarded as dead matter, although produced in living protoplasm. Chemically, they are defined as complex organic compounds con- taining nitrogen. Their exact composition is unknown, as ii has not been found possible heretofore to obtain them in pure enough condition for analysis. Although several elementary analyses are recorded, they cannot be considered reliable. It is not known whether or not the enzymes belong to the group of proteids. Solutions of most of the enzymes give some or all of the general reactions for proteids, but there is always an uncertainty as to the purity <>f the solutions. With reference to the fibrin ferment of blood, one of the enzymes, observations have recently been made which seem to show that it belongs to the group of combined proteids, nucleo-albumins (for detail- -re the section on Blood). But even should this be true, we arc not justified in making any general application of this fact to the whole group. 280 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. ( 'lassification of Enzymes. — Enzymes are classified according to the kind of reaction they produce — namely: 1. Proteolytic enzymes, or those acting upon proteids, converting them to a soluble modification, peptone or proteose. As examples of this group we have in the animal body pepsin of the gastric juice and trypsin of the pancreatic juice. In plants a similar enzyme is found in the pineapple family (bromelin) and in the papaw (papain). 2. Amylolytic enzymes, or those acting upon the starches, converting them to a soluble form, sugar, or sugar and dextrin. As examples of this group we have in the animal body ptyalin, found in saliva, amylopsin, found in pancreatic juice, and in the liver an enzyme capable of converting glycogen to sugar. In the plants the best-known example is diastase, found in germinating seeds. This particular enzyme has been known for a long time from the use made of it in the manufacture of beer. In fact, the name " dias- tase " is frequently used in a generic sense, " the diastatic enzymes/' to cha- racterize the entire group of starch-destroying ferments. 3. Fat-splitting enzymes, or those acting upon the neutral fats, breaking them up into glycerin and the corresponding fatty acid. The best-known example in the animal body is found in the pancreatic secretion; it is known usually as steapsin, although it has been given several names. Similar enzymes are known to occur in a number of seeds. 4. Sugar-splitting enzymes, or those having the property of converting the double into the single sugars — the di-saccharides, such as cane-sugar and maltose, into the mono-saccharides, such as dextrose and levulose. Two enzymes of this character are found in the small intestine of the animal body, oik; acting upon cane-sugar and one on maltose. The one acting on cane-sugar is known as invertine or invertase, while that acting on maltose is designated as maltase. 5. Coagulating enzymes, or those acting upon soluble proteids, precipitating them in an insoluble form. As examples of this class we have fibrin ferment {thrombin), formed in shed blood, and rennin,the milk-curdling ferment of the gastric juice. An enzyme similar to rennin has been found in pineapple-juice. These five classes comprise the chief groups of enzymes that are known to occur in the animal body. One or more examples of each group take part in the digestion of food at some time during its passage through the alimentary canal. From time to time other enzymes have been recognized in the liquids or tissues of the body. 1 Thus in shed blood and indeed in other tissues an enzyme (glycolytic enzyme) that i> capable of destroying sugar seems to be present. When sugar is added to shed blood it disappears as such, although the products formed have not been recognized. Similarly from many tissues of the body oxidizing enzymes have been extracted that are capable of caus- ing energetic oxidation of organic bodies; for instance, they can convert salicylaldehyde to salicylic acid. It i> possible that these oxidizing enzymes, 1 For :i recent summary of tacts and literature upon enzymes see < rreen : The Soluble Ferments and Fermt ntation, 1897. CHEMISTRY OF DIGESTION AND NUTRITION. 281 or oxidases, form u group that plays an important part in the functional metabolism of the tissues, but at present our knowledge of their existence and functional value in the living organism is very uncertain. A great number of general reactions have been discovered, applicable, with an exception here and there, to the whole group of enzymes. Among these reactions the following are the most useful or significant : 1. Solubility. — The enzymes are soluble in water. They are also solu- ble in glycerin, this being the most generally useful solvent for obtaining extracts of the enzymes from the organs in which they are formed. 2. Effect of Temperature. — In a moist condition they are destroyed by temperatures below the boiling-point ; 60° to 80° C. are the limits actually observed. Very low temperatures retard or even suspend entirely (0° C.) their action, without, however, destroying the enzyme. For each enzyme there is a temperature at which its action is greatest. 3. Incompleteness of Action. — With the exception perhaps of the coagulat- ing enzymes, they are characterized by the fact that in any given solution they never completely destroy the substance upon which they act. It seems that the products of their activity, as they accumulate, finally prevent the enzymes from acting further; when these products are removed the action of the enzyme begins again. The most familiar example of this very striking peculiarity is found in the action of pepsin on proteids. The products of digestion in this case are peptones and proteoses, and when they have reached a certain concen- tration they prevent any further proteolysis on the part of the pepsin. 4. Relation of the Amount of Enzyme to the Effect it Produces. — With most substances the extent of the chemical change produced is proportional to the amount of the substance entering into the reaction. With the enzymes this is not so. Except for very small quantities, it may be said that the amount of change caused is independent of the amount of enzyme present, or, to state the matter more accurately, " with increasing amounts of enzymes the extent of action also increases, reaching a maximum with a certain percentage of enzyme; increase of enzyme beyond this has no effect." 1 This fact was formerly inter- preted to mean that the enzyme is not used up — that is, not permanently altered — by the reaction that it causes. This belief, indeed, must be true substan- tially, but it has been found practically that a given solution of enzyme cannot be used over and over again indefinitely. It is generally believed now that, although an enzyme causes an amount of change in the substance it acta upon altogether out of proportion to the amount of its own substance, neverthe- less it is eventually destroyed; its action is not unlimited. Whether this using up of the enzyme is a necessary result of its activity, or is, as it were, an acci- dental effect from spontaneous changes in its own molecule, remains unde- termined. Theories of the Manner of Action of the Enzymes. — It is now believed that the action of many of the body enzymes, especially the digestive enzymes, is that of hydrating agents; they produce their effeel by what is 1 Tummumi : Zeitechrift fur physiologi&che Chemie, 1892, I'.d. xvi. S. '_'7I. 282 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. known as hydrolysis; that is, they cause the molecules of the substance upon which they act t<> take up one or more molecules of water ; the resulting molecule then splits or is dissociated, with the formation of two or more sim- pler bodies. This is one of the most significant facts in connection with the art ion of the enzymes; it is well illustrated by the action of invertin on cane- sugar, as follows : C 12 H 22 O u +H 2 = C 6 II I2 6 + C 6 H 12 6 Cane-sugar. Dextrose. Levulose. In what way enzymes cause the substances they act upon to take up water is unknown. The fact that they are not themselves used up in the reaction pro- portionally to the change they cause formerly influenced physiologists and chem- ists to explain their effeel as due to catalysis, or contact action. In its original sense this designation meant that the molecules of enzyme act by their mere presence or contiguity, but it need scarcely be said that a statement of this kind does not amount to an explanation of their manner of action ; to say they "act by catalysis" means nothing in itself. Efforts to explain their action have resulted in a number of hypotheses, a detailed account of which would hardly be appropriate here. It may be mentioned that two ideas have found most general acceptance : one, that the enzyme acts by virtue of some peculiar physical property, such as the physical state of its molecules, or by setting up vibrations in the molecules of the substance acted upon; the other idea is that the enzyme enters into a definite chemical reaction, in which, however, it plays the part of a carrier or go-between, so that, although the enzyme is directly concerned in producing a chemical change, the final outcome is that it remains in its original condition. A number of chemical reactions of this general character are known, in which some one substance passes through a cycle of changes, aiding in the production of new compounds, but itself returning always to its first condition ; for example, the part taken by H 2 S0 4 in the manufacture of ether from alcohol, or the successive changes of haemo- globin to oxyhemoglobin and back again to haemoglobin after giving up its oxygen to the tissues. Perhaps the most suggestive reaction of this character is the one quoted by Chittenden 1 to illustrate this very hypothesis as to the manner of action of enzymes, as follows : Oxygen and carbon monoxide gas, if perfectly dry, will not react upon the passage of an electric spark. If, however, a little aqueous vapor is present, they may be made to unite readily, with the formation of C0 2 . The water in this case, without doubt, enters into the reaction, but in the end it is re-formed, and the final result is as though the water had not directly participated in the process. The reaction- supposed to take place are explained by the following equations: CO + 2II..O + 2 = CO(OH) 2 + H 2 2 . B a 2 + GO = CX3(OH) 2 . 2CO(()H) 2 = 2C0 2 + 2H 2 0. 1 Cartwright Lectures, Medical Record, New York, April 7, 1894. CHE3IISTBY OF DIGESTION AND NUTRITION. 283 B. Salivary Digestion. The first of the digestive seeretions with which the food comes in contact is saliva. This liquid is a mixed secretion from the six large salivary glands (parotids, submaxillaries, and sublinguals) and the smaller mucous and serous glands that open into the mouth. The physiological anatomy of these glands and the mechanism by which the secretions are produced and regulated will be found described fully in the section on Secretion ; we are concerned here only with the composition of the secretion after it is formed, and with its action upon foods. Properties and Composition of the Mixed Saliva. — Filtered saliva is a clear, viscid, transparent liquid. As obtained usually from the mouth, it is more or less turbid, owing to the presence in it, in suspension, of particles of food or of detached cells from the epithelium of the mouth. A some- what characteristic cell contained in it in small numbers is the so-called " salivary corpuscle." These bodies are probably leucocytes, altered in struc- ture, that have escaped into the secretion. So far as is known, they have no physiological value. The specific gravity of the mixed secretion is on an aver- age 1003, and its reaction is normally alkaline. The total amount of secretion during twenty-four hours varies naturally with the individual and the condi- tions of life; the estimates made vary from 300 to 1500 grams. Chemically, in addition to the water, the saliva contains mucin, ptyalin, albumin, and inor- ganic salts. The proportions of these constituents are given in the following analysis (Hammerbacher) : In 1000 parts. Water 994.203 Solids : {Mucin (and epithelial cells) 2.202 ^ Ptyalin and albumin 1.390 V 5.797 Inorganic salts 2.205 ) Potassium sulphocyanide 0.041 The inorganic salts, in addition to the sulphocyanide, which occurs only in traces, consist of the chlorides of potassium and sodium, the sulphate of potassium, and the phosphates of potassium, sodium, calcium, and magnesium ; the earthy phosphates form about 9.6 per cent, of the total ash. Mudn is an important constituent of saliva; it gives to the secretion its ropy, viscid cha- racter, which is of so much value in the mechanical function it fulfils in swallowing. This substance is formed in the salivary glands. Its formation in the protoplasm of the cells may be followed microscopically (see the section on Secretion). Chemically, it is now known to be a combination of a proteid with a carbohydrate group (see section on The Chemistry of the llody). So far as known, mucin has no function other than its mechanical use. The pres- ence of potassium sulphocyanide (K( !NS) among the salts of saliva has always been considered interesting, since, although it occurs normally in urine as well as in saliva, it is not a salt found commonly in the secretions of the body, and its occurrence in saliva seemed to indicate some special activity on the pari of the salivary gland, the possible value of which has been a subjeel of specula- 284 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. tion. In the saliva, however, the sulphocyanide is found in such minute traces and its presence is so inconstant that no special functional importance can be attributed to it. It is supposed to be derived from the decomposition of proteids, and it represents, therefore, one of the end-products of proteid metab- olism. Potassium sulphocyanide may be detected in saliva by adding to the latter a dilute acidulated solution of ferric chloride, a reddish color being produced. Ptyalin and its Action. — From a physiological standpoint the most important constituent of saliva is ptyalin. It is an unorganized ferment or enzyme belonging to the amylolytic or diastatic group (p. 280) and possessing the general properties of enzymes already enumerated. It is found in human saliva and in that of many of the lower animals — for example, the pig and the herbivora — but it is said to be absent in the carnivora. Ptyalin has not been isolated in a sufficiently pure condition for satisfactory analysis, so that its chemical nature is undetermined ; we depend for its detection upon its specific action — that is, its effect upon starch. Speaking roughly, we say that ptvalin converts starch into sugar, but when we come to consider the details of its action we find that it is complicated and that it consists in a series of livdrolytic splittings of the starch molecule, the exact products of the reaction depending upon the stage at which the action is interrupted. To demonstrate the action of ptyalin on starch it is only necessary to make a suitable starch paste by boiling some powdered starch in water, and then to add a little fresh saliva. If the mixture is kept at a proper temperature (30° to 40° C), the presence of sugar may be detected within a few minutes. The sugar that is formed was for a time supposed to be ordinary grape-sugar (dextrose, C 6 H, 2 6 ), but later experiments have shown conclusively that it is maltose (C 12 H 22 O n ,- H 2 G), a form of sugar more closely related in formula to cane-sugar (see Chemical section). In experiments of the kind just described two facts may easily be noticed : first, that the conversion of starch to sugar is not direct, but occurs through a number of intermediate stages ; second, that the starch is not entirely converted to sugar under the conditions of such experiments — namely, when the digestion is carried on in a vessel, digestion in vitro. The second fact is an illustration of the incomplete- ly ss of action of the enzymes, a general property that has already been noticed. We may suppose, in this as in other cases, that the products of digestion, as they accumulate in the vessel, tend to retard and finally to sus- pend the amylolytic action of the ptyalin. In normal digestion, however, it is usually the case that the products of digestion, as they are formed, are removed by absorption, and if the above explanation of the cause of the incompleteness of action is correct, then under normal conditions we should expect a complete conversion of starch to sugar. Lea l states that if the products of ptyalin action are partially removed by dialysis during digestion in vitro, a much larger percentage of maltose is formed. His experiments would seem to indicate that in the body the action of the amylolytic ferments 1 Journal of Physiology, 1890, vol. xi. j». 227. CHEMISTRY OF DIGESTION AND NUTRITION. 285 may be complete, and that the final product of their action may be maltose alone. It will be found that this statement applies practically not to the ptyalin, but to the similar amylolytic enzyme in the pancreatic secretion, owing to the fact that, normally, food is held in the mouth for a short time only, and that ptyalin digestion is soon interrupted after the food reaches the stomach. With reference to the intermediate stages or products in the conversion of starch to sugar it is difficult to give a perfectly clear account. It was formerly thought that the starch was first converted to dextrin, and this in turn was converted to sugar. It is now believed that the starch molecule, which is quite complex, consisting of some multiple of C 6 H 10 O 5 — possibly (C 6 H 10 O 5 ) 20 — first takes up water, thereby becoming soluble (soluble starch, amylodextrin), and then splits, with the formation of dextrin and maltose, and that the dextrin again undergoes the same hydrolytic process, with the formation of a second dextrin and more maltose; this process may continue under favorable con- ditions until only maltose is present. The difficulty at present is in isolating the different forms of dextrin that are produced. It is usually said that at least two forms occur, one of which gives a red color with iodine, and is there- fore known as erythrodextrin, while the other gives no color reaction with iodine, and is termed achroodextrin. It is pretty certain, however, that there are several forms of achroodextrin, and, according to some observers, erythro- dextrin also is really a mixture of dextrins with maltose in varying propor- tions. In accordance with the general outline of the process given above, Neumeister 1 proposes the following schema, which is useful because it gives a clear representation of one theory, but which must not be considered as satis- factorily demonstrated (see also the section on Chemistry of the Body). r Maltose. /Maltose. Erythrodextrin. < /Maltose. Achroodextrin a. < /Maltose. Achroodextrin /3. / /Maltose. Achroodextrin y ( (maltodextrin). ""» \Maltose. This schema represents the possibility of an ultimate conversion of all the starch into maltose, and it shows at the same time that maltose may be pres- ent very early in the reaction, and that it may occur together with one or more dextrins, according to the stage of the digestion. It should be said in conclu- sion that this description of the manner of action of the ptyalin is supposed to apply equally well to the amylolytic enzyme of the pancreatic secretion, the two being, so far as known, identical in their properties. From the stand- point of relative physiological importance the description of the details of amylolytic digestion should have been left until the functions of the pancre- atic juice were considered. It is introduced here because, in the Datura! order 1 Lehrburh der physiologiscken Chemie, 1893, p. 232. 286 AN AMERICAN TEXT- HOOK OF PHYSIOLOGY. of' treatment, ptyalin is the first of this group of ferments to be encountered. It is interesting also to remember in this connection that starch can be con- verted into sugar by a process of hydrolytic cleavage by boiling with dilute mineral aeids. Although the general action of dilute acids and of amylolytic enzymes is similar, the two processes are not identical, since in the first process dextrose is the sugar funned, while in the second it is maltose. Moreover, variations in temperature affect the two reactions differently. Conditions Influencing - the Action of Ptyalin. — Temperature. — As in the ease of the other enzymes, ptyalin is very susceptible to changes of temper- ature. At 0° C. its activity is said to be suspended entirely. The intensity of its action increases with increase of temperature from this point, and reaches its maximum at about 40° C. If the temperature is raised much beyond this point, the action of the ptyalin decreases, and at from 65° to 70° C. the enzyme is destroyed. In these latter points ptyalin differs from diastase, the enzyme of malt. Diastase shows a maximum action at 50° C. and is destroyed at 80° C. Effect of Reaction. — The normal reaction of saliva is slightly alkaline. Chittenden has shown, however, that ptyalin acts as well, or even better, in a perfectly neutral medium. A strong alkaline reaction retards or prevents its action. The most marked influence is exerted by acids. Free hydrochloric acid to the extent of only 0.003 per cent. (Chittenden) is sufficient to prac- tically stop the amylolytic action of enzyme, and a slight increase in acidity not only stops the action, but also destroys the enzyme. The latter fact is of practical importance because it indicates that the action of ptyalin on starch must be suspended after the food reaches the stomach. Condition of the Starch. — It is a well-known fact that the conversion of starch to sugar by enzymes takes place much more rapidly with cooked starch — for example, starch paste. In the latter condition sugar begins to appear in a lew minutes (one to four), provided a good enzyme solution is used. With starch in a raw condition, on the contrary, it may be many minutes, or even several hours, before sugar can be detected. The longer time required for raw starch is partly explained by the well-known fact that the starch-grains are surrounded by a layer of cellulose or cellulose-like material that resists the action of ptyalin. When boiled, this layer breaks and the starch in the interior becomes exposed. In addition, the starch itself is changed during the boiling; it takes up water, and in this hydrated condition is acted upon more rapidly by the ptyalin. The practical value of cooking vegetable foods is evident from these statements without further comment. Physiological Value of Saliva. — Although human saliva contains ptyalin, and this enzyme is known to possess very energetic amylolytic properties, yet it is probable that it has an insignificant action in normal digestion. The time that food remains in the mouth is altogether too short to suppose that the starch is profoundly affected by the ptyalin. Indeed, the saliva of dogs and cats is said to contain no ptyalin, while horse's saliva is free from ptyalin, although it contains a zymogen that may give rise to ptyalin. it would seem that what- AN AMERICAN TENT-BOOK OE PHYSIOLOGY. 287 ever change takes place must be confined to the initial stages. After the mixed saliva and food are swallowed it is usually supposed that the acid reaction of the gastric juice soon stops completely all further amylolvtic action, although this point is often disputed. 1 The complete digestion of the carbohydrates takes place after the food (chyme) has reached the small intestine, under the influence of the amylopsin of the pancreatic secretion. For these reasons it is usually believed that the main value of the saliva, to the human being and to the carnivora at least, is that it facilitates the swallowing of food, it is ini pos- sible to swallow perfectly dry food. The saliva, by moistening the food, not only enables the swallowing act to take place, but its viscous consistency must aid also in the easy passage of the food along the oesophagus. In addition the solution of parts of the food in the saliva gives occasion for the stimula- tion of the taste nerves, and, as we shall see in studying the mechanism of gastric secretion, the conscious sensations thus produced are very important for gastric digestion. O. Gastric Digestion. After the food reaches the stomach it is exposed to the action of the secre- tion of the gastric mucous membrane, known usually as the gastric juice. The physiological mechanisms involved in the production and regulation of this secretion, and the important part played in gastric digestion by the movements of the stomach, will be found described in other sections (Secretion, Move- ments of Alimentary Canal). It is sufficient here to say that the secretion of gastric juice begins with the entrance of food into the stomach. By means of the muscles of the stomach the contained food is kept in motion for several hours and is thoroughly mixed with the gastric secretion, which during this time is exerting its digestive action upon certain of the food-stuffs. From time to time portions of the liquefied contents, known as chi/nic, are forced into the duodenum, and their digestion is completed in the small intestine. Gastric digestion and intestinal digestion go more or less hand in hand, and usually it is impossible to tell in any given case just how much of the food will undergo digestion in the stomach and how much will be left to the action of the intestinal secretions. It is possible, however, to collect the gastric secre- tion or to make an artificial juice and to test its action upon food— lull- In- digestions in vitro. Much of our fundamental knowledge of the digestive action of the gastric juice has been obtained in this way, although this has been supplemented, of course, by numerous experiments upon lower animals and human being's. Methods of Obtaining' Normal Gastric Juice. — The older methods used for obtaining normal gastric juice were very unsatisfactory. For instance, an animal was made to swallow a clean sponge to which a string was attached so that the sponge could afterward be removed and its contents be squeezed out ; or there was given the animal to eat some indigestible material, to start the 6ecretion of juice by mechanical stimulation, the animal being killed at the 'Austin: Boston Medical and Surgical Journal, 1899. 288 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. proper time and the contents of its stomach being collected. A better method of obtaining normal juice was suggested by the famous observations of Beau- mont 1 upon Alexis St. Martin. St. Martin, by the premature discharge of his gun, was wounded in the abdomen and stomach. On healing, a fistulous opening remained in the abdominal wall, leading into the stomach, so that the contents of the latter could be inspected. Beaumont made numerous interest- ing and most valuable observations upon his patient. Since that time it has become customary to make fistulous openings into the stomachs of dogs when- ever it is necessary to have the normal juice for examination. A silver canula is placed in the fistula, and at any time the plug closing the canula may be removed and gastric juice be obtained. In some cases the oesophagus has been occluded or excised so as to prevent the mixture of saliva with the gastric juice. Gastric juice may be obtained from human beings also in cases of vom- iting or by means of the stomach-pump, but in such cases it is necessarily more or less diluted or mixed with food and cannot be used for exact analyses, although specimens of gastric juice obtained by these methods are valuable in the diagnosis and treatment of gastric troubles. Properties and Composition of Gastric Juice. — The normal gastric secre- tion is a thin, colorless or nearly colorless liquid with a strong acid reaction and a characteristic odor. Its specific gravity varies, but it is never great, the average being about 1002 to 1003. Upon analysis the gastric juice is found to contain a trace of proteid, probably a peptone, some mucin, and inorganic salts, but the essential constituents are an acid (HC1) and two enzymes, pepsin and rennin. A satisfactory analysis of the human juice has not been reported, owing to the difficulty of getting proper specimens. According to Schmidt, 2 the gastric juice of dogs, free from saliva, has the following composition, given in 1000 parts : Water 973.0 Solids 27.0 Organic substances 17.1 Free HC1 3.1 NaCl 2.5 CaCl, 0.6 KC1 LI NII 4 C1 0.5 Ca3(P0 4 ) 2 1-7 Mg,,fP0 4 ) 2 0.2 FeP0 4 0.1 Gastric juice docs not give acoagulum upon boiling, but the digestive enzymes are thereby destroyed. One of the interesting facts about this secretion is the way in which it withstands putrefaction. It may be kept for a long time, for months even, without becoming putrid and with very little change, if any, in its digestive action or in its total acidity. This fact shows that the juice possesses antiseptic properties, and it is usually supposed that the presence of the free acid accounts for this quality. 1 Tlte Phmi'ihujii of Digestion, 1833. 2 Hammarsten: Text-book of Physiological Chemistry translated by Mandel), 1893, p. 177. CHEMISTRY OF DIGESTION AND NUTRITION. 289 The Acid of Gastric Juice. — The nature of the free acid in gastric juice was formerly the subject of dispute, some claiming that the acidity is due to HC1, since this acid can he distilled off from the gastric juice, others contend- ing that an organic acid, lactic acid, is present in the secretion. All recent experiments tend to prove that the acidity is due to HC1. This fact was first demonstrated satisfactorily by the analyses of Schmidt, who showed that if, in a given specimen of gastric juice, the chlorides were all precipitated by silver nitrate and the total amount of chlorine was determined, more was found than could be held in combination by the bases present in the secretion. Evidently, some of the chlorine must have been present in combination with hydrogen as hydrochloric acid. Confirmatory evidence of one kind or another has since been obtained. Thus it has been shown that a number of color tests for free mineral acids react with the gastric juice : methyl-violet solutions are turned blue, congo-red solutions and test-paper are changed from red to blue, 00 tropseolin from a yellowish to a pink-red, and so on. A number of additional tests of the same general character will be found described in the laboratory handbooks of physiology. 1 It must be added, however, that lactic acid undoubtedly occurs, or may occur, in the stomach during digestion. Its pres- ence is usually explained as being due to the fermentation of the carbohydrates, and it is therefore more constantly present in the stomach of the herbivora. The amount of free acid varies according to the duration of digestion ; that is, the secretion does not possess its full acidity in the beginning, owing probably to the fact (Heidenhain) that in the first periods of digestion, while the secre- tion is still scanty in amount, a portion of its acid is neutralized by the swallowed saliva and the alkaline secretion of the pyloric end of the stomach (see the section on Secretion). Estimates of the maximum acidity in the human stomach are usually given as between 0.2 and <).."> per cent. The acidity of the dog's gastric juice is greater — 0.46 to <>.."}(; per cent. ( Pawlow). Origin of the HC1. — The gastric juice is the only secretion of the body con- taining a free acid. The fact that the acid is a mineral acid makes this circum- stance more remarkable, although other instances of a similar kind arc known; for example, Dolium galea, a mollusc, secretes a salivary juice containing free H 2 S0 4 and free HC1. When and how the IIC1 is formed in the stomach is still asubject of investigation. Histologically, attempts have been made to show that it is produced in the border cells of the peptic glands in the fundic end of the stomach (see Secretion). It cannot be said, however, that the evidence for this theory is at all convincing; it can be accepted only provisionally. Ingenious efforts have been made to determine the place of production of the acid by micro-chemical methods. Substance thai give color reactions with acids have been injected into the blood, and sections of the mucous membrane of the stomach have then been made to determine microscopically the part of the gastric glands in which the acid is produced ; but beyond proving that the acid is formed in the mucous membrane these experiments have given negative results, the color reaction for acid occurring throughout the thickness of the 1 Stirling : Outlines of Practiced Physiology. Vol. I.— 19 290 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. membrane. 1 The chemistry of the production of free HC1 also remains unde- termined. No free acid occurs in the blood or the lymph, and it follows, there- fore, that it is manufactured in the secreting cells. It is quite evident, too, that the source of the acid is the neutral chlorides of the blood ; these are in some way decomposed, the chlorine uniting with hydrogen to form HC1 which is turned out upon the free surface of the stomach, while the base remains behind and probably passes back into the blood. The latter part of the pro- cess, the passage of the base into the blood-current, enables us to explain in part the facts, noticed by a number of observers, that the alkalinity of the blood is increased and the acidity of the urine is decreased after meals. Attempts to express the reaction that takes place in the decomposition of the chlorides are still too theoretical to merit more than a brief mention in a book of this character. According to Heidenhain, the cells secrete a free organic acid, which then acts upon and decomposes the chlorides. According to Maly, the TTC1 is the result of a reaction between the phosphates and the chlorides of the blood, as expressed in the two following equations: NaH 2 P0 4 + NaCl = Na 2 HP0 4 + HC1 ; or, 3CaCl 2 + 2Na 2 HP0 4 = Ca 3 (P0 4 ) 2 + 4NaCl + 2HC1. A recent theory by Liebermann supposes that the mass action of the C0 2 formed in the tissues of the gastric mucous membrane upon the chlorides, with the aid of a nucleo-albumin of acid properties that can be isolated from the gastric glands, may account for the production of the HC1. Although it is customary to speak of the HC1 as existing in a free state in the gastric juice, certain differences in reaction between this secretion and aqueous solu- tions of the same acidity have led to the suggestion that the HC1, or a part of it at least, is held in some sort of combination with the organic (proteid) con- stituents of the secretion, so that its properties are modified in some minor points just as the properties of hemoglobin are modified by the combination in which it is held in the corpuscles. The differences usually described are that in the gastric juice or in mixtures of HC1 and proteid the acid does not dialyze nor distil off so readily as in simple aqueous solutions. The peptones and proteoses formed during digestion seem to combine with the acid very readily — so much so, in fact, that in certain cases specimens of gastric juice taken from the stomach, although they give an acid reaction with litmus-paper, may not give the special color reactions for free mineral acids. In such cases, how- ever, the acid may still be able to fulfil its part in the digestion of proteids. Nature and Properties of Pepsin. — Pepsin is a typical proteolytic enzyme that exhibits the striking peculiarity of acting only in acid media; hence peptic digestion in the stomach is the result of the combined action of pepsin and HC1. Pepsin is influenced in its action by temperature, as is the case with the other enzymes ; low temperatures retard, and may even suspend, its activity, while high temperatures increase it. The optimum temperature is stated to be from 37° to 40° C, while exposure for some time to 80° C. results, when the 1 Friinkel : I'jluger's Archivfur die gesammte Physiologic, 1891, Bd. 48, S. 63. CHEMISTRY OF DIGESTION AXD NUTRITION. 291 pepsin is in a moist condition, in the total destruction of the enzyme. Pepsin has never been isolated in sufficient purity for satisfactory analysis. It may be extracted, however, from the gastric mucous membrane by a variety of methods and in different degrees of purity and strength. The commercial preparations of pepsin consist usually of some form of extract of the gastric mucous membrane to which starch or sugar of milk has been added. Laboratory preparations are usually made by mincing thoroughly the mucous membrane and then extract- ing for a long time with glycerin. Glycerin extracts, if not too much diluted with water or blood, keep for an indefinite time. Purer preparations of pepsin have been made by what is known as "Briicke's method," in which the mucous membrane is minced and is then self-digested with a 5 per cent, solution of phosphoric acid. The phosphoric acid is precipitated by the addition of lime- water, and the pepsin is carried down in the flocculent precipitate. This pre- cipitate, after being washed, is carried into solution by dilute hydrochloric acid, and a solution of cholesterin in alcohol and ether is added. The choles- terin is precipitated, and, as before, carries down with it the pepsin. This precipitate is collected, carefully washed, and then treated repeatedly with ether, which dissolves and removes the cholesterin, leaving the pepsin in aqueous solution. This method is interesting not only because it gives the purest form of pepsin, but also in that it illustrates one of the properties of this enzyme — namely, the readiness with which it adheres to precipitates occur- ring in its solutions. Pepsin illustrates very well two of the general properties of enzymes that have been described (p. 281): first, its action is incomplete, the accumulation of the products of digestion inhibiting further activity at a certain stage; and, secondly, a small amount of the pepsin, if given sufficient time and the proper conditions, will digest a very large amount of proteid. Artificial Gastric Juice. — In studying peptic digestion it is not necessary for all purposes to establish a gastric fistula to get the normal secretion. The active agents of the normal juice are pepsin and acid of a proper strength ; and, as the pepsin can be extracted and preserved in various ways, and the 1 1 CI can easily be made of the proper strength, an artificial juice can be obtained at any time which may be used in place of the normal secretion for many purposes. In laboratory experiments it is customary to employ a glycerin extract of the gasl ric mucous membrane, and to add a small portion of this extract to a large bulk of 0.2 per cent. 1 101. The artificial juice thus made, when kept at a temperature of from 37° to 40° C, will digest proteids rapidly if the preparation of pepsin is a good one. While the strength of the acid employed is generally from 0.2 to 0.3 per cent., digestion will take place in solutions of greater or less acidity. Too great or too small an acidity, however, will retard the process; that is, there is for the action of the pepsin an optimum acidity which lies somewhere between 0.2 and 0.5 percent. Other acids may be used in place of the IIC1 — for example, nitric, phosphoric, or lactic — although they are not so effective, and the opti- mum acidity is different for each; fur phosphoric acid it is given as 2 percent. Action of Pepsin-Hydrochloric Acid on Proteids. — It has been knovvn for a long time that solid proteids, such as boiled egg-, when exposed to the 292 AX AMERICAN TEXT-BOOK OF PHYSIOLOGY. action of a normal or an artificial gastric juice, swell up and eventually pass into solution. The soluble proteid thus formed was known not to be coagu- lated by heat ; it was remarkable also for being more diffusible than other forms of soluble proteids, and was further characterized by certain positive and negative reactions that will be described more explicitly farther on. This end-product of digestion was formerly described as a soluble proteid with properties fitting it for rapid absorption, and the name of peptone, was given to it. It was quickly found, however, that the process was complicated — that in the conversion to so-called " peptone " the proteid under digestiou passed through a number of intermediate stages. The intermediate products were partially isolated and were given specific names, such as acid-albumin, para peptone, and propeptone. The two latter names, unfortunately, have not always been used with the same meaning by authors, and latterly they have fallen somewhat into disuse, although they are still frequently employed to indicate some one or other of the intermediate stages in the formation of pep- tones. The most complete investigation of the products of peptic digestion, and of proteolytic digestion in general, we owe to Kiihne and to those who have followed along the lines he laid down, among whom may be mentioned Chittenden and Neumeister. Their work has thrown new light upon the whole subject and has developed a new nomenclature. In our account of the process we shall adhere to the views and terminology of this school, as they seem to be generally adopted in most of the recent literature. It is well, however, to add, by way of caution, that investigations of this character are still going on, and the views at present accepted are liable, therefore, to changes in detail as our experimental knowledge increases. Without giving the historical development of Kuhne's theory, it may be said that at present the following steps in peptic digestion have been described: The proteid acted upon, whether soluble or insoluble, is converted first to an acid-albumin (see Chemical section) to which the name syntonin is usually given. In arti- ficial digestions the solid proteid usually swells first from the action of the acid, and then slowly dissolves. Syntonin has the general properties of acid- albumins, of which properties the most characteristic is that the albumin is precipitated upon neutralizing the solution with dilute alkali. If, in the begin- ning of a peptic digestion, the liquid is neutralized, a more or less abundant precipitate of syntonin will form, the quantity depending upon the stage of digestion. Syntonin in turn, under the influence of the pepsin, takes up water and undergoes hydrolytic cleavage, with the formation of several solu- ble proteids known together as primary albumoses or proteoses? Each of these proteids again takes up water and undergoes cleavage, with the formation of a second set of soluble proteids known as secondary proteoses, in contradis- tinction to the primary proteoses, but to which the specific name of deutero- 1 The term proteose is used by Bome authors in place of the older name innh)/.. -is.",. CHEMISTRY OF DIGESTION AND NUTRITION. 301 Several partial analyses have been reported. According to Zawadsky, 1 the composition of the secretion in a young woman was as follows : In 1000 parts. Water 864.05 Organic substances 132.51 Proteids 92.05 Salts 3.44 The organic substances held in the secretion are in part of an albuminous nature, since they coagulate upon heating, but the exact nature of the proteid or proteids has not been determined satisfactorily. The most important of the organic substances — the essential constituents, indeed, of the whole secretion — are three enzymes acting respectively upon the proteids, the carbohydrates, and the fats. The proteolytic enzyme is called "trypsin;" the amvlolvtic enzyme is described under different names : " amylopsin " is perhaps the best, and will be adopted in this section ; for the fat-splitting enzyme we shall use the term "steapsin." Owing to the presence of these enzymes the pancreatic secretion is capable of exerting a digestive action upon each of the three im- portant classes of food-stuffs. It is said that the pancreatic juice contains also a coagulating enzyme, similar to rennin, capable of curdling milk. Trypsin. — Trypsin is a more powerful proteolytic enzyme than pepsin. Unlike the latter, trypsin acts best in alkaline media, but it is effective also in neutral liquids, or even in solutions not too strongly acid. Trypsin is affected by changes in temperature like the other enzymes, its action being retarded by cooling and hastened by warming. There is, however, a temperature, that may be called the optimum temperature, at which the trypsin acts most powerfully ; if, however, the temperature is raised to as much as 70° to 80° C, the enzyme is destroyed entirely. Trypsin has never been isolated in a condi- tion sufficiently pure for analysis, so that its chemical composition is unknown. Extracts containing trypsin can be made from the gland very easily and by a variety of methods. The usual laboratory method is to mince the gland and to cover it with glycerin for some time. Iu using this and other methods for preparing trypsin extracts it is best not to take the perfectly fresh gland, but to keep it for a number of hours before using. The reason for this is that the enzyme exists in the fresh gland in a preparatory stage, a zymogen (see sec- tion on Secretion), which in this case is called " trypsinogen." Upon standing, the latter is slowly converted to trypsin — a process that may be hastened by the action of dilute acids and by other means. An artificial pancreatic juice is prepared usually by adding a small quantity of the pancreatic extract to an alkaline liquid; the liquid usually employed is a solution of sodium carbonate of from 0.2 to 0.5 per cent. To prevent putrefactive changes, which come on with such readiness in pancreatic digestions, a lew drops of an alcoholic solution of thymol may be added. A mixture of this kind, if kept at the proper temperature, digests proteids very rapidly, and most of our knowledge of the action of trypsin has been obtained from a study of the products of such digestions. 1 Centralblattjur Physiologie, 1891, Bd. v. S. 179. 302 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Products of Tryptic Digestion. — Tryptic digestion resembles peptic diges- tion in that proteoses and peptones are the chief products formed, but the two processes differ in a number of details. The naked-eye appearances, in the first place, are different in cases in which the proteid acted upon is in a solid form ; for while in the pepsin-hydrochloric digestion the proteid swells up and grad- ually dissolves, under the action of trypsin it does not swell, but suffers erosion, as it were, the solid mass of proteid being eaten out until finally only the indi- gestible part remains, retaining the shape of the original mass, but falling into fragments when shaken. In the second place, the hydrolytic cleavages seem to be of a more intense nature. In peptic digestion, after the syntonin stage is passed, there is a gradual change to peptone through the intermediate primary and secondary proteoses. Under the influence of trypsin, according to the most recent experiments, the solid proteid undergoes a transformation directly to secondary proteoses (deutero-proteoses), the intermediate stages being skipped. It was formerly thought that the solid proteid was converted first into a soluble proteid, and that if the solution was alkaline some alkali-albumin was formed, precipitable by neutralization, and comparable to the syntonin of pepsin-hydro- chloric digestion. This soluble proteid was thought to be split into proteoses of the hemi- and anti- groups which were then converted to the corresponding peptones, according to Kiihne's schema (p. 293). There seems to be no doubt that with the proteid most frequently used in artificial digestion — namely, fibrin from coagulated blood— the first effect is a conversion to a soluble globulin-like form of proteid ; but Neumeister finds that this does not happen with other proteids, and he thinks that in the case of fibrin it is not due to a true digestive action of trypsin, but to ;i partial solution of the fibrin by the Inorganic salts in the liquid. In general, however, the preliminary stage of a soluble proteid is missed, as also is that of the primary proteoses. The proteid falls at once by hydrolytic cleavage into deutero-proteoses, and these in turn are transformed to peptones. Just at this point comes in one of the most characteristic differences between the action of pepsin and that of tryp- sin. Pepsin cannot affect the peptones further, but trypsin may act upon the supposed hemi-constituent and split it up, with the formation of a number of much simpler nitrogenous bodies, most of which are amido-acids. The final products of prolonged tryptic digestion are, first, a peptone which cannot further be decomposed by the enzyme and which constitutes what is known as anti-peptone? and, second, a number of simpler organic substances, amido- 1 In the account of tryptic digestion as in the case of pepsin the nomenclature of Kiihne is adhered to. It should he staled, however, that of late years some douht has been thrown upon the existence of an anti-peptone. Siegfried [Ardkiv fur Physiologie, 1894) identifies it with a body to which he 7, pepsin carries the digestion of gelatin mainly to. the gelatose stage ; trypsin, however, produces gelatin peptones. It seems probable, therefore, that the final digestion of the albuminoids also is effected in the small intestine. Amylopsin. — The enzyme of the pancreatic secretion that acts upon starches is found in extracts of the gland, made according to the general methods already given, and its presence may be demonstrated, of course, in the secretion obtained by establishing a pancreatic fistula. The proof of the existence of this enzyme is found in the fact that if some of the pancreatic secretion or some of the extract of the gland is mixed with starch paste, the 1 Lehrbuch der physiologischen Chemie, 1S93, S. 200. CHEMISTRY OF DIGEST I OX AND NUTRITION. 305 starch quickly disappears and maltose or maltose and dextrin are found in its place. Amylopsin shows the general reactions of enzymes with rela- tion to temperature, incompleteness of action, etc. Its specific reaction is its effect upon starches. Investigation has shown that the changes caused by it in the starches are apparently the same as those produced by ptyalin. In fact, the two enzymes ptyalin and amylopsin are identical in properties as far as our knowledge goes, so that it is not uncommon, in German liter- ature especially, to have them both described under the name of ptyalin. The term amylopsin is convenient, however, in any case, to designate the special origin of the pancreatic enzyme. As to the details of its action, it is unnecessary to repeat what has been said on page 285. The end-products of its action, as far as can be determined from artificial digestions, are a sugar, maltose (C^H^Oj^H^O), and more or less of the intermediate achroodextrins, the relative amounts depending upon the completeness of digestion. As has previously been said, there are indications that under the favorable conditions of natural digestion all the starch may be changed to maltose, but possibly it is not necessary that the action should be so complete in order that the carbohydrate may be absorbed into the blood, as will be shown when we come to speak of the further action of the intestinal secretion upon maltose and the dextrins. The amylolytic action of the pancreatic juice is extremely import- ant. The starches constitute a large part of our ordinary diet. The action of the saliva upon them is probably, for reasons already given, of subordinate importance. Their digestion takes place, therefore, entirely or almost entirely in the small intestine, and mainly by virtue of the action of the amylopsin contained in the pancreatic secretion. The action of the amylopsin is supple- mented to some extent, apparently, by a similar enzyme formed in small quantities in the intestinal wall itself, the nature of which will be described presently in connection with intestinal secretion. Steapsin. — Stcapsin, or lipase, is the name given to a fat-splitting enzyme occurring in the pancreatic juice. It is of the greatest importance in the digestion and absorption of fats. The peculiar power of the pancreatic juice to >plit neutral fats with the liberation of free fatty acid was first described by Bernard. His discovery has since been corroborated for different animals, including man, by the use of normal pancreatic juice obtained from a fistula, or by the aid of the tissue of the fresh gland, or, finally, by means of extracts of the gland. When neutral fats (see Chemical section for the composition of fats) are treated with an extract containing steapsin, they take up water and then undergo cleavage (hydrolysis), with the production of glycerin and the free fatty acid found in the particular fat used. This reaction is explained by the following equation, in which a general formula for l'ats is used: (:,H 5 (C n II 2n+1 COO) 3 + 3H z O = C 3 H,(()I I), + 3(CJ I,.,, , ,< !< )OII). Fat. Glycerin. Free fatty acid. The reaction in the case of palmitin would be — C 8 H 6 (C I6 H 31 COO) s + 3H 2 = C,H 8 (OH) s + 3(C u H 81 COOH) Palmitin. Glycerin. Palmitic acid. Vol. I.— 20 306 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. While this action is undoubtedly caused by an enzyme, it has not been possible to isolate the so-called "steapsin " in a condition of even approximate purity. As a matter of fact also, ordinary extracts of pancreas, such as the laboratory extracts in glycerin, do not usually show the presence of this enzyme unless special precautions arc taken in their preparation. It would seem that steapsin is easily destroyed. With fresh normal juice or with pieces of fresh pancreas the fat-splitting effect can be demonstrated easily. One striking method of making the demonstration is to use hutter as the fat to be decomposed. If butter is mixed with normal pancreatic juice or with pieces of fresh pancreas, and the mixture i> kept at the body-temperature, the several fats contained in butter will be decomposed and the corresponding fatty acids will be liberated, among them butyric acid, which is readily recognized by its familiar odor, that of rancid butter. 'Flic action of steapsin, as in the case of the other enzymes, is very much influenced by the temperature. At the body-temper- ature the action is very rapid. The nature of the fat also influences the rapiditv of the reaction; it may be said, in general, that fats with a high melting-point are less readily decomposed than those with a low melting- point. It has been shown, however, that even spermaceti, which is a body related to the fats and whose melting-point is 53° C, is decomposed, although slowlv and imperfectly, by steapsin. The fat-splitting action of the steapsin undoubtedly takes place normally in the intestines, but it is cpiestiouable whether all the fat eaten undergoes this process. In fact, it maybe said that two views are taught at present regarding the digestion and absorption of fats. According to the older view, only a certain small proportion of the fat undergoes splitting, or saponification, as it is sometimes called. The remain- der of the fat becomes emulsified by the products (fatty acids) formed in the splitting, and arc absorbed in an emulsified condition as neutral fats. Accord- ing to the more recent view. 1 all the fat is supposed to be acted upon by the steapsin, with or without previous cmulsification, with the formation of glycerin and fatty acids. These two products, the latter perhaps in part as a soap formed by reaction with the alkaline salts of the intestine, are absorbed in solution, and subsequently are recombined, probably in the substance of the epithelial (ills, to form a neutral fat again. On both theories one of the first results of the action of the steapsin is the formation of an emulsion, the value of which on the first theory is that it brings the fat into a form in which it can be ingested by the epithelial cells of the villi, while on the second theory it consists in the fact that by subdividing the fat globules minutely the completion of the process of saponification is hastened. On cither view, therefore, emulsification is an interesting preliminary to the absorption of fat, and some discussion of the nature of the process seems to be demanded. Emulsification of Fats. — An oil is emulsified when it is broken up into minute globules that do not coalesce, but remain separated and more or less uniformly distributed throughout the medium in which they exist. Artificial emulsions can be made by shaking oil vigorously in viscous solutions 1 Mo..re and Rockwood: Journal <>/ Physiology, 1897, vol. 21, p. 58. CHEMISTRY OF DIGESTION AND NUTRITION. 307 of soap, mucilage, etc. Milk is a natural emulsion that separates partially on standing, some of the oil rising to the top to form cream. Bernard made the important discovery that when oil and pancreatic juice are shaken together an emulsion of the oil takes place very rapidly, especially if the temperature is about that of the body. The main cause of the em unification has been shown to be the formation of free fatty acids due to the action of steapsin, and the union of these acids with the alkaline salts present to form soaps. This fact has been demonstrated by experiments of the following character: If a perfectly neutral oil is shaken with an alkaline solution (} per cent, sodium-carbonate solution), no emulsion occurs and the two Liquids soon sepa- rate. If to the same neutral oil one adds a little free fatty acid, or if one uses rancid oil to begin with and shakes it with \ per cent, sodium-carbonate solution, an emulsion forms rapidly and remains for a long time. Oil con- taining fatty acids when shaken with distilled water alone will not give an emulsion. It has been shown, moreover, by Gad and Ratchford that with a certain percentage of free fatty acids (5J per cent.) rancid oil and a sodium- carbonate solution will form a fine emulsion spontaneously — that is, without shaking. Shakino- however, facilitates the emulsification when the amount of free acid varies from this optimum percentage. In what May the formation of soaps in an oily liquid causes the oil to become emulsified is still a matter of speculation. The splitting of the oil into small drops seems to be caused, in cases of spontaneous emulsification, by the act of formation of the soap — that is, the union of the alkali with the fatty acid — in other cases by the mechanical shaking, or by these two causes combined. The application of these facts to the action of the pancreatic juice in the small intestine is easily made. When the chyme, containing more or less of liquid fat, comes into contact with the pancreatic juice, a part of the oil is quickly split by the steapsin, with the formation of free fatty acids. These acids unite with the alkalies and the alkaline salts present in the secretions of the small intestine (pancreatic juice, bile, intestinal juice) to form soaps. The formation of the soaps, aided, perhaps, by the peristaltic movements of the intestine, emulsifies the remainder of the fats and thus prepares them for absorption or further saponification. It has been suggested that the proteids in solution in the pancreatic juice aid in the emulsification, but there is no experimental evi- dence to show that this is the ease. A factor of much more Importance is the influence of the bile. In man the pancreatic juice and the bile are poured into the duodenum together, and in all mammals the two secretions are mixed with the food at some part of the duodenum. Now, it has been shown beyond question that a mixture of bile and pancreatic juice will cause a splitting of fats into fatty acids and glycerin much more rapidly than will the pancreatic juice alone. 1 This effect of the bile is not due to the presence in it of a fat-splitting enzyme of its own : the bile seems merely t" favor in some way the action of the steapsin contained in the pancreatic secretion. 1 Nencki : Archiv fiir experimenfelU Pathologic ». Pharmakologie, 1886, Bd, 20, S. 367; Ratch- ford: Journal of Physiology, 1891, vol. 12, p. 27. 308 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Intestinal Secretion. — The small intestine is lined with tubular glands, the crypts of Lieberkiihn, that are supposed to form a secretion of consid- erable importance in digestion. To obtain the intestinal secretion, or suceus enterims, as it is often called, recourse lias been had to an ingenious operation for establishing a permanent intestinal fistula. This operation, which usually goes under the name of the " Thhy-Vella fistula," consists in cutting out a small portion of the intestine without injuring its supply of blood-vessels or nerves, and then sewing the two open ends of this piece into the abdominal wall so as to form a double fistula. The continuity of the intestines is estab- lished by suture, while the isolated loop with its two openings to the exterior can lie used for collecting the intestinal secretion uncontaminated by partially- digested food. The secretion is always small in quantity, and it must be started by a stimulus of some kind. According to Rohmann, 1 it varies in quantity in different parts of the small intestine, being very scanty in the upper part and more abundant in the lower. The intestinal secretion is a yellowish liquid with a strong alkaline reaction. The reaction is due to the presence of sodium carbonate, the quantity of which is about 0.25 to 0.50 per cent. The chemical composition of the secretion has not been satisfactorily determined, but its digestive action has been investigated with success. Upon proteids and fats it is said to have no specific action — that is, it contains neither a proteolytic nor a fat-splitting enzyme. The possible value of its sodium carbonate in aiding the emulsification of fats has been referred to in the preceding paragraph. Upon carbohydrates the secretion has an important action. In the first place, it has been shown that it contains an amylolvtic enzyme that is more abun- dant in the upper than in the lower part of the intestine. This enzyme doubt- less aids the amylopsin of the pancreatic secretion in converting starches to sugar (maltose) or sugar and dextrin. What is still more important, however, is the presence of inverting enzymes (invertase) capable of converting cane- sugar (saccharose) into dextrose and levulose, and of a similar enzyme (mal- tase) capable of changing maltose to dextrose. Both of these effects are examples of the conversion of di-saccharides to niono-saecharides. The di-saccharides of importance in digestion are cane-sugar, milk-sugar, and maltose. The first of these forms a common constituent of our daily diet; the second occurs always in milk ; and the third, as we have seen, is the main end-product of the digestion of starches. These substances are all readily Boluble, and we might expect that they would be absorbed directly into the blood without undergoing further change. As a matter of fact, however, it seems that they are first dissociated under the influence of the sugar-splitting enzymes into simpler mono-saccharide compounds, although in the case of lactose this statement is perhaps not entirely justified, our knowledge of the fate of this sugar during absorption being as yet incomplete. According to some authors, lactose is absorbed unchanged (sec Chemical section), 'flic general nature of this change is expressed in the three following reaction- : 1 /'///(•/./■'.< Arehiv fur die gesammte Physiologie, 1887, l>d. 41,8.411. CHEMISTRY OF DIGESTION AND NUTRITION. 309 C 12 T!„O u + H a O = C 6 H 12 6 + C f> H 12 6 . Maltose. Dextrose. Dextrose. C 12 H 22 O u + H 2 = C fi H,A + C 6 H 12 6 . Cane-sugar. Dextrose.. Levulose. C 12 H 22 O n + H 2 = C 6 H 12 6 + 6 H 12 ( ),, Lactose. Dextrose. Galactose. For the reactions by means of which these different isomeric forms of sugar are distinguished reference must be made to the Chemical section. The final stage in the artificial digestion of starches is the formation of maltose or of a mixture of maltose and dextrins. In the intestines, however, the process is carried a step farther by the aid of the sugar-splitting enzymes, and the maltose, and ap- parently the dextrins also, are converted into dextrose. According to this descrip- tion, all of the starch is finally absorbed into the blood in the form of dextrose ; and this conclusion falls in with the fact that the sugar found normally in the blood exists always in the form of dextrose. With reference to the sugar-splitting enzymes found in the small intestine, it should be added that they occur more abundantly in the mucous membrane than in the secretion itself. Indeed, the secretion is normally so scanty, especially in the upper part of the intestine, that it cannot be supposed to do more than moisten the free surface, and it is probable that the action of these enzymes takes place upon or in the mucous membrane, as the last step in the series of digestive changes of the carbohydrates immediately preceding their absorption. Digestion in the Large Intestine. — Observations upon the secretions of the large intestine have been made upon human beings in cases of anus praeter- naturalis in which the lower portion of the intestine (rectum) was practically isolated. These observations, together with those made upon lower animals, unite in showing that the secretion of the large intestine is mainly composed of mucus, as the histology of the mucous membrane would indicate, and that it is very alkaline, and probably contains no digestive enzymes of its own. When the contents of the small intestine pass through the ileo-csecal valve into the colon they still contain a quantity of incompletely digested material mixed with the enzymes of the small intestine. It is likely, therefore, that seme at least of the digestive processes described above may keep on for a time in the large intestine; but the changes hereof most interest are the absorption that takes place and the bacterial decompositions. The latter arc described briefly below. Bacterial Decompositions in the Intestines. — Bacteria of different kinds have been found throughout the alimentary canal from the mouth t<> the rectum. In the stomach, however, under normal conditions, the strong acid reaction prevents the action of those putrefactive bacteria that decom- pose proteids, and prevents or greatly retards the action of those thai set up fermentation in the carbohydrates. Under certain abnormal conditions known to ns under the general term of dyspepsia, bacterial fermentation of the carbohydrates may be pronounced, l>nt this must be considered as path- ological. 310 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. In the small intestine the secretions are all alkaline, and it was formerly taken for granted that the intestinal contents an' normally alkaline, [fthis were so, the bacteria would find a favorable environment. It was supposed that putrefaction of the proteids mighl occur, especially during the act of tryptic digestion, and this supposition was home out by the extraordinary readiness of ar- tificial pancreatic digestions to undergo putrefaction when not protected in some way. Two recent cases ' of fistula of the ileum at its junction with the colon in human beings have given opportunity for exact study of the contents of the small intestine. The results are interesting, and to a certain extent are opposed to the preconceived notions as to reaction and proteid putrefaction which have just been stated. They show that the contents of the intestine at the point where they are about to pass into the large intestine are acid, provided a mixed diet is used, the acidity being due to organic acids (aeetie) and being equal to 0.1 per cent, acetic acid. These acids must have come from the bacterial fer- mentation of the carbohydrates, and a number of bacteria capable of producing such fermentation were isolated. The products of bacterial putrefaction of the proteids. on the contrary, were absent, and it has been suggested that the acid reaction produced by the fermentation of the carbohydrates serves the useful purpose, under normal conditions, of preventing the putrefaction of the pro- teids. With reference, therefore, to the point we are discussing — namely, the bacterial decomposition of the contents of the intestines — we may conclude, upon the evidence furnished by these two cases, that in the human being, when living on a mixed diet, some of the carbohydrates undergo bacterial decompo- sition in the small intestine, but that the proteids are protected. We may further suppose that in the case of the proteids the limits of protection are easilv overstepped, and that such a condition as a large excess of proteid in the diet or a deficient absorption from the small intestine may easily lead to exten- sive intestinal putrefaction involving the proteids as well as the carbohydrates. In the large intestine, on the contrary, the alkaline reaction of the secretion is more than sufficient to neutralize the organic acids arising from fermentation of the carbohydrates, and the reaction of the contents is therefore alkaline. Here, then, what remains of the proteids undergoes, or may undergo, putrefac- tion, and this process must be looked upon as a normal occurrence in the large intestine. The extent of the bacterial action upon the proteids as well as the carbohydrates may vary widely even within the limits of health, and if excessive may lead to intestinal troubles. Among the products formed in this way, the following are known to occur: Leucin, tyrosin, and other amido-acids ; indol ; skatol ; phenols; various members of the fatty-acid series, such as lactic, butyric, and caproic acids; sulphuretted hydrogen; methane; hydrogen; methyl mercaptan, etc. Some of these products will be described more fully in treating of the composition of the feces. To what extent these products are of value to the body it is difficult, with our imperfect knowledge, to say. It ha- been pointed out, on the one hand, that some of them (skatol, fatty 1 Macfayden, Ncncki, and Sieber: Archivfur experimentelle Pathologie u. Pharmakologie, 1891' Bd. 'J- 1 , S. 311 ; Jakowski : Archives des Sciences biologiques, St. Petersburg, 1892, t. 1. CHEMISTRY OF DIGESTION AND NUTRITION. 311 acids, CO,, CH 4 , and H 2 S) promote the movements of the intestine, and may be of value from this standpoint; on the other hand, some of them are absorbed into the blood, to be eliminated again in different form in the urine (indol aud phenols), and it may be that they are of importance in the metab- olism of the body; but concerning this our knowledge is deficient. On the whole, we must believe that the food in its passage through the alimentary canal is acted upon mainly by the digestive enzymes, the so-called " unorgan- ized" ferments, but that the action of the bacteria, or organized ferment-, is responsible for a part of the changes that the food undergoes before its final elimination in the form of feces. These two kinds of action vary greatly within normal limits, and to a certain extent they seem to be in inverse relationship to each other. When the digestive enzymes and secretion- are deficient or ineifective the field of action for the bacteria is increased, and this seems to be the case in some pathological conditions, the result being intes- tinal troubles of various kinds. The limits of normal bacterial action have not been worked out satisfactorily, but it is evident that our knowledge <>f digestion will not be complete until this is accomplished. It should be stated in conclusion that, however constant and important the occurrence of bacterial fermentation may be in the alimentary canal, it cannot be regarded as essential to the life of the animal, since Nuttall and Theirfelder, 1 in a series of ingenious experiments made upon newly-born guinea-pigs, have shown that these animals may thrive, for a time at least, when the entire alimentary canal is free from bacteria. E. Absorption ; Summary of Digestion and Absorption of the Food-stuffs ; Feces. In the preceding sections we have followed the action of the various digestive secretions upon the food-stuifs as far as the formation of the supposed end-products. In order that these products may be of actual nutritive value to the body, it is necessary, of course, that they shall be absorbed into the circulation and thus be distributed to the tissues. There are two possible routes for the absorbed products to take: they may pass immediately into the blood, or they may enter the lymphatic system, the so-called "lacteals" of the alimentary canal. In the latter case they reach the blood finally before being distributed to the tissues, since the thoracic duct, into which the lym- phatics of the alimentary canal all empty, opens into the blood-vascular system at the junction of the left internal jugular and subclavian veins. The sub- stances that take this route are distributed to the tissues by the blood, but it is to be noticed that, owing to the sluggish How of the lymph-circulation (see section on Circulation), a relatively long time elapses after digestion . before they enter the blood-current. The products that enter the blood directly from the alimentary canal are distributed rapidly ; but in this case we must remember that they first pass through the liver, owing to the existence of 1 Zeittschriflfiir phyaiologische Ohemie, 18'.)-"), lid. >J1 ; 1896, Bd. 22, ami L897, Bd. 23. 312 AN AMERICAN TEXT- BOOK OF PHYSIOLOGY. the portal circulation, before they reach the general circulation. During this passage through the liver, as we shall find, changes of the greatest importance take place. The physiology of absorption is concerned with the physical and chemical means by which the end-products of digestion are taken up bv the blood or the lymph, and the relative importance of the stomach, the small intestine, and the large intestine in this process. Leaving aside the fats, whose absorption is a special case, the absorption of the other products of digestion was formerly thought to be a simple physical process. The processes of diffusion and osmosis, as they are known to occur outside the body, were supposed to account for the absorption of all the soluble products. This belief is still held by many, hut the facts known with regard to the absorp- tion of the carbohydrates, proteids, and fats after the changes undergone during digestion are not wholly accounted for by the laws of diffusion and osmosis as they are known to us (see p. 65 for a discussion of the nature of these processes). For the present at least it seems to be necessary to refer many of the phenomena of physiological absorption to the peculiar properties of the living epithelial cells lining the alimentary canal. Some of the important facts regarding absorption are as follows : Absorption in the Stomach. — In the stomach it is possible that there might be absorption of the following substances : water; salts; sugars and dextrins that may have been formed in salivary digestion from starch, or that may have been eaten as such ; the proteoses and peptones formed in the peptic digestion of proteids or albuminoids. In addition, absorption of soluble or liquid substances — drugs, alcohol, etc. — that have been swallowed may occur. It was formerly assumed without definite proof that the absorp- tion in the stomach of such things as water, salts, sugars, and peptones was very important. Of late years a number of actual experiments have been made, under conditions as nearly normal as possible, to determine the extent of absorption in this organ. These experiments have given unexpected results, showing, upon the whole, that absorption does not take place readily in the stomach — certainly nothing like so easily as in the intestine. The methods made use of in these experiments have varied, but the most interesting results have been obtained by establishing a fistula of the duodenum just beyond the pylorus. 1 Through a fistula in this position substances cau be introduced into the stomach, and if the cardiac orifice is at the same time shut off by a ligature or a small balloon, they can be kept in the stomach a given time, then be removed, and the changes, if any, be noted. After establishing the fistula in the duodenum food may be given to the animal, and the contents of the stomach as they pass out through the fistula may be caught and examined. The older methods of introducing the substance to be observed into the stomach through the oesophagus or through a gastric fistula were of little use, since, if the substance disappeared, there was no way of deciding whether it was absorbed or was -imply passed on into the intestine. 1 ( lompare von Mering: Verhandl. f diffusion through dead membranes. Pro- teids, like egg-albumin, which are practically non-dialyzable are absorbed readily from the intestine. Moreover, when one considers the rate of absorp- tion of peptone from the alimentary tract, it seems to be much too rapid and complete to be accounted for entirely by the diffusibility of this substance as determined by experiments with parchment dialyzers. It is believed, there- fore, that the initial act in the absorption of proteids is dependent in some way upon the peculiar properties of the layer of living epithelial cells lining the mucous membrane. Whether the peculiarity is a physical one depending on some special structure of the cells that makes them permeable to the pro- teid molecules, or whether it is a more obscure and complicated process con- nected with the living activity of the cells, remains undetermined for the present. After the proteids have passed through the epithelium it is a matter of importance to determine whether they enter the blood or the lymph circulation. Experiments have shown conclusively that they are transmitted directly to the blood-capillaries: ligature of the thoracic duct, for example, which shuts oil' the entire lymph-How coming from the intes- tine, does not interfere with the absorption of proteids. There is one other fact of great significance in connection with this subject: the proteids are absorbed mainly, if not entirely, as proteoses and peptones, and they pass immediately into the blood ; nevertheless, examination of the blood directly after eating, while the process of absorption is in full activity, fails to show any peptones or proteoses in the blood. In fact, if these substances are injected directly into the blood, they behave as foreign, and even as toxic, bodies. In certain doses they produce insensibility with lowered blood- pressure, and they may bring on a condition of coma ending in death. Moreover, when present in the blood, even in small quantities, they are eliminated by the kidneys and are evidently unfit for the use of the tissues. It follows from these facts that while the peptones and proteoses arc being absorbed by the epithelial cells they arc at the same time changed into some other form of proteid. YVhal this change is has not been determined. Ex- periments have Bhown thai peptones disappear when brought into contact with fresh pieces of the lining mucous membrane of the intestine which are -till in a living condition. The statement has been made that the peptones and proteoses are converted to serum-albumin, or at least to a native albumin of some kind, but we have no definite knowledge beyond the fact that the peptones and proteoses, a- such, disappear. It is well to call attention to the CHEMISTRY OF DIGESTION AND NUTRITION. :U7 fact that the digestion of proteids is supposed, according to the schema already described, to consist in a process of hydration and splitting, with the forma- tion, probably, of smaller molecules. The reverse act of conversion of pep- tones hack to albumin implies, therefore, a process of dehydration and poly- merization that presumably takes place in the epithelial cells. It is at this point in the act of absorption of proteids that our knowledge ismosl deficient. Absorption of Sugars.— The carbohydrates are absorbed mainly in the form of sugar or of sugar and dextrin. Starches are converted in the intes- tine into maltose or maltose and dextrin, and then by the sugar-splitting enzymes of the mucous membrane are changed to dextrose. Ordinary cane- sugar is hydrolyzed into dextrose and levulose before absorption, and milk- sugar possibly undergoes a similar change to dextrose and galactose, though less is known of this. So far as our knowledge goes, then, we may say that the carbohydrates of our food are eventually absorbed in the form mainly of dextrose or of dextrose and levulose, leaving out of consideration, of course, the small part that normally undergoes bacterial fermentation. In accordance with this statement, we find that the sugar of the blood exists in the form of dextrose. It is apparently a form of sugar that can be oxidized very readily by the tissues. In fact, it has been shown that if cane-sugar is in- jected directly into the blood, it cannot be utilized, at least not readily, by the tissues, since it is eliminated in the urine; whereas if dextrose is intro- duced directly into the circulation, it is all consumed, provided it is not injected too rapidly. The sugars are soluble and dialyzable, but, as in the cn*r of peptones, exact study of their absorption shows that it does not fellow in detail the known laws of osmosis through dead membranes. Experiments indicate, however, that in a general way the behavior of solutions of sugar placed in isolated loops of the intestine may be understood by assuming that a diffusion takes place, and it may be therefore that the peculiarities observed are connected with the structure of the living epithelium. We have to deal here, in fact, with the same difficulty as was encountered in the case of the proteids. A special vital activity of the epithelial cells ciinnot be excluded, and we must be content to await a fuller development of experimental inves- tigation before attempting to come to a final conclusion. As in the case of the proteids, the absorbed sugars — dextrose or dextrose and levulose — pass directly into the blood, and do not under normal conditions enter the lymph- vessels. This has been demonstrated by direct examination of the blood of the portal vein during digestion (von Mering 1 ), a distinct increase in its sugar-contents being found. Examination of the lvmph shows no increase in sugar unless excessive amounts of carbohydrates have been eaten (Ileiden- hain). Absorption of Fats. — As has been stated, fats are absorbed either in solid form, as emulsified droplets, or as fatty acids or soaps. In the latter case the fatty acids are again recombined tit particles of neutral fat, pre- sumably within the substance of the epithelial cells. So far as the emulsified fat 1 Dn Bois-Reymond's Archivfur Analomit uml Physiologie, 1^77, S. II.",. 318 AN AMERICAN TEXT- HOOK OF PHYSIOLOGY. i- concerned, the process of absorption must be of a mechanical nature. The details of the process have been worked ouf microscopically and have given rise to numerous researches. It is unnecessary to speak of the various theories that have been held, as it has been shown by nearly all the recent work that the immediate agent in the absorption of fats is again the epi- thelial cells of the villi of the small intestine. The fat-droplets may be seen within these cells, and can be studied microscopically alter digestion in the act of passing, or rather of being passed, through the cell-substance. Reference to the histology of the villi will show that each villus possesses a comparatively large lymphatic capillary lying in its middle and ending blindly, apparently, near the apex of the villus. Between this central lym- phatic — or lacteal, as it is called here — and the epithelium lies the stroma, or main substance of the villus, which, in addition to its blood-capillaries and plain muscle-fibres, consists mainly of lymphoid or adenoid tissue containing numerous leucocytes. The fat-droplets have to pass from the epithelium to the central lymphatic, for it is one of the most certain facts in absorption, and one which has been long known, that the fat absorbed gets eventually into the iacteals in an emulsified condition and thence is conveyed through the svstem of lymphatic vessels to the thoracic duct and finally to the blood. The name " lacteal," in fact, is given to the lymphatic capillaries of the villus on account of the milky appearance of their contents, after meals, caused by the emulsified fat. It should be added, however, that it has not been possible to demonstrate experimentally that all the absorbed fat passes into the thoracic duct. Attempts have been made to collect all the fat passing through the thoracic duct after a meal containing a known quantity of fat, but even after making allowance for the unabsorbed fat in the feces there is a considerable percentage of the fat absorbed that cannot be recovered from the lymph of the thoracic duct. While this result does not invalidate the conclusion stated above that the fat passes chiefly, perhaps entirely, into the Iacteals, it does indicate that there arc some factors concerned in the process of fat- absorption that are at present unknown to us. The passage of the fat- droplets to the central lacteal is not difficult to understand. The adenoid tissue of the stroma is penetrated by minute unformed lymph-channels that are doubtless connected with the central lacteal. In each villus lymph is continually formed from the circulating blood, so that there must be a slow stream of lymph through the stroma to the lacteal. When the fat-droplets have passed through the epithelial cells (and basement membrane) they drop into the interstices of the adenoid tissue and are carried in this stream into the lacteal. The Iacteals were formerly designated as the "absorbents," under the false impression that they attended to all the absorption going on in the intestines, including that of peptones, sugars, and fats. It is now known that their action under ordinary conditions is limited to the absorption of fats. Absorption of "Water and Salts. — From what has been said (p. 312) it is evident that absorption of water takes place very slightly, if at all, in the -o.inael). Whenever soluble substances, such as peptones, sugars, or salts, are CHEMISTRY OF DIGESTION AND NUTRITION. 319 absorbed in this organ, a certain amount of water must go with them, but the bulk of the water passes out of the pylorus. In the small intestine absorp- tion of water and of inorganic salts evidently takes place readily,and accord- ing to the experiments of Kohmann and lleideuhaiu, already referred to, the laws governing their absorption are different from what we should expect at first sight if the process were simply one of diffusion. The differences as regards the absorption of salts are especially emphasized by the experiments of Heidenhain. 1 Making use of an interesting method, for which reference must be made to the original paper, Heidenhain has shown that not only dilute solutions, but solutions of nearly the same osmotic pressure as the blood were readily absorbed. Indeed, specimens of the animal's own serum introduced into a loop of the intestine were completely absorbed, although in this case there was practically no difference in composition between the liquid in the intestine and the blood of the animal. In another paper by Heiden- hain 2 he has proved that the absorption of water in the small intestine, when ordinary amounts are ingested, takes place entirely through the blood-vessels of the villus, and not through the lacteals; when larger quantities of water are swallowed, a small part may be absorbed through the lacteals, as shown by the increased lymph-flow, but by far the larger quantity is taken up directly by the blood. In the large intestine the contents become progressively more solid as thev approach the rectum ; the absorption of w r ater is such that the stream is mainly from the intestinal contents to the blood, giving us a phenomenon somewhat similar to the absorption of water by the roots of a plant. This process is difficult to understand upon the supposition that it is caused by osmosis, using that term in its ordinary sense, unless we assume that it is due entirely to the osmotic pressure of the indiffusible proteids of" the blood as explained on p. 69. Composition of the Feces. — The feces differ widely in amount and in composition with the character of the food. Upon a diet comp< ^>v<\ exclu- sively of meats they are small in amount and dark in color; with an ordinary mixed diet the amount is increased, and it is largest with an exclusively vege- table diet, especially with vegetables containing a large amount of indigest- ible material. The average weight of the feces in twenty-four hours upon a mixed diet is given as 170 grains, while with a Vegetable diet it may amount to as much as 400 or 500 grams. The quantitative composition, therefore, will vary greatly with the diet. Qualitatively, we find in the \'wv^ the following things: (1) Indigestible material, such as ligaments of meat or cellulose from vegetables. (2) Undigested material, such as fragments of meat, starch, or fats which have in some way escaped digestion. Naturally, the quantity of this material present is slight under normal conditions. Some fats, however, are almost always found in feces, either as neutral fats or as fatty acids, and to a small extent as calcium or magnesium soaps. The quantity of fat found is 1 Pfliiger'a Archiv fur die gesammle Physiologic, 18{»4, Bd. '>*'<, S. 579. 2 Ibid., 1888, Bd. 43, supplement. 320 AN AMERICAN TEXT- HOOK OE PHYSIOLOGY. increased by an increase of the fats in the fond. (3) Products of the intes- tinal secretions. Evidence lias accumulated in recent years 1 to show that the l'rcv> in man on an average diet arc composed mainly of the material of the intestinal secretions. The nitrogen of the feces, formerly supposed to represent undigested food, seems rather to have its origin in these secretions, and, therefore, like tin- nitrogen of the urine represents so much metabolism in the body. (4) Products of bacterial decomposition. The most character- istic of these products arc indol and skatol. These two substances are formed normally in the large intestine from the putrefaction of proteid material. They occur always together. Indol has the formula CJLX, and skatol, which is a methyl indol. the formula Cdf.X. They are crystal- line bodies possessing a disagreeable fecal odor; this is epecially true of skatol, to which the odor of the i'vfc< is mainly due. Indol and skatol are eliminated from the body only in part in the feces; a certain propor- tion of each is absorbed into the blood and is eliminated in a modified form through the urine — indol as indican (indoxyl-sulphuricacid), from which indigo was formerly made, and skatol as skatoxyl-sulphuric acid (see Chemical section for further information as to the chemistry of these bodies). (5) Cholesteriu, which is found always in small amounts and is probably derived from the bile. (0) Excretin, a crystallizable, non-nitrogenous substance to which the formula C 78 H 156 S0 2 has been assigned, is found in minute quantities. (7) Mucus and epithelial cells thrown off from the intestinal wall. (8) Pigment. In addition to the color due to the undigested food or to the metallic compounds contained in it, there is normally present in the feces a pigment, hydrobilirubin, derived from the pigments (bilirubin) of the bile. Hydrobilirubin is formed from the bilirubin by reduction in the large intestine. (9) Inorganic salts — salts of sodium, potassium, calcium, magnesium, and iron. The importance of the calcium anil iron salts will be referred to in a subsequent chapter, when speaking of their nutritive importance. (10) Micro-organisms. Great quantities of bacteria of different kinds are found in the W'cv^. In addition to the feces, there is found often in the large intestine a quantity of gas that may also be eliminated through the rectum. This gas varies in composition. The following constituents have been determined to occur at one time or another: CH 4 , CO,, H, X, H 2 S. They arise mainly from the bacterial fermentation of the proteids, although some of the N may be derived from air swallowed with the food. F. Physiology of the Liver and the Spleen. The liver plays an important part in the general nutrition of the body; its functions are manifold, but in the long run they depend upon the properties of the liver-cell, which constitutes the anatomical and physiological unit of the organ. These cells arc seemingly uniform in structure throughout the whole Bubstance of the liver, but to understand clearly the different functions they fulfil one must have a clear idea of their anatomical relations to one another 1 See Prausnitz: Zeit&chrift fur Biologie, 1897, Bd. 35, S. 335; and Tsuboi : Ibid., S. 08. CHEMISTRY OF DIGESTION AND NUTRITION. 321 and to the blood-vessels, the lymphatics, and the bile-ducts. The histology of the liver Lobule, and the relationship of the portal vein, the hepatic artery, and the bile-duct to the lobule, must be obtained from the text-books upon histol- ogy and anatomy. It is sufficient here to recall the fact that each lobule is supplied with blood coming in part from the portal vein and in part from the hepatic artery. The blood from the former source contains the soluble prod- ucts absorbed from the alimentary canal, such as sugar and proteid, and these absorbed products are submitted to the metabolic activity of the liver-cells before reaching the general circulation. The hepatic artery brings to the liver- cells the arterialized blood sent out into the systemic circulation from the left ventricle. In addition, each lobule gives origin to the bile-capillaries which arise between the separate cells and which carry off* the bile formed within the cells. In accordance with these facts, the physiology of the liver-cell falls naturally into two parts — one treating of the formation, composition, and physi- ological significance of bile, and the other dealing with the metabolic changes produced in the mixed blood of the portal vein and the hepatic artery as it flows through the lobules. In this latter division the main phenomena to be studied are the formation of urea and the formation and significance of glycogen. Bile. — From a physiological standpoint, bile is partly an excretion carrying off" certain waste products, and partly a digestive secretion playing an import- ant role in the absorption of fats, and possibly in other ways. Bile is a con- tinuous secretion, but in animals possessing a gall-bladder its ejection into the duodenum is intermittent. For the details of the mechanism of its secretion, its dependence on nerve- and blood-supply, etc., the reader is referred to the section on Secretion. Bile is easily obtained from living animals by establishing a fistula of the bile-duct or, as seems preferable, of the gall-bladder. The latter operation has been performed a number of times on human beings. In some cases the entire supply of bile has been diverted in this way to the ex- terior, and it is an interesting physiological fact that such patients may con- tinue to enjoy fair health, showing that, whatever part the bile takes normally in digestion and absorption, its passage into the intestine is not absolutely necessary to the nutrition of the body. The quantity of bile secreted during the day has been estimated for human beings of average weight (43 to 73 kilo- grams) as varying between ;j<>»> and 800 cubic centimeters. This estimate is based upon observations on cases of biliary fistula. 1 Chemical analyses of the bile show that, in addition to the water and salts, it contains bile-pigments, bile-acids, cholesterin, lecithin, neutral fats and soaps, sometimes a trace of urea, and a mucilaginous nueleo-albumin formerly designated improperly as mucin. The last-mentioned substance is not formed in the liver-cells, but is added to the bile by the mucous membrane of the bile-ducts and gall-bladder. The quantity of these substances present in the bile must vary greatly in different animals and under different conditions. As an illustration of their relative 1 Copeman and Winston: Journal of Physiology, 1889, vol. x. p. 213; Robson : Proceedings of the Royal Society, Loudon, L890, vol. 17, p. 499; Pfaff and Balch Journalof Experimental Medicine, L897, vol. ii. p. 49. Vol. t. 21 322 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. importance in human bile and of the limits of variation the two following analyses by Hammarsten J may be quoted : i. 11. Solids 2.520 2.840 Water 97.480 97.160 Mucin and pigment 0.529 0.910 Bile-salts 0.931 0.814 Taurocholate 0.3034 0.053 Glycocholate 0.6276 0.761 Fatty acids from soap 0.1230 0.024 Cbolesterin 0.0630 0.096 Lecithin Fat Soluble salts 0.8070 0.8051 Insoluble salts 0.0250 0.0411 } 0.0220 0.1286 The color of bile varies in different animals according to the preponderance of one or the other of the main bile-pigments, bilirubin and bUiverdin. The 6ile of carnivorous animals has usually a bright golden color, owing to the pres- ence of bilirubin, while that of the herbivora is a bright green from the biliverdin. The color of human bile seems to vary : according to some author- ities, it is yellow or brownish yellow, and this seems especially true of the bile as found in the gall-bladder of the cadaver ; according to others, it is of a dark- olive color with the greenish tint predominating. Its reaction is feebly alka- line, and its specific gravity varies in human bile from 1050 or 1040 to 1010. 1 1 u n iau bile does not give a distinctive absorption spectrum, but the bile of some herbivora, after exposure to the air at least, gives a characteristic spectrum. The individual constituents of the bile will now be described more in detail, but with reference mainly to their origin, fate, and function in the body. For a description of their strictly chemical properties and reactions reference must be made to the Chemical section. Bile-pigments. — Bile, according to the animal from which it is obtained, contains one or the other, or a mixture, of the two pigments bilirubin and biliverdin. Biliverdin is supposed to stand to bilirubin in the relation of an oxidation product. Bilirubin is given the formula Ci 6 H 18 N 2 3 , and biliverdin (',, H^X/) 4 , the latter being prepared readily from pure specimens of the former by oxidation. These pigments give a characteristic reaction, known as"Gmelin's reaction," with nitric acid containing some nitrous acid (nitric acid with a yellow color). If a drop of bile and a drop of nitric acid are brought into contact, the former undergoes a succession of color changes, the order being green, blue, violet, red, and reddish yellow. The play of colors is due to successive oxidations of the bile-pigments; starting with bilirubin, the first stage (green) is due to the formation of biliverdin. The pigments firmed in some of the other stages have been isolated and named. The reaction is very delicate, and it is often used to detect the presence of bile- pigments in other liquids — urine, for example. The bile-pigments originate i Reported in Gentralblati fur Physiologic, 1894, No. v . CHEMISTRY OF DIGESTION AND NUTRITION. 323 from haemoglobin. This origin was first indicated by the fact that in old blood-clots or in extravasations there was found a crystalline product, the so-called " haematoidin," which was undoubtedly derived from haemoglobin, and which upon more careful examination was proved to be identical with bilirubin. This origin, which has since been made probable by other reac- tions, is now universally accepted. It is supposed that when the blood- corpuscles go to pieces in the circulation (p. 45) the haemoglobin is brought to the liver, and then, under the influence of the liver-cells, is converted t<> an iron-free compound, bilirubin or biliverdin. It is very significant to find that the iron separated by this means from the haemoglobin is for the most part retained in the liver, a small portion only being secreted in the bile. It seems probable that the iron held back in the liver is again used in some way to make new haemoglobin in the haematopoietic organs. The bile-pigments are carried in the bile to the duodenum and are mixed with the food in its long passage through the intestine. Under normal conditions neither bilirubin nor biliverdin is found in the feces, but in their place is found a reduction pro- duct, hydrobilirubin, formed in the large intestine. Moreover, it is believed that some of the bile-pigment is reabsorbed as it passes along the intestine, is carried to the liver in the portal blood, and is again eliminated. That this action occurs, or may occur, has been made probable by experiments "I Wertheimer l on dogs. It happens that sheep's bile contains a pigment (cholohsematin) that gives a characteristic spectrum. II' some of this pig- ment is injected into the mesenteric veins of a dog, it is eliminated while passing through the liver, and can be recognized unchanged in the bile. The value of this "circulation of the bile," so far as the pigments are con- cerned, is not apparent. Bile-acids. — "Bile-acids" is the name given to two organic acids, glyco- eholic and taurocholic, which are always present in bile, and, indeed, form very important constituents of that secretion ; they occur in the form of their respective sodium salts. In human bile both acids are usually found, but the proportion of taurocholate is variable, and in some cases this latter acid may be absent altogether. Among herbivora the glyeocholate predominates as a ride, although there are some exceptions ; among the carnivora, on the other hand, taurocholate occurs usually in greater quantities, and i'i the dog's bile it is present alone. Glycoeholic acid has the formula ( ' J . |;! N( >,.,, and taurocholic acid has the formula CoJI^NSOj. Each of them can be obtained in the form of crystals.' When boiled with acids or alkalies these acids take up water and undergo hydrolytic cleavage, the reaction being represented by the following equations: c 2S h 43 no 6 + h 2 o = C 24 H 40 O, + ch 2 (NH 2 )COOH. Glycoeholic acid. Cfaolic acid. Glycocoll (amido-acetic add). C 26 H 45 NS0 7 + H 2 34 H 4() O, + fVH.XIl ,S( )...( )U feurocholic acid. Cholicacid. Taurin (amido-ethyl Bulphonic acid 1 Archives de Physiologie normale ei paihologique, 1892, p. 577. •°,24 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Tlnse reactions are interesting not only in that they throw light on the structure of the acids, but also because similar reactions doubtless take place in the intes- tine, cholic acid having been detected in the intestinal contents. As the for- mulas show, cholic acid is formed in the decomposition of each acid, and we may regard the bile-acids as compounds produced by the synthetic union of cholic acid with glycocoll in the one case and with taurin in the other. Cholic acid or its compounds, the bile-acids, are usually detected in suspected liquids by the well-known Pettenkofer reaction. As usually performed, the test is made by adding to the liquid a few drops of a 10 per cent, solution of cane-sugar and then strong sulphuric acid. The latter must be added carefully and the temperature be kept below 70° C. If bile-acids arc present, the liquid assumes a beautiful red-violet color. It is now known that the reaction con- sists in the formation of a substance (furfurol) by the action of the acid on sugar, which then reacts with the bile-acids. The bile-acids are formed directly in the liver-cells. This fact, which was for a long time the subject of discussion, has been demonstrated in recent years by an important series of researches made upon birds. It has been shown that if the bile-duct is ligated in these animals, the bile formed is reabsorbed and bile-acids and pigments may be detected in the urine and the blood. If, however, the liver is com- pletely extirpated, then no trace of either bile-acids or bile-pigments can be found in the blood or the urine, showing that these substances are not formed elsewhere in the body than in the liver. It is more difficult to ascer- tain from what substances they arc formed. The fact that glycocoll and taurin contain nitrogen, and that the latter contains sulphur, indicates that some proteid or albuminoid constituent is broken down during their pro- duction. A circumstance of considerable physiological significance is that these acids or their decomposition products are absorbed in part from the intestine and are again secreted by the liver: as in the case of the pigments, there is an intestinal-hepatic circulation. The value of this reabsorption may lie in the fact that the bile-acids constitute a very efficient stimulus to the bile-secreting activity of the cells, being one of the best of cholagogues, or it may be that it economizes material. From what we know of the history of the bile-acids it is evident that they are not to be considered as excreta: they have some important function to fulfil. The following suggestions as to their value have been made: In the first place, they serve as a menstruum for dissolving the cholesterin which is constantly preseut in the bile and which is an excretion to be removed ; secondly, they facilitate the absorption of fats from the intes- tine. The value of bile in fat -absorption will presently be referred to more in detail. It is an undoubted fact that when bile is shut off from the intes- tine the absorption of fats is very much diminished, and it has been shown that this action of the bile in fat absorption is owing to the presence of the bile-acids. Cholesterin. — Cholesterin is a non-nitrogenous substance of the formula C 26 H 44 G or CyE^OH). It is a constant constituent of the bile, although it CHEMISTRY OF DIGESTION AND NUTRITION. 325 occurs in variable quantities. Cholesterin is very widely distributed in the body, being found especially in the white matter (medullary substance) of nerve-fibres. It seems, moreover, to be a constant constituent of all animal and plant cells. It is assumed that cholesterin is not formed in the liver, but that it is eliminated by the liver-cells from the blood, which collects it from the various tissues of the body. That it is an excretion is indicated by the fact that it is eliminated unchanged in the feces. Cholesterin is insoluble in water or in dilute saline liquids, and is held in solution in the bile by means of the bile-acids. We must regard it as a waste product of cell-life, formed probably in minute quantities, and excreted mainly through the liver. It is partly eliminated through the skin, in the sebaceous and sweat secretions, and in the milk. Lecithin, Fats, and. Nucleo-albumin. — Lecithin also seems to be present, generally in small quantities, in the cells of the various tissues, but it occurs especially in the white matter of nerve-fibres. It is probable, therefore, that, so far as it is found in the bile, it represents a waste product formed in different parts of the body and eliminated through the bile. The special importance, if any, of the small proportion of fats and fatty acids in the bile is unknown. The ropy, mucilaginous character of bile is due to the presence of a body formed in the bile-ducts and gall-bladder. This substance was formerly designated as mucin, but it is now known that in ox-bile at least it is not a true mucin, but is a nucleo-albumin (see Chemical section). Ham- marsten reports that in human bile some true mucin is found. Outside the fact that it makes the bile viscous, this constituent is not known to possess any especial physiological significance. General Physiological Importance of Bile. — The physiological value of bile has been referred to in speaking of its several constituents, but it will be convenient here to restate these facts and to add a few remarks of general interest. Bile is of importance as an excretion in that it removes from the body waste products of metabolism, such as cholesterin, lecithin, and bile- pigments. With reference to the pigments, there is evidence to show that a part at least may be reabsorbed while passing through the intestine, and be used again in some way in the body. The bile-acids represent end-products of metabolism involving the proteids of the liver-cells, but they are undoubt- edly reabsorbed in part, and cannot be regarded merely as excreta. As a digestive secretion the most important function attributed to the bile is the part it takes in the digestion of fits. Tn the first place, it aids in the splitting of a part of the neutral fats and the subsequent emulsification of the re- mainder (p. 307). More than this, bile aids materially in the absorption of the digested fats. A number of observers have shown that when a permanent biliary fistula is made, and the bile is thus prevented from reaching the intes- tinal canal, a large proportion of the flit of the food escapes absorption and is found in the \\'t-vs. This property of the bile IS known to depend upon the bile-acids it contains, but how they act is not clearly understood. It was formerly believed, on the basis of some experiments by von Westinghausen, 326 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. that the bile-acids dissolve or mix with the fats and at the same time moisten the mucous membrane, and for these reasons aid in bringing the fat into immediate contact with the epithelial cells. It was stated, for instance, that oil rises higher in capillary tubes moistened with bile than in similar tubes moistened with water, and that oil will filter more readily through paper moistened with bile than through paper wet with water. Groper, 1 who repeated these experiments, finds that they are erroneous. It seems certain, however, that the bile-aeids enable the bile to hold in solution a considerable quantity of fatty acids, and possibly this fact explains its connection with fat absorption. It was formerly believed that bile is also of great importance in restraining- the processes of putrefaction in the intestine. It was asserted that bile is an efficient antiseptic, and that this property comes into use normally in preventing excessive putre- faction. Bacteriological experiments made by a number of observers have shown, however, that bile itself has very feeble antiseptic properties, as is indicated by the fact that it putrefies readily. The free bile-aeids and cholalic acid do have a direct retarding effect upon putrefactions outside the body ; but this action is not very pronounced, and has not been demonstrated satis- factorily for bile itself. It seems to be generally true that in cases of biliary fistula the feces have a very fetid odor when meat and fat are taken in the food. But the increased putrefaction in these cases may possibly be due to some indirect result of the withdrawal of bile. It has been suggested, for instance, that the deficient absorption of fat that follows upon the removal of the bile results in the proteid and carbohydrate material becoming coated with an insoluble layer of fat, so that the penetration of the digestive enzymes is retarded and greater opportunity is given for the action of bacteria. We may conclude, therefore, that while there does not seem to be sufficient warrant at present for believing that the bile exerts a direct antiseptic action upon the intestinal contents, nevertheless its presence limits in some way the extent of putrefaction. Lastly, bile takes a direct part in suspending or destroying peptic digestion in the acid chyme forced from the stomach into the duodenum. The chyme meeting with bile and pancreatic juice is neutralized or is made alkaline, which alone would prevent further peptonization. Moreover, when chyme and bile are mixed a precipitate occurs, consisting partly of proteids (proteoses and syntonin) and partly of bile-acids. It is probable that pepsin, according to its well-known property, is thrown down in this flocculent pre- cipitate and, as it were, prepared for its destruction. Glycogen. — One of the most important functions of the liver is the for- mation of glycogen. This substance was found in the liver in 1857 by Claude Bernard, and is one of several brilliant discoveries made by him. Glycogen has the formula (C 6 H 10 O 5 ) n , which is also the general formula given to vegetable starch; glycogen is therefore frequently spoken of as "animal starch." It gives, however, a port-wine-red color with iodine solutions, instead of the familiar deep blue of vegetable starch, and this reaction serves to detect glyco- 1 Arrhiv fur Anatomie wnd Physiologic ("Physiol. Abtlieilung"), 1889, S. 505. CHEMISTRY OF DIGESTION AND NUTRITION. 327 gen not only in its solutions, but also in the liver-cells. Glycogen is readily soluble in water, and the solutions have a characteristic opalescent appearance. Like starch, glycogen is acted upon by ptyalin and araylopsin, and the end- products are apparently the sam< — namely, maltose, or maltose and some dextrin. For a more complete account of the chemical relations of glycogen reference must be made to the Chemical section. Occurrence of Glycogen in the Liver. — Glycogen can be detected in the liver-cells microscopically. It' the liver of a dog is removed twelve or fourteen hours after a hearty meal, hardened in alcohol, and sectioned, the liver-cells will be found to contain clumps of clear material which give the iodine reaction for glycogen. Even when distinct aggregations of the glycogen cannot be made out, its presence in the cells is shown by the red reaction with iodine. By this simple method one can demonstrate the important fact that the amount of glycogen in the liver increases after meals and decreases again during the fasting hours, and if the fast is sufficieutly prolonged it may dis- appear altogether. This fact is, however, shown more satisfactorily by quanti- tative determinations, by chemical means, of the total glycogen present. The amount of glycogen present in the liver is quite variable, being influenced by such conditions as the character and amount of the food, muscular exercise, bodv-temperature, drugs, etc. From determinations made upon various animals it may be said that the average amount lies between 1.5 and 4 per cent, of the weight of the liver. But this amount may be increased great ly bv feeding upon a diet largely made up of carbohydrates. It is said that in the dog the total amount of liver-glycogen may be raised to 17 per cent., and in the rabbit to 27 per cent., by this means, while it is estimated for man (Xeumeister) that the quantity may be increased to at least 10 per cent. It is usually believed that glycogen exists as such in the liver-cells, being depos- ited in the substance of the cytoplasm. Reasons have been brought forward recently to show that possibly this is not strictly true, but that the glycogen is held in some sort of weak chemical combination. It has been shown, for instance, that although glycogen is easily soluble in cold water, it cannot be extracted readily from the liver-cells by this agent. One musl use hoi water, salts of the heavy metals, and other similar means that may be supposed to break up the combination in which the glycogen exists. For practical purposes, however, we may speak of the glycogen as lying free in the liver-cells, jusl as we speak of haemoglobin existing as such in the red corpuscles, although it is probably held in some sort of combination. Origin of Glycogen. — To understand clearly the views held as to the origin of liver glycogen, it will be necessary to describe briefly the effect of the different food-stulf- upon its formation. Effect of Carbohydrates <>n the Amount of Glycogen. — The amount of glycogen in the liver is affected very quickly by the quantity of carbohydrates in the food. It' the carbohydrates are given in exec--, the supply of glycogen maybe increased largely beyond the average amount present, as ha- been stated above. Investigation of the different sugars has shown that dextrose, levulose, 328 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. saccharose (cane-sugar), and maltose arc unquestionably direct glycogen-formers, that i-. that glycogen is formed directly from them or from the products into which they are converted during digestion. Now, our studies in digestion have shown that the starches are converted into maltose, or maltose and dextrin, during digestion, and, further, that these substances are changed or inverted to the simpler sugar dextrose during absorption. ( lane-sugar, which forms such an important part of our diet, is inverted in the intestine into dextrose and levulose, ami is absorbed in these forms. It is evident, therefore, that the hulk of our carbohydrate food reaches the liver as dextrose, or as dextrose and levulose, and these forms of sugar must he converted into glycogen in the liver-cells by a process of dehydration such as may he represented in substance by the formula < ',1 1 ,.,<),- II, () = C 6 H 1() O v There is no doubt that both dextrose and levulose increase markedly the amount of glycogen in the liver ; and, since cane-sugar is inverted in the intestine before absorption, it also must he a good glycogen-former — a fact that has been abundantly demonstrated by direct experiment. Lusk ' has shown, however, that if cane-sugar is in- jected under the skin, it has a very feeble effect in the way of increasing the amount of glycogen in the liver, since under these conditions it is probably absorbed into the blood without undergoing inversion. Experiments with sub- cutaneous injection of lactose gave similar results, and it is generally believed that the liver-cells cannot convert the double sugars to glycogen, at least not readily; hence the value of the hydrolysis of these sugars in the alimentary canal before absorption. The relations of lactose to glycogen-formation have not been determined satisfactorily. If it contributes at all to the direct forma- tion of glycogen, it is certainly less efficient than dextrose, levulose, or cane- sugar. When the proportion of lactose in the diet is much increased, it quickly begins to appear in the urine, showing that the limit of its consumption in the body is soon reached. This latter fact is somewhat singular, since in infancy especially milk-sugar forms a constant and important item of our diet, and one would suppose that it is especially adapted to the needs of the body. Effect of Proteids <>n Glyeogen-formaiion. — It was pointed out by Bernard, in his first studies upon glycogen-formation, that the liver can produce glycogen from proteid food. This conclusion has since been verified by more exact investigations. When an animal is fed upon a diet of proteid alone, or on proteid and gelatin, the carbohydrates being entirely excluded, glycogen is still formed in the liver, although in smaller amounts than in the case of carbohy- drate foods. This is an important fact to remember in studying the metabo- lism of the proteids in the body, for, as glycogen is a carbohydrate and con- tains no nitrogen, it implies that the proteid molecule is dissociated into a nitrogenous and a non-nitrogenous part, the latter being converted to glycogen by the liver-cells. The possibility of the production of glycogen from proteids accord- with a well-known fact in medical practice with reference to the path- ological condition known as diabetes. In this disease sugar is excreted in the urine, sometime-; in large quantities. As the sugar of the blood is believed 1 Voit: Zeitachrift fur Biologie, 1891, xxviii. B. 285. CHEMISTRY OF DIGESTION AND NUTRITION. 329 to be formed ordinarily from the carbohydrates in the food, it was thought that by excluding this food-stuff from the diet the excretion of sugar might be prevented. It has been found, however, that in severe eases at least sugar continues to be present in the urine even upon a pure proteid diet. If we suppose that some of the proteid goes to form glycogen, the result ob- served is explained, for the glycogen, as will be explained presently, is finally converted to sugar and is given oft' to the blood. An interesting additional fact that points to the same conclusion is that the percentage of sugar in the blood remains practically constant after prolonged starvation, at a time when the animal is living at the expense of the proteids and fats of its own body. Effect of Fats and other Substances upon Glyeogen-formatwn. — It has been found that fats take no part in the formation of liver glycogen. Some attempts have been made to prove that fat in the body, and particularly in the liver, may be converted to sugar, but the evidence at present seems to be against this possibility. 1 The Function of Glycogen : Glycogenic Theory. — The meaning of the formation of glycogen in the liver has been, and still is, the subject of discus- sion. The view advanced first by Bernard is perhaps most generally accepted. According to Bernard, glycogen forms a temporary reserve supply of carbo- hydrate material that is laid up in the liver during digestion and is gradually made use of in the intervals between meals. During digestion the carbohy- drate food is absorbed into the blood of the portal system as dextrose or as dextrose and levulose. If these passed through the liver unchanged, the con- tents of the systemic blood in sugar would be increased perceptibly. It is now known that when the percentage of sugar in the blood rises above a certain low limit, the excess will be excreted through the kidney and will be lost. But as the blood from the digestive organs passes through the liver the ex- cess of sugar is abstracted from the blood by the liver-cells, is dehydrated to make glycogen, and is retained in the cells in this form for a short period. From time to time the glycogen is reconverted into sugar (dextrose) and is given off to the blood. By this means the percentage of sugar in the systemic blood is kept nearly constant (0.1 to 0.2 per cent.) and within limits best adapted for the use of the tissues. The great importance of the formation of glycogen and the consequent conservation of the sugar-supply of the tissues will be more evident when we come to consider the nutritive value of carbohydrate food. Carbohydrates form the bulk of our usual diet, and the proper regula- tion of the supply to the tissues is therefore of vital importance in the main- tenance of a normal healthy condition. The second part of this theory, which holds that the glycogen is reconverted to dextrose, is supported by observations Upon livers removed from the body. It has been found that shortly after the removal of the liver the supply of glycogen begins t<> disappear and a corre- sponding increase in dextrose occurs. Within a comparatively short time all the glycogen is gone and only dextrose is found. It is for this reason that in 1 Kumagawa ami Miura: Arehiv fur Anatomie und Physiologie ("Physiol. Abtheilung"), 1 s'. is, s. 431, contains also reference to the literature of the subject. 330 AN AMERICAN TEXT-BOOK OE PHYSIOLOGY. the estimation of glycogen in the liver it is necessary to mince the organ and to throw it into boiling water as quickly as possible, since by this means the liver- eel].- are killed and the conversion of the glycogen is stopped. How the glycogen is changed to dextrose by the liver is a matter not fully explained. According to some authors, the conversion is due to an enzyme produced in the liver. Extracts of liver, as of some other tissues, do yield an anxiolytic enzyme that changes glycogen to dextrose. 1 It is possible, therefore, that the conversion of glycogen to dextrose is effected by a special enzyme produced in the liver-cells. In this description of the origin and meaning of the liver glycogen reference has been made only to the glycogen derived directly from digested carbohydrates. The glycogen derived from proteid foods, once it is formed in the liver, has, of course, the same functions to fulfil. It is converted into sugar, and eventually is oxidized in the tissues. For the sake of completeness it may be well to add that some of the sugar of the blood firmed from the glycogen may under certain conditions be converted into fat in the adipose tissues, instead of being burnt, and in this way it may be retained in the body as a reserve supply of food of a more stable character than is the glycogen. Glycogen in the Muscles and other Tissues. — The history of glycogen is not complete without some reference to its occurrence in the muscles. Glycogen is, in fact, found iu various places in the body, and is widely distributed through- out the animal kingdom. It occurs, for example, in leucocytes, in the placenta, in the rapidly-growing tissues of the embryo, and in considerable abundance in the oyster and other molluscs. But in our bodies and in those of the mam- mals generally the most significant occurrence of glycogen, outside the liver, is in the voluntary muscles, of which glycogen forms a normal constituent. It has been estimated that the percentage of glycogen in resting muscle varies from 0.5 to 0.9 per cent., and that in the musculature of the whole body there may be contained an amount of glycogen equal to that in the liver itself. Apparently muscular tissue, as well as liver-tissue, has a glycogenetie func- tion — that is, it is capable of laving up a supply of glycogen from the sugar brought to it by the blood. The glycogenetie function of muscle has been demonstrated directly by Kulz,- who has shown that an isolated muscle irrigated with an artificial supply of blood to which dextrose had been added is capable of changing the dextrose to glycogen, as shown by the increase in the latter sub- stance in the muscle after irrigation. Muscle glycogen is to be looked upon, probably, for reasons to be mentioned in the next paragraph, as a temporary and local reserve supply of material, 80 that, while we have in the liver a large general depot for the temporary storage of glycogen for the use of the body at large, the muscular tissue, which is the most active tissue of the body from a chemical standpoint, is also capable of laying up in the form of glycogen any excess of sugar brought to it. The fact that glycogen occurs so widely in the rapidly-growing tissues of embryos indicates that this glycogenetie func- tion may at times be exercised by any tissue. 1 Tebb: Journal <;/" Physiology, 1897 98, voL xxii. }>. 423. '- /..it. thrift fiir Biologic, 1890, 8. 237. CHEMISTRY OF DIGESTION AND NUTRITION. 33 J Conditions Affecting the Supply of Glycogen in Muscle and Liver. — In accordance with the view given above of the general value of glycogen — namely, that it is a temporary reserve supply of carbohydrate material that may be rapidly converted to sugar and oxidized with the liberation of energy — it is found that the supply of glycogen is greatly affected by conditions calling for increased metabolism in the body. Muscular exercise will quickly exhaust the supply of muscle and liver glycogen, provided it is not renewed by new food. In a starving animal glycogen will finally disappear, except perhaps in traces, but this disappearance will occur much sooner if the animal is made to use its muscles at the same time. It has been shown also by Morat and Dufourt that if a muscle has been made to contract vigorously, it will take up much more sugar from an artificial supply of blood sent through it than a similar muscle which has been resting; on the other hand, it has been found that if the nerve of one leg is cut so as to paralyze the muscles of that side of the body, the amount of glycogen will increase rapidly in these muscles as compared with those of the other leg, that have been contracting meantime and using up their glycogen. Formation of Urea in the Liver. — The nitrogen contained in the proteid material of our food is finally eliminated, after the metabolism of the proteid is completed, mainly in the form of urea. As will be explained in another part of this section, it has been definitively proved that the urea is not formed in the kidneys, the organs that eliminate it. It has long been considered a matter of the greatest importance to ascertain in what organ or tissues urea is formed. Investigations have gone so far as to demonstrate that it arises in part at least in the liver; hence the property of forming urea must be added to the other important functions of the liver-cell. Schroder 1 performed a number of experiments in which the liver was taken from a freshly-killed dog and irri- gated through its blood-vessels by a supply of blood obtained from another dog. If the supply of blood was taken from a fasting animal, then circulating it through the isolated liver was not accompanied by any increase in the amount of urea contained in it. If, on the contrary, the blood was obtained from a well-fed dog, the amount of urea contained in it was distinctly increased by passing it through the liver, thus indicating that the blood of an animal after digestion contains something that the liver can convert to urea. It is to be noted, moreover, that this power is not possessed by all the organs, since blood from well-fed animals showed no increase in urea after being circu- lated through an isolated kidney or muscle. As further proof of the area- forming power of the liver Schroder found that if ammonium carbonate was added to the blood circulating through the liver — to that from the fasting as well as from the well-nourished animal — a very decided increase in Hie urea always followed. It follows from the last experimenl that the liver-cells arc able to convert carbonate of ammonium into urea. The reaction may l»c ex- pressed by the equation (MI, ),('()— 2H a O= CON, II,. SchondorffMn some later work showed that if the Id 1 of a fasting dog is irrigated through 1 Archiv fur experimentelle Pathologie und Pharmakologie, Bde xv. and xix., L882 and 1885. 2 Pfliiger'a Archiv fur die gesammtc Pltysioloi/ir, is 1 .):!, |', ( |. 1 i v. S. 1'Jii. 332 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. the hind legs of a well-nourished animal, no increase in urea in the blood can be detected ; but if the blood, after irrigation through the hind legs, is subse- quently passed through the liver, a marked increase in urea results. Obviously, the blood in this experiment derives something from the tissues of the leg which the tissues themselves cannot convert to urea, but which the liver-cells can. Finally, in some remarkable experiments upon dogs made by four in- vestigators (Halm, Massen, Nencki, and Pawlow), which will be described briefly in the next section in connection with urea, it was shown that when the liver is practically destroyed there is a distinct diminution in the urea of the urine. In birds uric acid takes the place of urea as the main nitrogenous excretion of the body, and Minkowski has shown that in them removal of the liver is followed by an important diminution in the amount of uric acid excreted. From experiments such as these it is safe to conclude that urea is formed in the liver and is then given to the blood and excreted by the kidney. When we come to describe the physiological history of urea (p. 334 ), an account will be given of the views held with regard to the antecedent substance or substances from which the liver produces urea. Physiology of the Spleen. — Much has been said and written about the spleen, but we are yet in the dark as to the distinctive function or functions of this organ. The few facts that are known may be stated briefly without going into the details of theories that have been offered at one time or another. The older experimenters demonstrated that this organ may be removed from the body without serious injury to the animal. An increase in the size of the lymph-glands and of the bone-marrow has been stated to occur after extirpation ; but this is denied by others, and, whether true or not, it gives but little clue to the normal functions of the spleen. Laudenbach 1 finds that one result of the removal of the spleen is a marked diminution in the number of red corpuscles and the quantity of haemoglobin. He infers, therefore, that the spleen is normally concerned in some way in the formation of red corpuscles. These facts are significant, but they need, perhaps, further confirmation. The mosl definite facts known about the spleen are in connection with its move- ments. It has been shown that there is a slow expansion and contraction of the organ synchronous with the digestion periods. After a meal the spleen begins to increase in size, reaching a maximum at about the fifth hour, and then slowly returns to its previous size. This movement, the meaning of which is not known, i~ probably due to :i slow vaso-dilatation, together, perhaps, with! a relaxation of the tonic contraction of the musculature of the trabecular In addition to this slow movement, Roy 2 has shown that there is a rhythmic contraction and relaxation of the organ, occurring in cats and dogs at intervals of about one minute. Roy supposes that these contractions are effected through the intrinsic musculature of the organ — that is, the plain muscle-tissue present in the capsule and trabecules — and he believes that the contractions serve to keep up a circulation through the spleen and to make it< vascular supply more 1 Centralblatt fiir Physiologie, 1895, Bd. ix. S. 1. 2 Journal of I'lii/xinl,,,/*/, 1 SS 1 , vol. iii. p. 203. CHEMISTRY OF DIGESTION AND NUTRITION. 333 or less independent of variations in general arterial pressure. These observa- tions are valuable as indicating the importance of the spleen functions. The fact that there is a special local arrangement for maintaining its circulation makes the spleen unique among the organs of the body, but no light is thrown upon the nature of the function fulfilled. The spleen is supplied richly with nerve-fibres which when stimulated either directly or reflexly cause the organ to diminish in volume. According to Schaefer, 1 these fibres are contained in the splanchnic nerves, which carry also inhibitory fibres whose stimulation pro- duces a dilatation of the spleen. The chemical composition of the spleen is complicated but suggestive. Its mineral constituents are characterized by a large percentage of iron, which seems to be present as an organic compound of some kind. Analysis shows also the presence of a number of fatty acids, fats, cholesterin, and, what is perhaps more noteworthy, a number of nitrogenous extractives such as xanthin, hypoxanthin, adenin, guanin, and uric acid. The presence of these bodies seems to indicate that active metabolic changes of some kind occur in the spleen. As to the theories of the splenic functions, the following may be mentioned : (1) The spleen has been supposed to give rise to new red corpuscles. This it undoubtedly does during fetal life and shortly after birth, and in some animals throughout life, but there is no reliable evidence that the function is retained in adult life in man or in most of the mammals. (2) It has been supposed to be an organ for the destruction of red corpuscles. This view is founded partly on very unsatisfactory microscopic evidence according to which certain large amoeboid cells in the spleen ingest and destroy the old red corpus- cles, and partly upon the fact that the spleen-tissue seems to be rich in an iron- containing compound. This theory cannot be considered at present a- anything more than a suggestion. (3) It has been suggested that uric acid is pro- duced in the spleen. This substance is found in the spleen, as stated above, and it has been shown by Horbacewsky that the spleen contains a substance from which uric acid or xanthin may readily be formed ; but further investiga- tion lias shown that the same substance is found in lymphoid tissue generally. If, therefore, uric acid is produced in the spleen, it is a function of the large amount of lymphoid tissue contained in it, and a function which it shares with similar tissues in the rest of the body. The lymphoid tissue of the spleen must also possess the property of producing lymphocytes, since, according to the gen- eral view, these corpuscles are formed in lymphoid tissue generally wherever the so-called " germ-centres " occur. (4) Lastly, a theory has been supported by Schiff and Iler/.en, according to which the spleen produces something (an enzyme) which, when carried in the blood to the pancreas, acts upon the tryp- sinogen contained in this gland, converting it into trypsin. The experi- mental evidence upon which this view rests has not been confirmed l>v other observers. 1 Proceedings of tin- Royal s<,cii' Physiology. 1896, vol. xx. 334 AN AMERICAN TEXT-HOOK OF PHYSIOLOGY. G. The Kidney and the Skin as Excretory Organs. The secretion of the kidneys is the urine. The means by which this secretion is produced, it- relations to the histological structure of the kidney, and its con- nections with the blood- and nerve-supply of that organ \\ ill !><• found described in the section <>n Secretion. In this section will be discussed only the chemical composition of urine, and especially the physiological significance of itsdiffer- em constituents. Theurineof man isa yellowish liquid varying greatly in depth of color. It has an average specific gravity of 1020, and an acid reaction. The acid reaction is not due to a free acid, but is usually attributed to an acid salt, the acid phosphate of sodium (Xall.POj). Under certain normal conditions human urine may show a neutral or even a slightly alkaline reaction, especially after meals. In fact, the reaction ot* the urine seems to depend directly on the character of the food. Among carnivorous animals the urine is uniformly acid, and among herbivorous animals it is uniformly alkaline, so long as they are using a vegetable diet, hut when starving or wheu living upon the mother's milk — that is, whenever they are existing upon a purely animal diet — the urine becomes acid. The explanation, as given by Drechsel, is that upon an animal diet more acids are produced (from the sulphur and phosphorus) than the bases present can neutralize, whereas upon a vegetable diet carbonates are formed from the oxidation of the organic acids of the food in quantities sufficient to neutralize the mineral acids. The chemical composition of urine is very complex. Among the constituents constantly present under the conditions of normal life we have, in addition to water and inorganic salts, the following substances: Urea; uric acid; xanthin ; creatinin ; hippuric acid; the urinary pigments (urobilin); sulphocyanides in traces; acetone; oxalic acid, probably as calcium oxalate ; several ethereal sulphuric acids, such as phenol and cresol sulphuric acids, indoxyl sulphuric acid (indican), and skatoxvl sulphuric acid; aromatic oxy-acids ; some combinations of glycuronic acid ; some representa- tives of the fatty acids; and dissolved gases (X and C0 2 ). This list would be very much extended if it attempted to take in all those substances occasion- ally found in the urine. The complexity of the composition and the fact that so many different organic compounds occur or may occur in small quantities is readily understood when we consider the nature of the secretion. Through the kidneys there are eliminated not only what we might call the normal end- products of the metabolism of the tissues, excluding the C0 2 , but also, in large part, the products of decomposition in the alimentary canal, the end- products of many organic substances occurring in our foods and not usually classed a- food-stufls, foreign substances introduced as drugs, etc., all of which are eliminated either in the form in which they arc taken or as derivative products of some kind. "We shall speak briefly of the most important of the normal constituents, dwelling especially upon their origin in the body and their physiological significance. For details of chemical properties and reactions, reference musl be made to the Chemical section. Urea. — Urea, which is given the formula CH 4 N 2 0, is usually considered CHEMISTRY OF DIGESTION AND NUTRITION. 335 as an amide of carbonic acid, having therefore the structural formula of C0< y„- It occurs in the urine in relatively large quantities (2 per cent. -f-). As the total quantity of urine secreted in twenty-four hours by an adult male may he placed at from 1500 to 1700 cubic centimeters, it follows that from 30 to 34 grams of urea are eliminated from the body during this period It is the most important of the nitrogenous excreta of the body, the end-product of the physiological oxidation of the proteids of the body, and also of the albuminoids when they appear in the food. If we know how much urea is secreted in a given period, we know approximately how much proteid has been broken down in the body in the same time. In round numbers, 1 gram of proteid will yield \ gram of urea, as may be calculated easily from the amount of nitrogen contained in each. Since, however, some of the nitrogen of proteid is eliminated in other forms — uric acid, creatinin, etc. — even an exact determination of all the urea would not be sufficient to determine with accuracy the total amount of proteid broken down. This fact is arrived at more perfectly, as we shall explain later, by a determination of the total nitrogen of the urine and other excretions. In addition to the urine, urea is found in slight quantities in other secretions, in milk (in traces), and in sweat. In the latter liquid the quantity of urea in twenty-four hours may be quite appreciable — as much, for instance, as 0.8 gram — although such a large amount is found only after active exercise. It has been ascertained definitely that urea is not formed by the kidneys: it is brought to the kidneys in the blood for elimination, the cells of the convoluted tubules being especially adapted for taking up this material and transmitting it through their substance to the lumen of the tubules. That urea is not made in the kidneys is demonstrated by such facts as these: If blood, on the one hand, is irrigated through an isolated kidney, no urea is formed, even though substances (such as ammonium carbonate) from which urea is readily produced are added to the blood; on the other hand, urea is constantly present in the blood (0.03 18 to 0.1529 per cent.), and if the two kidneys are removed, it continues to accumulate steadily iu the blood as long as the animal survives. It has been ascertained that the urea is produced in part in the liver; an account of some of the experiments demon- strating this fact is given on page 331. The most important questions that remain to be decided are, Through what steps is the proteid molecule metab- olized to the form of urea? and, What is the antecedent substance brought to the liver, from which it makes urea? It is impossible to answer these questions perfectly, but recent investigations have thrown a great deal of light on the whole process, and they give hope that before long the entire history of the derivation of urea from proteids and albuminoids will be known. The results of this work may be stated briefly as follows: 1. Urea arises from proteids by a process of hydrolysis and oxidation, with the formation eventually of ammonia compounds, which are then conveyed to the liver and there changed to urea. Drechsel lias suggested that am- monium carbamate tonus one at least of the ammonia compounds that arc con- 336 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. verted to urea, and gives the following evidence for this view. In the firsl place, Drechsel found carbamic acid in the blood of dogs, and Drechsel and Abel have shown that it occurs normally in the urine of horses as calcium carbamate ; and Abel lias shown that it may be found in the urine of dogs or infants after the use of lime-water. Drechsel has shown, further, that ammonium carbamate may be converted into urea. If one compares the formulas of ammonium carbamate ami urea, it is seen that the former may pass over into the latter by the loss of a molecule of water, a — CO< XI F - — H = CO< XH 2. OXH, - XH 2 Ammonium carbamate. Urea. Drechsel supposes, however, that this dehydration is effected in an indirect manner; that there is first an oxidation removing two atoms of hydrogen, and then a reduction removing an atom of oxygen. He succeeded in showing that when an aqueous solution of ammonium carbamate is submitted to elec- trolysis, aud the direction of the current is changed repeatedly so as to get alternately reduction and oxidation processes at each pole, some urea will be produced. These facts show the existence of ammonium carbamate in the body, and the possibility of its conversion to urea. It remain- possible, however, that other salts or compounds of ammonia may likewise be con- verted normally to urea by the liver, since it has been shown experimentally in artificial circulation through this organ that salts such as ammonium car- bonate, or even such complex ammonia compounds as leucin and glycocoll, may give rise to urea. Experiments made by Halm. Pawlow, Massen, and Nencki ' show that in dogs removal of the liver is followed by a decrease in the amount of urea in the urine and an increase in the ammonia contents. In these remarkable experiments a fistula was made between the portal vein and the inferior vena cava, the result of which was that the whole portal circulation of the liver was abolished, and the only blood that the organ received was through the hepatic artery. If, now, this artery was ligated or the liver was cut away, as was done in some of the ex- periments, then the result was practically an extirpation of the entire organ — an operation which has always been thought to be impossible with mammals. The animals in these investigations survived this operation for some time, but they died finally, showing a series of symptoms which indicated a deep disturbance of tin' nervous system. It was found that the symptoms of poisoning in these animals could be brought on before they developed spontaneously by feeding the dogs upon ;i rich meat diet, or with .-alts of ammonia or carbamic acid. Later investigations 2 showed that in normal animals the ammonia contents of the blood in the portal vein are from three to four times what is found in the arte- rial blood, but that after the operation described the ammonia in the arterial blood increases and at the time of the development of the fatal symptoms 1 Ardiir far experimentelle Pathologie and Pharmakolor/ie, 1893, Bd. xxxii. S. 161. 2 Nenoki, Pawlow, and Zaleski : Ibid., 1895, Bd. xxxvii. S. 26; also, Xencki and Pawlow: Archives '/•.-• Sciences biologiques, t. 5, p. 213. CHEMISTRY OF DIGESTION AND NUTRITION. 337 reaches about the percentage which is normal to the blood of the portal vein. It would seem from these investigations that the liver stands between the portal circulation and the general systemic circulation and protects the latter from the comparatively large amount of ammonia compounds contained in the portal blood by converting these compounds to urea. If the liver is thrown out of function, ammonia compounds accumulate in the blood and cause death. The rich amount of ammonia in the portal blood seems to come chiefly from the decomposition of proteid material in the glands of the stomach and pancreas during secretion. Similar ammonia salts are probably formed in other active proteid tissues, since the percentage of ammonia in the tissues is considerably greater than in the blood, and these compounds also are doubtless converted to urea in the liver, in part at least. As to the origin of the ammonia compounds there is little direct evidence. They come in the long run, of course, from the nitrogenous food-stuffs, proteids and albuminoids. Drechsel, having reference to one form only, namely, ammonium carbamate, supposes that the proteids first undergo hydrolytic cleavage, with the formation of amido- bodies, such as leucin, tyrosin, aspartic acid, glycocoll, etc.; that these bodies undergo oxidation in the tissues, with the formation of NH 3 , C0 2 , and H 2 ; and that the XH :j and CG 2 then unite synthetically to form ammonium carbamate, which is carried to the liver and changed to urea. There is reason to believe that the formation of ammonia compounds takes place in the tissues generally. 2. Even after the removal of the liver some urea is still found in the urine. This fact proves that other organs are capable of producing urea, but what the other organs are and by what process they make urea are points yet undeter- mined. It seems probable that some of the ammonia compounds which are now known to be formed in the tissues generally and to be given off to the blood may be converted into urea elsewhere than in the liver. Just as the glycogenic function of the liver-cells is shared to a less extent by other tis- sues — e. g. the muscle-fibres — it is possible that their power of converting ammonia salts to urea may be possessed to a lesser degree by other cell-, and for this reason removal of the liver is not followed at once by a fatal result. Concerning this point, however, we must wait for further investigation. Drechsel has recently called attention to a method of obtaining urea directly from proteid outside of the body. Mis method is interesting not only because it is the first laboratory method discovered of producing urea from proteid, but also because it is possible that substantially the same process may occur inside the body. The method consists, in brief, in fust boiling the pro- teid with an acid; IIC1 was used, together with some metallic zinc, so ;i- to keep up a constant evolution of hydrogen and to exclude atmospheric oxygen. Among the products of decomposition of the proteid thus produced was a substance termed lysatinin (C 6 H u N s O), and when this body was isolated and treated with boiling baryta-water (Ba(OH) 2 ) some urea was obtained. It is to be noted that in this case the urea was obtained not by the oxidation of the proteid, but by a series of decompositions or cleavages of the proteid molecule. Vol. I.— 22 338 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Now, lysatinin occurs also in the body as one of the products of the con- tinued action of trypsin on proteids (see p. 303). It is possible, therefore, that by further hydrolysis this substance, when it occurs, is converted to urea, and that normally a part of the urea arises from proteids by this process. Uric Acid and Xanthin Bodies. — Uric acid, which has the formula CgH 4 X 4 3 , is found constantly, but in relatively small quantities, in human urine and in the urine of mammals generally. The total quantity in the urine of man under normal conditions varies from 0.2 to 1 gram every twenty-four hours. In the urine of birds and reptiles it forms the chief nitrogenous constituent. In these animals it takes the place physiologically of urea in mammalia in that it represents the main end-product of the metabolism of the proteids in the body. It i» evident that at some point in the process the metabolism of the proteids in mammalia differs from that in birds and reptiles, since in the one urea, and in the other uric acid, is the outcome. Uric acid occurs in such small quantities in mammals that its place of origin has been investigated with dif- ficulty. Among birds and reptiles uric acid represents the chief nitrogenous excretion of the urine, taking the place physiologically of urea in the mam- malia. As in the case of urea, it has been shown that in birds uric acid originates in the liver. Extirpation of the kidneys in these animals leads to an accumulation of uric acid in the blood and tissues. Removal of the liver, on the contrary, causes a decrease in the excretion of uric acid and an increase in the ammonia contents of the urine. It may be concluded, therefore, that in birds uric acid is formed in part in the liver from ammonia compounds (ammonium lactate). Reasoning from analogy, we should sup- pose that in the mammalia uric acid has a similar origin, but experiments fail to support this view. When a mammal is fed with ammonium lactate or urea there is no increase in the excretion of uric acid. Within recent years a new hypothesis has been advanced by Horbacewsky, and consider- able experimental evidence has since given material support to his views. 1 According to Horbacewsky, uric acid may be regarded as a specific end- product of the nucleins contained in the nuclei of cells, and is formed by an oxidation of a grouping in the nuclein which may also give rise to other members of the class of so-called alloxuric bases, such as xanthin, hypo- xanthin, or adenin. Feeding a man with food rich in nucleins — the thymus gland, for instance — leads to a marked increase in the excretion of uric acid, and feeding with one, at least, of the alloxuric bases, hypoxanthin, gives a similar result. On this view uric acid should give an indication of the extent of the katabolism or disintegration of the cell-nuclei, especially perhaps in the lymphoid tissue. It is probable, however, that the actual amount of uric acid excreted in the urine does not represent truly the entire amount formed in the body. When uric acid is fed to an animal it does not all reappear in the urine, indicating that this substance may undergo metab- olism in the body to a limited extent, its nitrogen appearing probably as urea. Possibly, therefore, some of the uric acid normally produced in the body undergoes a similar fate, only a portion escaping in the urine. 1 Minkowski : Archivfur ezperimenteUe Pathologie wnd Pharmakoloffie, Bd. 41, S. 375. CHEMISTRY OF DIGESTION AND NUTRITION. 339 Xanthin (C 5 H 4 N 4 2 ), hypoxanthin (C 5 H 4 N 4 0), guanin (C 5 H 4 N 4 ONH), and adenin (C 5 H 4 N 4 NH) arc substances closely related to uric acid, and are found in traces in the urine. Since they also originate in the disintegration of nucleins, it is probable that their physiological significance is the same as that of uric acid, and that to the extent to which they occur they also repre- sent an end-product of the katabolism of cell-nuclei. These bodies are found in greatest quantity in muscle, and are present, therefore, in meat- extracts. It is interesting in this connection to call attention to the fact that theobromin (dimethyl-xanthin) and caffein (trimethyl-xanthin) are closely related to the xanthin bodies. Creatinin. — Creatinin (C 4 H 7 X h O) is a crystalline nitrogenous substance constantly found in urine. It is closely related to creatin (C 4 H 9 N 3 2 ), the two substances differing by a molecule of water; the creatin changes to creatinin upon heating with mineral acids. Creatinin occurs in urine to the extent of about 1.12 grams per day in man. In dogs it has been found that the amount may vary between 0.5 and 4.9 grams per day according to the diet, an increase in the amount of meat in the diet causing an increase in the creatinin. This is readily explained by the fact that creatin is a constant constituent of muscle, and when taken into the stomach it is eliminated in the urine as creatinin. It is evident, therefore, that part of the creatinin of the urine is derived from the meat eaten, and does not represent a metabolism within the body. A part, however, comes undoubtedly from the destruction of proteid within the body. In this con- nection the following facts are suggestive and worthy of consideration, although they cannot be explained satisfactorily : The mass of proteid tissue in the body is found in the muscles, and the end-product of the destructive metabolism of proteid is supposed to be chiefly urea. Nevertheless, urea is not found in the muscles, while creatin occurs in considerable quantities, as much as 90 grains being contained in the body-musculature at any one time. Only a small quantity (1.12 grams) of creatin is eliminated in the urine as creatinin during a day. What becomes of the relatively large quantity of creatin in the mus- cles? It has been suggested that it is one of the precursors of urea — that it represents an end-product of the proteid destroyed in muscle which is subse- quently converted to urea in the liver or elsewhere. This supposition is sup- ported by the fact that creatin may be decomposed readily in the laboratory, with the formation of urea among other products. But against this theory we have the important fact that creatin introduced into the blood is not con- verted to urea, but is eliminated as creatinin. Hippuric Acid. — This substance has the formula C 9 H 9 N0 3 . Its molecular structure is known, since upon decomposition it yields benzoic acid and gly- cocoll, and, moreover, it may be produced synthetically by the union of these two substances. Hippuric acid may be described, therefore, as a benzoyl-amido- acetic acid. It is found in considerable quantities in the urine of herbivorous animals (1.5 to 2.5 per cent.), and in much smaller amounts in the urine of man and of the earnivora. In human urine, on an average diet, about 0.7 340 -I.V AMERICAN TEXT-BOOK OF PHYSIOLOGY. gram is excreted in twenty-tour hours. If, however, the diet is largely table, tli is amount may be increased greatly. These last facts are readily explained. It has been found that if benzoic acid or related substances con- taining this group are fed to animals, they appear in the mine as hippuric acid. Evidently, a synthesis has taken place within the body, and Bunge and Schmiedeberg proved conclusively that in dogs, and probably, therefore, in man, the union of the benzoic acid to glycocoll occurs mainly in the kidney itself. We can understand, therefore, why vegetable foods which are known to contain substances belonging to the aromatic series and yielding benzoic acid should increase the output of hippuric acid in the urine. Since, however, in starving animals or in animals \\<\ entirely on meat hippuric acid is still pres- ent, although reduced in amount, it follows that it arises in part as one of the results of body-metabolism. Among the various products of the breaking- down of the proteid molecule, it is probable that some benzoic acid occurs, and, if so, it is excreted in combination with glycocoll as hippuric acid. It should lie added, finally, that some of the hippuric acid is supposed to be de- rived from the process of proteid putrefaction that occurs to a greater or less extent in the large intestine. Conjugated Sulphates. — A good part of the sulphur eliminated in the urine is in the form of ethereal salts with organic compounds of the aromatic and indigo series. Quite a number of these compounds have been described ; the most important are the compounds with phenol (C 6 H 5 OS0 2 OH), cresol (C 7 H 7 O.S0 2 OH), indol (C s H 6 XOS0 2 OH), and skatol (C 9 H 8 XOS0 2 OH). These four substances, phenol, cresol, indol, and skatol, are formed in the in- testine during the process of putrefactive decomposition of the proteids (p. 310). They are produced in small quantities, and they may be excreted in part in the feces, but in part they are absorbed into the blood. They are in them- selves injurious substances, but it is supposed that in passing through the liver — which must of necessity happen before they get into the general cir- culation — they are synthetically combined with sulphuric acid, making the so-called "conjugated sulphates," which are harmless, and which are event- ually excreted by the kidneys. Water and Inorganic Salts. — Water is lost from the body through three main channels — namely, the lungs, the skin, and the kidney, the last of these being the most important. The quantity of water lost through the lungs probably varies within small limits only. The quantity lost through the sweat varies, of course, with the temperature, with exercise, etc., and it may be said that the amounts of water secreted through kidney and skin stand in something of an inverse proportion to each other; that is, the greater the quantity lost through the skin, the less will be secreted by the kidneys. Through these three organs, but mainly through the kidneys, the blood is being continually depleted of water, and the loss must be made up by the ingestion of new water. When water is swallowed in excess the superfluous amount is rapidly eliminated through the kidneys. The amount of water CHEMISTRY OF DIGESTION AND NUTRITION. 341 secreted may be increased by the action of diuretics, such as potassium nitrate and caffein. Tin 1 inorganic suits of urine consist chiefly of the chlorides, phosphates, and sulphates of the alkalies and the alkaline earths. It may be said in general that they arise partly from the salts ingested with the food, which salts are eliminated from the Mood by the kidney in the water-secretion, and in part they are formed in the destructive metabolism thai takes place in the body, particularly that involving the proteids and related bodies. Sodium chloride occurs in the largest quantities, averaging about 1 5 grams per day, of which the larger part, doubtless, is derived directly from the -alt taken in the food. The phosphates occur in combination with Ca and Mg, but chiefly as the acid phosphates of Xa or K. The acid reaction of the urine is usually attributed to these latter substances. The phosphates result in part from the destruction of phosphorus-containing tissues in the body, but chiefly from the phosphates of the food. The sulphates of urine are found partly in an oxidized form as simple sulphates or conjugated with organic compounds, as described above, and in small part in a neutral or unoxidized form, such as potassium sulphocyanide, or ethyl-sulphide, (C 2 H 5 ) 2 S. The total quantity of sulphuric acid eliminated is estimated to average about 2.5 grams per day. Sulphur constitutes a constant element of the proteid molecule, and the quan- tity of it eliminated in the urine may be used, as in the ease of nitrogen, to determine the total destruction of proteid within a given period. Functions of the Skin. — The physiological activities of the skin are varied. It forms, in the first place, a sensory surface covering the body, and interposed, as it were, between the external world and the inner mechanism. Nerve-fibres of pressure, temperature, and pain are distributed over its sur- face, and by means of these fibres reflexes of various kinds are effected which keep the body adapted to changes in its environment. The physiology of the skin from this standpoint is discussed in the section on Cutaneous Sensations. Again, the skin plays a part of immense value to the body in regulating the body-temperature. This regulation, which is effected by variations in the blood-supply or the sweat-secretion, is described at appropriate places in the sections on Animal Heat, Circulation, and Secretion. In the female, during the period of lactation, the mammary glands, which must be reckoned aiming the organs of the skin, form an important secretion, the milk ; the physiology of this gland is described in the sections on Secretion ami Reproduction. In this section we are concerned with the physiology of the skin from a different stand- point — namely, as an excretory organ. The excretions of the -kin are formed in the sweat-glands and the sebaceous glands. The sweat-glands arc distrib- uted more or less thickly over the entire surface of the body, with the excep- tion of the prepuce and glans penis, while the sebaceous glands, usually in ( - Election with the hairs, are also found everywhere except upon the palms of the hands and the soles of the feet. Sweat. — Sweat, or perspiration, which is the secretion of the sweat-glands, is a colorless liquid with a peculiar odor and a salty taste. Its specific gravity 342 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. is given at 1004, and in man it usually has an acid reaction. As can readily be understood, the quantity secreted in twenty-four hours varies greatly, the secre- tion being influenced by variations in temperature, by exercise, and by psychical and pathological conditions; an average estimate places the daily secretion at from 700 to 900 grams. Chemically, the secretion consists of water and inor- ganic salts, traces of fats, fatty acid, eholesterin, and urea. Of the inorganic salts, Nad is by far the most abundant: it occurs in quantities varying from 2 to 3.5 parts per thousand. The elements of the sweat which are of import- ance from an excretory standpoint are water, inorganic salts, and urea or related nitrogenous compounds. As was said above, sweat constitutes the second in importance of the three main channels through which water is lost from the body. The quantity eliminated in the sweat is to a certain extent inversely proportional to that secreted by the kidneys; but the physiological value of the secretion of water by the sweat-glands seems to lie not so much in the fact that it is necessary in maintaining the water-equilibrium of the blood and tis- sues as in the important part it takes in controlling the heat-loss from the skin: the greater the evaporation of sweat, the greater the loss of heat. The urea is described as occurring in traces. As far as it occurs, it represents, of course, so much proteid destroyed, but usually in calculating the proteid loss of the body this element has been neglected. Argutinsky demonstrated, however, that in special cases — namely, during periods of unusual muscular work or after vapor- baths — the total weight of nitrogen eliminated by the skin may be of consider- able importance, amounting to as much as 0.7 to 0.8 gram. Under ordinary circumstances the excretion of urea and related compounds through the skin must be regarded as of very subsidiary importance, but the amount may be increased markedly under pathological conditions. Sebaceous Secretion. — The sebaceous secretion is an oily, semi-liquid material, the quantity of which cannot be estimated even approximately. Chemically, it consists of water and salts, albumin and epithelium, fats and fatty acids. Its excretory importance in connection with the metabolism of the body must be slight. Its chief physiological value must be sought in its effect upon the hairs, which are kept oiled and pliant by the secretion. Moreover, it forms a thin, oily layer over most of the surface of the skin ; and we may suppose that this layer of oil is of value in two ways — in preventing too great a loss of water through the skin, and in offering an obstacle to the absorption of aqueous solutions brought into contact with the skin. Excretion of C0 2 . — In some of the lower animals — the frog, for ex- ample — the skin takes an important part in the respiratory exchanges, elim- inating C0 2 and absorbing O. In man, and presumably in the mammalia generally, it has been ascertained that changes of this kind are very slight. Estimates of the amount of C0 2 given off from the skin of man during twenty-four hours vary greatly, but the amount is small, and is certainly less than one one-hundredth part of the amount given off' through the lungs. CHEMISTRY OF DIGESTION AND NUTRITION. 343 H. Body-metabolism ; Nutritive Value of the Food-stuffs. Determination of Total Metabolism. — We have so far studied the changes that the food-stuffs undergo during digestion, the form in which they are absorbed into the blood, their history in the tissues to some extent, and the final condition in which, after being decomposed in the body, they are eliminated in the excreta. To ascertain the true nutritional value of the food-stuffs it is of the utmost importance that we should have some means of estimating accurately the kind and the amount of body-metabolism during a given period in relation to the character of the diet used. Fortunately, this end may be reached by a careful study of the excreta. The methods employed can readily be understood in principle from a brief description. It has been made suf- ficiently clear before this, perhaps, that by determining the total amount of the nitrogenous excreta we can reckon back to the amount of proteid (or albu- minoid) destroyed in the body. In the case of proteids or albuminoids that undergo physiological oxidation all the nitrogen appears in the forms of urea, uric acid, creatinin, xanthin, etc., which are eliminated mainly through the urine, and may therefore be collected and determined. The following practical facts are, however, to be borne in mind in this connection : The nitrogenous excre- tion of the urine is mainly in the form of urea which can be estimated as such, but it is much more accurate to determine the total nitrogen in the urine during a given period, using some one of the approved methods for nitrogen-deter- mination, and to calculate back from the amount of nitrogen to the amount of proteid. By this means all the nitrogenous excreta which may occur in the urine are allowed for ; and since the various proteids differ but little in the amount of nitrogen which they contain, the average being from 15.5 to 16 per cent., it is only necessary to multiply the total quantity of nitrogen found in the excretions by 6.25 (proteid molecule : N :: 100 : 16) to ascertain the amount of proteid destroyed. In accurate calculations it is necessary to determine the total nitrogen in the feces as well as in the urine, and for two reasons: first, in ordi- nary diets of some vegetable and animal proteid they may escape digestion and this amount must be determined and deducted from the total proteid eaten in order to ascertain what nitrogenous material has actually been taken into the body; second, the secretions of the alimentary canal contain a certain quan- tity of nitrogenous material, which represents a genuine excretion, and should be included in estimates of the total proteid-destruction. Recent work seems to show that in ordinary diets most of the nitrogen of the feces has the latter origin. The nitrogen eliminated as urea, etc., in the sweat, milk, and saliva is neglected under ordinary circumstances because the amount is too small to affect materially any calculations made. To determine the total amount of non-nitrogenous material destroyed in the body during a given period, two data are required: first, the total nitrogen in the excreta of the body; second, the total amount of carbon given oil' from the lungs and in the various excreta. From the total nitrogen one calculates how much proteid was destroyed, and, deducting from the total carbon the amount corresponding to 341 .4.V AMERICAN TEXT-HOOK OF PHYSIOLOGY. tliis quantity of proteid, what remains represents the carboD derived from the metabolism of the non-nitrogenous material — that is, from the fat or carbo- hydrate. By methods of this kind it is possible to reckon back from the excreta to the total amount of material, consisting of proteid, fat, and carbo- hydrate, which lias been consumed in the body within a certain period. If, now, by analyzing the food or by making use of analyses already made (see p. 278), one determines how great a quantity of proteid, fat, and carbohydrate has been taken into the body in the same period, then, by comparison of the total ingesta and egesta, it is possible to strike a balance and to determine whether all the proteid, fat. and carbohydrate of the food have been destroyed, or whether some of the food has been stored in the body, and in this case whether it is nitrogenous or non-nitrogenous material, or, lastly, whether some of the reserve material of the body, nitrogenous or non-nitrogenous, has been destroyed in addition to the supply of food. It is needless to remark that " balance experiments" of this character are very laborious, particularly as they must be made over long intervals — one or more days. Nevertheless, a great deal of work of this kind has been done upon man as well as upon lower animals, especially by Voit ' and Pettenkofer. In the experiments upon man the urine and feces were, collected carefully and the total nitrogen was determined ; at the same time the total quantity of C0 2 given off from the lungs was estimated for the entire period. The determination of the C0 2 was made possible by keeping the man in a specially-constructed chamber through which air was drawn by means of a pump; the total quantity of air drawn through was indicated by a gasometer, and a measured portion of this air was drawn off through a separate gasometer and was analyzed for its C0 2 . It was found that the method is practicable : that by the means described a nearly perfect balance may be struck between the income and the outgo of the body. Experiments of this general character have been used to determine the fate of the food-stuffs in the body under different con- ditions, the essential part that each food-stuff takes in general nutrition, and so on. In this and the succeeding sections we shall have to consider some of the main results obtained ; but first it will be convenient to define two terms frequently used in this connection — namely, " nitrogen equilibrium " and " carbon equilibrium." Nitrogen Equilibrium. — By "nitrogen equilibrium" we mean that condition of an animal in which, within a definite period, the nitrogen of the excreta is equal in amount to the nitrogen of the food ; in other words, that condition in which the proteid (and albuminoid) food eaten exactly covers the loss of proteid (and albuminoid) in the body during the same time. W an animal is giving off more nitrogen in its excreta than it receives in its food, then the animal must be losing proteid from its body; if, on the contrary, the food that it eats contains more nitrogen than is found in the excreta, the animal must oe storing proteid in its body. A condition of nitrogen equilibrium is the normal state of a properly-nourished adult. It is important to remember that nitrogen equilibrium may be maintained at different levels; that is, one may ' Hermann'* Handiuch der Physwlogie, 18S1, lid. vi. CHEMISTRY OF DIGESTION AND NUTRITION. 345 begin with a starving animal and slowly increase the amount of nitrogenous food until nitrogen equilibrium is just established. If now the amount of nitrog- enous food is increased — say doubled — the excess does not, of course, continue to be stored up in the animal's body; on the contrary, in a short time the amount of proteid destroyed in the body will be increased to such an extent that nitrogen equilibrium will again be established at a higher level, the animal in this case eating more and destroying more. The highest limit at which nitro- gen equilibrium can be maintained is determined, apparently, by the power of the stomach and the intestines to digest and absorb proteid food. Further details upon this point will be given presently, in describing the nutritive value of the food-stuffs. Carbon Equilibrium. — The term " carbon equilibrium " is sometimes used to describe the condition in which the total carbon of the excreta (occurring in the C0 2 , urea, etc.) is exactly covered by the carbon of the food. As one can readily understand, an animal might be in a condition of nitrogen equilibrium and yet be losing or be gaining in weight, since, although the consumption of proteids in the body might just be covered by the proteids of the food, the consumption of non-proteids, fats and glycogen, might be greater or less than was covered by the supply of food. In addition, we might speak of mi equi- librium as regards the water, salts, etc., although these terms are not generally used. An adult in good health usually so lives as to keep in both nitrogen and general body equilibrium — that is, to maintain his normal weight — while slight variations in weight from time to time are probably for the most part due to a loss or a gain in body-fat — in other words, to changes in the carbon equilibrium. Nutritive Importance of the Proteids. — The digestion and absorp- tion of proteids have been considered in previous sections. We believe that the digested proteid, with the exception of the variable quantity that suffers decomposition in the intestine as a result of putrefaction or of the prolonged action of trypsin, is absorbed into the blood after undergoing an unknown modification during the act of absorption. Subsequently tins proteid materia] passes into the lymph ami is broughl into contacl with the tissues. lt> main nutritive importance lies in its relations to the tissues, and, speaking generally, we may say that the final late of the proteid molecule is that it undergoes a physiological oxidation whereby the complex molecule is broken down to form the simpler and more stable compounds, C0 2 , H 2 0, urea, sulphates and phosphates. This destruction of the proteid molecule takes place in or under the influence of the living cells, and it gives rise to a liberation of energy mainly in the form of heat. It is impossible to follow the various ways in which this physiological oxidation takes place. It is probable, however, that some of the proteid undergoes destruction without becoming a part, an organized part, of the living cells, although its oxidation is effected through the agency of the cells. It has been proposed by Yoit ' to designate the proteid that is oxidized in this way as 1 Hermann's Handbuch der Physiobgie, 1881, Bd. vi. S. 300. 346 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. "the circulating albumin or proteid." According to Voit, a well-fed animal has in its lymph and tissues always a certain excess of proteid which is to undergo the fate of the circulating proteid, and this supposition is used to explain the fact that for the first day or so a starving animal metabolizes more proteid, as determined by the nitrogenous excreta, than in the subse- quent days, after the supply of the circulating proteid has been destroyed. A portion of the proteid food, however, before its final destruction is utilized to replace the nitrogenous waste of the tissues ; it is built up into living proto- plasm to supply the place of organized tissue that has undergone disassimi- lation or to furnish new tissue in growing animals. To the proteid that is built up into tissue Voit gives the name of " organeiweiss," the best translation of which, perhaps, is " tissue-proteid." It should be stated that this division of the proteid into circulating proteid and tissue-proteid has been severely criticised by some physiologists, but it has the merit at least of furnishing. a simple explanation of some curious facts with regard to the use of proteid in the body. To avoid misunderstanding, it is well to say that the sepa- ration into circulating proteids and tissue-proteids does not mean that the proteid that is absorbed from the alimentary canal is of two varieties. The terms refer to the final fate of the proteid in the body: a certain portion is utilized to replace protoplasmic tissue, and it then becomes " tis- sue-proteid," while the balance is metabolized in various ways and con- stitutes the "circulating proteid." Any given molecule of proteid, as far as is known, may fulfil either function. With regard to the general nutri- tive value of piot eids, it has been demonstrated clearly that they are abso- lutely necessary for the formation of protoplasmic tissue. An animal fed only on non-nitrogenous food such as fats and carbohydrates will inevitably starve to death in time : this has been shown by actual experiments, and, besides, it follows from a priori considerations. Protoplasm contains nitrogen; fats and carbohydrates are non-nitrogenous, and therefore cannot be used to make new protoplasmic material. It is requisite, moreover, not only that the food shall contain some nitrogen, but that this nitrogen shall be in the form of proteid. If an animal is fed upon a diet containing fats and carbohydrates and nitrog- enous material other than proteids, such as amido-acids or gelatin, nitrogenous equilibrium cannot be maintained. There will be a steady loss of nitrogen in the excreta, due to a breaking-down of proteid tissue within the body, and the final result of maintaining such a diet would be the death of the animal. It may be said, then, with regard to animal metabolism that proteid food is absolutely necessary for the formation of new protoplasm; its place in this respect cannol betaken by any other element of our food. lint, in addition to this use. proteid, as has been described above, may be oxidized in the body with- out being first constructed into protoplasmic material. According to an older theory in physiology, advanced by Liebig, food-stuffs were either plastic or respiratory; by plastic foods he meant those that are built into tissue, and he supposed that the proteid- belonged to this class ; by respiratory foods he meant those that are oxidized or burnt in the body to produce heat : the fats and CHEMISTRY OF DIGESTION AND NUTRITION. 347 carbohydrates constituted this class. We now know that proteids are respi- ratory as well as plastic in the terms of this theory ; they serve as sources of energy as well as to replace tissue, and Liebig's classification has therefore fallen into disuse. Our present ideas of the twofold use of proteid food may be supported by many observations and experiments, but perhaps the most striking proof of the correctness of these views is found in the fact that a car- nivorous animal can be kept in both nitrogen and carbon equilibrium upon a meat diet only, excluding for the time a consideration of the water and inorganic salts. Pettenkofer and Voit kept a dog weighing 30 kilograms in nitrogen and carbon equilibrium upon a diet of 1500 grams of lean meat per day, and by increasing the diet to 2500 grams per day the animal even gained in weight, owing to an increase in fat. Pfliiger states also that he was able to keep a dog in body-equilibrium as long as eight months upon a meat diet. Facts like these demonstrate that the animal organism may get all its necessary energy from proteid food alone, although, as we shall see later, it is more econom- ical and more beneficial to get a part of it at least from the oxidation of fats and carbohydrates. Adopting the theory of " circulating proteids," we may say that any excess of proteid above that utilized for tissue-repair or tissue-growth will be metabolized in the body, with the liberation of energy. It makes no difference how much proteid material we consume : the excess beyond that used to replace tissue is quickly destroyed in some way, and its nitrogen appears in the urine as urea or one of the related compounds. A good example of the power of the tissues to oxidize large amounts of proteid is given in the following experiment, selected from a paper by Pfliiger. Dog, weight 28.1 kilograms, fed at 11a. m. with 2070.7 grams of meat : 2070.7 grams of meat contain G9.2 grams X. Total nitrogen eliminated in urine and feces in twenty-four hours (7 a.m. to 7 a.m.) 71. 2 " " Deficit of N 0.96 grams. The total nitrogen in the urine alone was 68.5 grams. In urine from 7 a.m. to 1 1 a. m., the fasting period 6.9 grams. In urine from 11 a.m. to 7 a. m., time after feeding 61.6 " Therefore in the four hours of fasting the animal eliminated in his urine 1.7 grams N per hour, while in the twenty hours after eating he excreted 3.1 grams N per hour. This experiment shows not only the completeness with which an excessive proteid diet is handled by the tissues, but also the rapidity with which the excess is destroyed. In so far as proteid food is burnt in the body only as a source of energy and without being used to form new tis- sue, its place can be supplied in part, but only in part, by non-nitrogenous food- stuffs — carbohydrates and fats. The double use of proteid as a tissue-former and an energy-producer would seem to imply that if, in any given case, sufficient pro- teid were used in the diet to cover the tissue-waste, the balance of the diet might Decomposed of fats and carbohydrates, and the animal thereby be kepi in aitrog- 348 AN AMERICAN TEXT-HOOK OF PHYSIOLOGY. enous equilibrium. Apparently this is not the case, as is seen from experiments of the following character : When an animal is allowed to starve, the nitrogen in the urine, after the first few days, becomes practically constant, and represents the amount of oxidation of proteid tissue taking place in the body. If, now, the animal is given an amount of proteid just equal to that being destroyed in the body, nitrogenous equilibrium is not established; some of the body-proteid con- tinues to be lost, and to get the animal into equilibrium a comparatively large exee— of proteid must be given in the food. The same result holds if carbo- hydrate- and fats are given along with the proteid, with the exception that upon this diet nitrogen equilibrium is more readily established — that is, less proteid is required in the food. Upon the theory of circulating proteids and tissue- proteids, this fact may lie accounted for by saying that of the proteid given as food, a part always undergoes destruction as circulating proteid without going to form tissue, so that to cover tissue-waste a larger amount of proteid must be taken a- food than would be necessary if it could all be used exclusively for the repair of tissue. Carbohydrates and fats diminish the amount of proteid destroyed as circulating proteid, and thereby enable us to keep in nitrogen equilibrium on a smaller proteid diet. With albuminoid food (gelatin) the facts seem to be different. If albuminoids be given in the food together with proteids or with proteids and a non-nitrogenous food-stuff (fats or carbo- hydrates), nitrogen equilibrium may be established upon a much smaller amount of proteid thau in the case of a diet consisting of proteid alone or of proteid together with fats and carbohydrates. It seems probable that albu- minoids can take the place entirely of circulating proteids, so that only enough proteid need be given to cover actual tissue-waste. This point will be referred to again in speaking of the value of the albuminoids. Z/UXU8 < bnmmption. — The fact that normally more proteid is eaten, even in a mixed diet, than is necessary to cover the actual tissue-waste led some of the older physiologists to speak of the excess as unnecessary, a luxus, and the rapid destruction of the excess in the body was described as a " luxus con- sumption." There can be no doubt about the fact that proteid may be, and normally is, eaten in excess of what is necessary to repair tissue-waste, or in excess of what is requisite to maintain nitrogenous equilibrium at a low level. But it is altogether improbable that the excess is really a "luxus." It has been stated, in speaking of nitrogenous equilibrium, that an animal may be kept in this condition upon a certain minimal amount of pro- teid, or upon various larger amounts up to the limit of the power of the alimentary canal to digest and absorb; but it has also been shown (Munk 1 ) that if an animal i< i^(\ upon a diet containing quantities of proteid barely sufficient to maintain N equilibrium, it will after a time show signs of mal- nutrition. It seems to be necessary, as Pfliiger pointed out, that the tissues should have a certain excess of proteid t<> destroy in order that their nutri- tional or metabolic powers may be kept in a condition of normal activity. Hence we find that well-nourished individuals habitually consume more proteid than would theoretically suffice for N equilibrium. For example, the average 1 I>n Bois-Reymond's Arehivjur Physiologie, 1891, S. 338. CHEMISTRY OF DIGESTION AND NUTRITION. 349 diet of an adult male contains, or should contain, from 100 to 118 grams of proteid per day, but it has been shown that nitrogen and body equilibrium in man may be maintained, for short periods at least, upon 40 or even 20' grama of proteid a day, provided large amounts of i'ats or carbohydrates are eaten. It is scarcely necessary to add that this beneficial excess has a limit, and that too great an excess of proteid food may cause troubles of digestion as well as of general nutrition. Nutritive Value of Albuminoids. — The albuminoid most frequently oc- curring in food is gelatin. It is derived from collagen of the connective tissues. Collagen of bones or of connective tissue takes up water when boiled and becomes converted into gelatin. We eat gelatin, therefore, in boiled meats, soups, etc., and, besides, it is frequently employed directly as a food in the form of table-gelatin. Collagen has the following percentage composition : C, 50.75 per cent; H, 6.47 ; N, 17.86; O, 24.32; S, 0.6. It resembles the proteid molecule closely in percentage composition, and it would seem that the tissues might use it as they do proteid, for the formation of new protoplasm. Experiments, however, have demonstrated clearly that this is not the case. Animals fed upon albuminoids together with fats and carbohydrates do not maintain N equilibrium; a certain proportion of tissue breaks down, giving an excess of nitrogen in the urine. The final result of such a diet would be continued loss of weight and, finally, malnutrition and death. Gelatin, how- ever, is readily digested, gelatoses and gelatin peptones being formed ; these are absorbed and oxidized in the body, with the formation of C0 2 , H 2 0, and urea or some related nitrogenous product. Gelatin serves, then, as a source of energy to the body in the same sense as do carbohydrates and fats. When any one of these three substances is used in a diet, the proportion of proteid necessary for the maintenance of X equilibrium may be reduced greatly. I Fpon the theory of circulating proteids, this is explained by saying that these sub- stances are burnt in place of proteid, and that the proportion of this latter material which undergoes the fate of circulating proteid is thereby diminished. Actual experiments have shown that gelatin is more efficacious than either Hits or carbohydrates in protecting the proteid in the body, and it has been sug- gested, therefore, that it may take the place, partly or completely, of the circu- lating proteid, according to the amount icd. If this suggestion is true, we may say that gelatin has a nutritive value the same as that of the proteids, except that it cannot be constructed into living proteid. The relative value of fats, carbohydrates, and gelatin in protecting proteid from destruction in the body is illustrated by the following experiment, reported by Voit. A dog- weighing .32 kilograms was led alternately upon proteid ami sugar, proteid and fat, and proteid and gelatin : Nourishment (gi r:unsi. Calcn ilated destruction of flesh Meat. Gelal in. Kat. Sugar. in body (grams). 4l«) — 200 — 150 400 — — 250 439 400 200 — — 356 ■Sivt'n: Skandinavischu Arehiv fur Physiologic 1899, Bd. 10, S. 91. 350 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Practically, however, the use of gelatin in diets is restricted by its unpalata- bleness when used in large quantities. Whatever may be the physiological cause of this peculiarity, there seems to be no doubt that when employed largely in the diet both animals and men soon develop such an aversion to it that it is necessary to discontinue its use. Munk ' has attempted to determine how tar the proteids offood maybe replaced by gelatin. In these experiments a dog was brought into a condition of nitrogenous equilibrium upon a diet of flesh, meal, rice, and lard, containing 9.73 grams of nitrogen. During the period this diet was continued the animal, whose weight was 16.5 kilograms, was oxidizing in its body 3.7 grams ofproteid daily for each kilogram of weight. In a second period lasting four davs the quantities of rice and lard were the same as before, but the proteid in its diet was reduced to 8.2 grams, which contained 1.3 grams of nitrogen ; the balance of the necessary nitrogen was supplied in the form of gelatin, so that in round numbers only one-seventh of the required daily amount of nitrogen was given as proteid. r Fhc result was that the animal maintained its nitrogen equi- librium for the short period stated. It was found that the experiments could not be continued longer than four days, owing to the growing dislike of the animal for the gelatin food. During the second period the animal was receiving in its food and burning in its body only 0.5 gram of proteid daily for each kilogram of weight, as against 3.7 grams upon a normal diet. It is usually stated that it is not possible to substitute fats or carbohydrates for the proteids of our diet to the same extent, but the experiments of Siven quoted on the preceding page indicate that this common belief may be incorrect. Nutritive Value of Fats. — The fats of food are absorbed into the lacteals as neutral fats. They eventually reach the blood in this condition, and are afterward in some way consumed by the tissues. The final products of their oxidation must be the same as when burnt outside the body — namely, 0O 2 and H 2 — and a corresponding amount of energy must be liberated. Speak- ing generallv, then, the essential nutritive value of the fats is that they furnish energv to the body, and, from a chemical standpoint, they must contain more available energy, weight for weight, than the proteids or the carbohydrates (see p. 365). In a well-nourished animal a large amount of fat is found normally in the adipose tissues, particularly in the so-called "panniculus adiposus" beneath the skin. Physiologically, this body-fat is to be regarded a- a reserve supply of nourishment. When food is eaten and absorbed in excess of the actual metabolic processes of the body, the excess is stored in the adipose tissue as fat, to be drawn upon in case of need — as, for instance, during partial or complete starvation. A starving animal, after its small supply of glycogen is exhausted, lives entirely upon body-proteids and fats; the larger the supply of fat, the more effectively will the proteid tissues be protected from desi met ion. In accordance with this fact, it has been shown that when subjected to complete starvation a fat animal will survive longer than a lean one. Our supply of fat is called upon not only during complete abstention from food, but also whenever the diet is insufficient to cover the oxidations of the body, as in deficient food, sickness, etc. 1 Pjlugcr's Arrhii fur 'He gesammte Phyniologie, 1894, Bde. lviii. S. 309. CHE3IISTBY OF DIGESTION AND NUTRITION. 35] Formation of Pat in the Body. — The origin of body-fat has always been an interesting problem to physiologists. Naturally, the first supposition made was that it comes directly from the fat of the food. According to this view, a certain proportion of the fat of the food was supposed to be deposited directly in the cells of adipose tissue, and in this way all our supply of fat originated. This theory was soon disproved. It was shown, especially upon cows and pigs, that the amount of fat formed in the body within a given time, including the fat of milk in the case of the cow, might be far in excess of the total amount of fat taken in the food during the same period, thus demonstrating that a cer- tain proportion at least of the body-fat must have some other origin. More- over, the genesis of the fat-droplets in fat-cells, as studied under the microscope, did not agree with the old view ; and there was the further fact that each animal has its own peculiar kind of fat; as Liebig says, "In hay or the other fodder of oxen no beef-suet exists, and no hog's lard can be found in the potato refuse given to swine." In fact, the evidence was so conclusive against this theory that physiologists for a time were led to adopt the opposite view that no fat at all can be obtained directly from the fat of the food. However, it has now been shown that under certain conditions fat may be deposited directly in the tissues from the fat of food. Lebedeff, and afterward Munk, proved that if a dog is first starved until the reserve supply of fat in the body is practically used up, and it is then fed richly upon foreign fats, such as rape-seed oil, linseed oil, or mutton tallow, it will again lay on fat, and some of the foreign fat may he detected in its body. The conditions necessary to be fulfilled in order to get this result make it probable that under normal conditions none of the fat of the body is derived directly from the fat of the food. On the contrary, the fat of the food is completely oxidized, and our body-fat is normally o in- structed anew from either proteids or carbohydrates. As to its origin from proteid, Voit has devoted numerous researches to the purpose of demon- strating that this is the main source of body-fat. His belief is that in the course of metabolism the proteid molecule undergoes a cleavage, with the for- mation of a nitrogenous and a non-nitrogenous part. The former, after further changes, is eliminated in the form of urea, etc. ; the latter may be converted into fat, or possibly into glycogen. The theoretical maximum of fat which can arise in this way is 51.5 per cent, of the entire amount of proteid. Voit attempted to demonstrate this theory by actual experiments. lb' showed that dogs fed upon large amounts of lean meat did not give off as much carbon in the excreta as they received in the food. The excess of carbon must have been retained in the body, and, in all probability, in the form of fat. As corrob- orative evidence he cites the apparently direct conversion of proteid material into fat in such cases as the formation of lat-droplets in the fat-cells or cells of the mammary glands, and in muscle-fibres and liver-cells undergoing fatty degeneration ; but evidence of this latter character is not conclusive, since we have no immediate proof that the faf arises directly from the proteid material in the cells. Voit's experimental evidence has been questioned recently by Pfliiger, his criticisms being directed mainly toward the calculations involved 3,52 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. in Vbit's experiments. The result of this criticism has been to make us more cautious in attributing the origin of body-fat solely or mainly to proteids, hut as regards the possibility of some proteid being converted into fat in the body there can be do reasonable doubt. It has been proved (p. 328) that glycogen may be formed from proteid, and since it is now generally accepted that fats are formed from carbohydrates, the possibility of an indirect production of fats from proteid- seems to follow necessarily. The connection between the carbohydrates of the food and the fat of the body has been a subject of discussion and investigation anions: physiologists for a number of years. It was the original belief of Liebig that carbohydrates are the source of body-fat. This view was afterward abandoned under the influence of the work of Pettenkofer and Voit, but renewed investigations seem to have re-established it upon -olid experimental grounds. In some older experiments of Lawes and Gilbert it was shown that the fat laid on by a young pig during a certain period was greater than could be accounted for by the total fat in the food during that period, plus the theoretical maximum obtain- able from the proteid fed during the same time. Of more recent experiments demonstrating the same point, a single example may be quoted from Rubiier. 1 a- follow-: A small dog, weighing 6.2 kilograms, was fed richly with meat for two davs and was then starved for two days ; its weight at the end of this time was 5.89 kilograms. The animal was then given for two days a diet of cane- sugar 100 grams, starch 85 grams, and fat 4.7 grams. It was kept in a respira- tion apparatus and its total excretion of nitrogen and carbon was determined : Total C excretion 87.10 grams C. " C ingesta 176.fi " " 89.5 " " retained in the body. flu- total nitrogen excreted = 2.55 grams. The carbon contained in the pro- teid thus broken down plus that in the 4.7 grams of fat = 13 grams. If we make the assumption that all of the C from these two sources was retained within the body, there would still be a balance of 76.5 grams C (89.5 — 13.0) which must have been stored in the body either as glycogen or as fat. The greatest possible storage of glycogen was estimated at 78 grams = 34.6 grams C, so that 76.5 — 34.6 = 41.9 grams C as the minimal amount which must have been retained as fat and must have arisen from the carbohydrates of the food. Similar experiments have been made upon herbivorous animals, and as the result of investigations of this character we are compelled to admit that the carbohydrates form one source, and possibly the main source, from which the body-fats arc derived. This belief accords with the well-known fact that in fattening stock the best diet is one containing a large amount of carbo- hydrate together with a certain quantity of proteid. On the view that fats were formed only from proteids, the efficacy of the carbohydrates in such a diet was supposed to lie in the fact that they protected a part of the proteid from oxidation, and thus permitted the formation offal from proteid; but it is now believed that the carbohydrates of a fattening diet are, in part, converted 1 Zeitschrift fiir Biologie, 1SS6, Bd. 22, 8. 272. CHEMISTRY OF DIGESTION AND N (TUITION. 353 directly to fat, although the chemistry of the transformation is not as yet understood. Diets, such as the well-known Banting diet, intended to reduce obesity are characterized, on the contrary, by a small proportion of carbo- hydrates and a relative excess of proteid. Nutritive Value of Carbohydrates. — The nutritive importance of the carbohydrates is similar in general to that of the fats ; they are oxidized aud furnish energy to the body. In addition, as has been described in the pre- ceding paragraph, they may be converted into fat and stored in the body as a reserve supply of nourishment. As a matter of fact, the carbohydrates form the bulk of ordinary diets. They are easily digested, easily oxidized in the body, and from a financial standpoint they form the cheapest food-stuff. The final products in the physiological oxidation of carbohydrates must be CO, and H 2 0. Inasmuch as the H and O in the molecule already exist in the proper proportions to form H 2 (C 6 H I2 6 , C 12 H 22 O n ), it follows that relatively less oxy- gen will be needed in the combustion of carbohydrates than in the case of proteids or of fats. Whatever may be the actual process of oxidation, we may consider that only as much O is needed as will suffice to oxidize the C of the sugar to CO a . CO Hence the ratio of O absorbed to CO., eliminated, -=-^, a ratio that is known o 2 as the respiratory quotient, will approach nearer to unity as the quantity of carbohydrates in the diet is increased. From our study of the digestion of carbohydrates (p. 318) we have found that most of the carbohydrates of our food pass into the blood as dextrose (or levulose), and any excess above a cer- tain percentage is converted temporarily to glycogen in the liver, the muscles, etc., to be again changed to dextrose before being used. The sugar undergoes final oxidation in the tissues to CO, and H 2 0. While it is possible that this oxidation may be direct — that is, that the sugar may be burnt directly to CO a and H 2 — it is usually supposed to be preceded by a splitting of the sugar mole- cule, although the steps in the process are not definitely known. There has been discovered recently in connection with the pancreas a num- ber of facts that are interesting not only in themselves, but doubly so because they promise, when more fully investigated, to throw some light on the man- ner of consumption of sugar by the tissues. (See also section on Internal Secretions.) It has been shown by yon Mering and Minkowski ' and others that if the pancreas of a dog is completely removed, the tissues lose the power of consuming sugar, so that it accumulates in the blood and finally escapes in the urine, causing what has been called "pancreatic diabetes." If a small part of the pancreas is left in the body, even though it is not connected by its duct with the duodenum, diabetes does not occur. The inference usually made from these experiments is that the pancreas gives off something to the blood — an internal secretion — that is necessary to the physiological consumption of sugar. In what way the pancreas exerts this influence has vet to be discovered ; possibly it is through the action of a specific enzyme that helps to break down the sugar; possibly it is by some other means. Bui the necessity of 1 Arrliir/iir experimentelle Pathologic uml Pharmakologie, 1893, xxxi. S. 85. Vol. I.— 23 354 AN AMERICAN TEXT-BOOK OE PHYSIOLOGY. the pancreas in some way for the normal consumption of sugar by the tissues generally seems to be indisputably established. It is a discovery of the utmost importance in its relations to the normal nutrition of the body, and also because of its possible bearing on the pathological condition known as diabetes mellitus. In this latter disease the tissues, for some reason, are unable to oxidize the sugar in normal amounts, and a good part of it, therefore, escapes through the urine. The facts and theories bearing upon diabetes are of unusual interest in connection with the nutritive history of the carbohydrates, but for a fuller description reference must be made to more elaborate works. Another statement in connection with the fate of sugar in the body is worthy of a brief reference: It has been asserted by Lepine and Barral that there is normally present in blood an enzyme capable of destroying sugar. Their theory rests upon the undoubted fact that sugar added to blood outside the body soon disappears. They call the process " glycolysis," and the enzyme to which they attribute this disappearance the "glycolytic enzyme." Others, however (Arthus), have claimed that this enzyme is only a post-mortem result of the disintegration of the corpuscles of the blood, and that it is not present in circulating blood. We must await further investigation upon this point, and be content here with a mere reference to the subject. Nutritive Value of "Water and Salts. — Water is lost daily from the body in large quantities through the kidney, the skin, the lungs, and the feces, and it is replaced by water taken in the food or separately, and partially also by the water formed in the oxidations of the body. A certain percentage of water in the tissues and in the liquids of the body is naturally absolutely essential to the normal play of metabolism ; and conditions, such as muscular exercise, that increase the water-loss bring about also an increased water- consumption, the regulation being effected through the nervous mechanism that mediates the sensation of thirst. The water taken into the body does not, however, serve directly as a source of energy, since it is finally eliminated in the form in which it is taken in ; it serves only to replace water lost from the tissues and liquids of the body, and it furnishes also the menstruum for the varied chemical reactions that take place. Continued deprivation of water leads to intolerable thirst, the cause of which is usually referred to the altered composition of the tissues gen era 11 y. including the peripheral nervous system. Inorganic Suits, — The essential value of the inorganic salts to the proper nutrition of the body does not com moldy force itself upon our attention, since, as a rule, we get our proper supply unconsciously with our food, without the sessity of making a deliberate selection. NaCl (common table-salt) forms an exception, however, to this rule. Speaking generally, inorganic salts do not serve asa source of heat-energy to the body — that is, the reactions that they may undergo are not accompanied by the transformation of a material amount of chemical energy into heat. On the other hand, their presence and distribution by virtue of their osmotic pressure may exercise an important influence upon the movement of water in the body. Most of the salts found in the urine and other excreta are eliminated in the same form in which thev CHEMISTRY OF DIGESTION AND NUTRITION. 355 were received into the body, Some of them, however, notably the phosphates and the sulphates, are formed in the course of the metabolism of the tissues, and without doubt reactions of various kinds occur affecting the composition of many of the salts — for example, the decomposition of the chlorides to form the HC1 of gastric juice. But these reactions do not materially influence the supply of energy in the body : the value of the salts lies in the general fact that they are necessary to the maintenance of the normal physical and chem- ical properties of the tissues and the body-fluids. Experimental investigation l has shown in a surprising way how immediately important the salts are in this respect. Forster fed dogs and pigeons on a diet in which the saline constit- uents had been much reduced, although not completely removed. The animals were given proteids, fats, and carbohydrates, but they soon passed into a moribund condition. It seemed, in fact, that the animals died more quickly on a diet poor in salts than if they had been entirely deprived of food. Similar experiments were made by Lunin upon mice, with corresponding results. He showed, moreover, that while mice live very well upon cow's milk alone, yet if given a diet almost free from inorganic salts, consisting of the casein and fats of milk plus cane-sugar, they soon died. Moreover, if all the inorganic salts of milk were added to this diet in the proportion in which they exist in the ash of milk, the mixture still failed to support life. It would seem from this result that the inorganic salts cannot fulfil completely their proper functions in the body unless they exist in some special combination with the organic constituents of the food. In this connection it is well to bear in mind that proteids as they occur in nature seem always to be combined with inorganic salts, and the properties of proteids, as we know them, are undoubtedly dependent in part upon the presence of this inorganic constituent. We may assume that the original synthesis of the organic and inorganic constituents is made in the plant kingdom, and that, in its own way, the inorganic constituent of the molecule is as necessary to the proper nutrition of the animal tissues as is the organic. One salt (NaCl) is consumed by many animals, including man, in excess of the amount uncon- sciously ingested with the food. Bunge points out that purely carnivorous animals are not known to crave this salt, while the herbivora with some exceptions — for example, the rabbit — take it at times largely in excess. The need of salt on the part of these animals is well illustrated among the wild forms by the eagerness with which they visit salt-licks. Bunge advances an ingenious theory to account for the difference between the herbivora and the carnivora in regard to the use of salt. He points out that in plant food there is a relatively large excess of potassium salts. When these salts enter the liquids of the body they react with the NaCl present and a mutual decomposition ensues, with the formation of KCl and the sodium salt of the acid formerly combined with the potassium, and the new salts thus formed are eliminated by the kidneys as soon as they accumulate beyond the normal limit. 1 Bunge: Physiological and Pathological Chemistry, translated by Wboldridge, L890. 356 AN AMERICAN TEXT-BOOK OF J'HYSIOLOGY. In this way the normal proportion of NaCl in tli£ tissues and the body-fluids is lowered and a craving for the Bait is produced. Bunge states that it has been shown among men that vegetarians habitually consume more salt than those who are accustomed to eat meats. The salts of calcium and of iron have also a special importance that needs a word of reference. The particular import- ance of the iron salts lies in their relation to haemoglobin. The continual formation of new red blood-corpuscles in the body requires a supply of iron Baits for the synthesis of the haemoglobin, and, although there is a probability (see p. 323) that the iron compound of the disintegrating corpuscles is again used in part for this purpose, we must suppose that the body requires addi- tional iron in the food from time to time to take the place of that which is undoubtedly lost in the excretions. It has been shown that iron is contained in animal and vegetable foods in the form of an organic compound, and the evidence at hand goes to show that only when it is so combined can the iron be absorbed readily and utilized in the body, while the efficacy of the inor- ganic salts of iron as furnishing directly a material for the production of haemo- globin is, to say the least, open to doubt. Bunge isolated from the yolk of eggs an iron-containing nuclei n which he calls hcematogen, because in the developing lien's eor in Ca salts, the bones fail to develop properly, and a condition similar to rickets in children becomes apparent. In addition to their relations to bone-formation and the fact that they form a normal con- stituent of the tissues and liquids of the body, calcium salts are necessary to the coagulation of blood (see p. 57), and, moreover, they seem to be connected in some intimate way with the rhythmic contractility of heart-muscle, and, indeed, with the normal activity of protoplasm in general, animal as well as plant. Notwithstanding the special importance of calcium in the body, no great amount of it seems to be normally absorbed or excreted. Voit bas shown that the calcium eliminated from the body is excreted mainly through the intestinal walls, but that most of the Ca in the feces is the unabsorbed (a of the food. It is possible that the Ca must be present in some special com- bination in order to be absorbed and utilized in the body. A point of special interest in connection with the nutritive value of the inorganic salts was brought out bv Bunge in some analyses of the body-ash of sucking animals in com- parison with analyses of the milk and the blood of the mother. In the CHEMISTRY OF DIGESTION AND NUTRITION. 357 case of the dog he obtained the following results (mineral constituents in 100 parts of ash) : Young Pup. Dog's Milk. Dog's Serum. K 2 8.5 10.7 2.4 Na 2 8.2 6.1 52.1 CaO 35.8 34.4 2.1 MgO 1.6 1.5 0.5 F 2 3 0.34 0.14 0.12 P 2 5 39.8 37.5 5.9 CI 7.3 12.4 47.6 The remarkable quantitative resemblance between the ash of milk and the ash of the body of the young indicates that the inorganic constituents of milk are especially adapted to the needs of the young; while the equally striking difference between the ash of milk and the ash of the maternal blood seems to show that the inorganic salts of milk are formed from the blood-serum not simply by diffusion, but rather by some selective secretory act. These facts come out most markedly in connection with the CaO and the P 2 5 . For further details as to the history of calcium and iron in the body, consult the section on Chemistry of the Body, under calcium and iron. I. Accessory Articles of Diet ; Variations of Body-metabolism under Different Conditions ; Potential Energy of Food ; Dietetics. Accessory Articles of Diet. — By accessory articles of diet we mean those substances that are taken with food, not for the purpose of replacing tissue or yielding energy, but to add to the enjoyment of eating, to stimulate the appetite, to aid in digestion and absorption, or for some other subsidiary purpose. They include such things as the condiments (mustard, pepper, etc.), the flavors, and the stimulants (alcohol, coffee, tea, chocolate, beef-extracts). They all possess, undoubtedly, a positive nutritive or digestive value beyond contributing to the mere pleasures of the palate, but their importance is of a subordinate character as compared with the so-called alimentary principles. They may be omitted from the diet, as happens or may happen in the ease of animals, without affecting injuriously the nutrition of the body, although it is probable tli.it neither man nor the lower animals would voluntarily eat food entirely devoid of flavor. Stimulants. — The well-known stimulating effect of alcohol, tea, coffee, etc., is generally attributed to a specific action on the nervous system whereby the irri- tability of the tissue is increased. The physiological effect of tea, coffee, and chocolate is due to the alkaloids callein (triinetliyl-xanthin) and thcobromin (dimethyl-xanthin). In small doses these substances are oxidized in the body and yield a corresponding amount of energy, but their value from this standpoint is altogether unimportant compared with their act ion as stimulants. Alcohol also, when not taken in too large quantities, may be oxidized in the body and furnish a not inconsiderable amount of energy. It is, however, a matter of controversy at present whether alcohol in small doses can be con- 358 AN AMERICA X TEXT- BO OK OF PHYSIOLOGY. sidered a true food-stuff, capable of replacing a corresponding amount of fats or of carbohydrates in the daily diet. The evidence is partly for and partly againsl such a use of alcohol. A number of observers' contend that when the body is brought into a condition of nitrogenous equilib- rium on a given diet of proteids, hits, and carbohydrates, and a certain pro- portion of the carbohydrates or fats is then replaced by an isodynamic amount of alcohol — that is, by an amount of alcohol that on combustion would yield the same amount of heat — the body does not remain in nitrogenous equi- librium, but, on the contrary, loses in nitrogen, thus indicating that the oxida- tion of alcohol in the body does not protect the proteid from consumption as in the case of the non-nitrogenous food-stuffs, fats, and carbohydrates. Miura, for example, brought himself into a condition of nitrogen equilibrium upon a mixed diet. Then for a certain period a portion of the carbohydrates was omitted from the diet and its place substituted by an isodynamic amount of alcohol. The result was a loss of proteid from the body, showing that the alcohol had not protected the proteid tissue as it should have done if it acts as a food. In a third period the old diet was resumed, and after nitrogen equilibrium had again been established the same proportion of carbohydrate was omitted from the diet, but alcohol was not substituted. When the diet was poor in proteid, it was found that less proteid was lost from the body when the alcohol was omitted than when it was used, indicating that, so far from protecting the proteid of the body by its oxidation, the alcohol exercised a directly injurious effect upon proteid-consumption. Atwater, 2 on the con- trary, as the result of elaborate experiments in which the heat production was determined calorimetrically and the body metabolism was determined also from an examination of the excreta, finds that alcohol, when substituted for the non-nitrogenous food-stuffs, does protect the proteid of the body from consumption just as the fats and carbohydrates do, and is, therefore, entitled scientifically to the designation of a food-stuff. So also Geppert and Zuntz found that alcohol in small doses caused no increase in the oxygen consumed, in spite of the fact that it was burnt in the body; the supposition in this case was that the burning of the alcohol saved some of the body material from consumption. Numerous other researches might be quoted to show that the effect of moderate quantities of alcohol upon body-metabolism is not yet satis- factorily understood. Before making any positive statements as to the details of its action it is wise, therefore, to wait until reliable experimental results have accumulated. The specific action of alcohol on the heart, stomach, and other organs has been investigated more or less completely, but the literature is too greaf and the results are too uncertain to permit any extended resume to be given here. When alcohol is taken in excess it produces the familiar symptoms of intoxication, which may pass subsequently into a con- dition of stupor or even death, provided the quantity taken is sufficiently 1 Zefochrift f. Uin. Medicin, 1892, Bel. xx. 8. 1M7. See also Rosemann : Archiv fur die ges- ammte Physiologic, 1899, Bd. 77, S. 40."), for references. 2 American Journal of Physiology, 1900, vol. 3, p. xii. CHEMISTRY OF DIGESTION AND NUTRITION. 359 great. So, also, the long-continued use of alcohol in large quantities is known to produce serious lesions of the stomach, liver, nerves, blood-vessels, and other organs. As has been stated before, alcohol is absorbed easily from the stomach and seems to increase the absorption of other soluble substances. 1 Upon the digestive action of the proteolytic and anxiolytic enzymes alcohol in certain strengths has a retarding effect, but in small percentages its action is not noticeable. 2 Upon the secretion of saliva and gastric juice it has a dis- tinct stimulating action, 3 and its action as a general stimulant to the central nervous system is indicated by its effect on the reaction time, and under certain conditions upon muscular exertion as measured by the ergograph. 4 The effect of alcohol upon the body evidently varies greatly with the quan- tity used. It may perhaps be said with safety that in small quantities it is beneficial, or at least not injurious, barring the danger of acquiring an alcohol habit, while in large quantities it is directly injurious to various tissues. Condiments and Flavors. — These substances probably have a directly bene- ficial effect on the processes of digestion by promoting the secretion of saliva, gastric juice, etc., in addition to the important fact that they increase thepal- atableness of food, and hence increase the desire for food and the secretion of the gastric juice. With reference to the condiments, Brandl has shown that mustard and pepper also markedly increase the absorption of soluble products from the stomach. Beef-tea, Meat-extracts. — The recent experiments of Pawlow and his co- workers (see section on Secretion) have shown that these substances have a specific value in their stimulating effect upon the gastric glands. They appear to contain substances that act as definite secretogogues toward these glands. Conditions Influencing Body-metabolism. — In considering the influence of the various food-stuffs upon body-metabolism we have for the most part neglected to mention the effect of changes in the condition of the body. It goes without saying that such things as muscular work, sleep, variations in temperature, etc. have or might have an important effect upon the character and amount of the chemical changes going on in the body, and in conse- quence a great many elaborate investigations have been made to ascertain pre- cisely the effect of conditions such as those mentioned upon the amount of the excretions, the production of heat in the body, and other similar points which throw light upon the nature of the metabolic processes. Effect of Muscular Work. — It is a matter of common knowledge that mus- cular work increases the amount of food consumed, and then lore the total body-metabolism, but it has been a point in controversy whether the increased oxidations affect the proteid or the non-proteid material. According (<> Liebig, the source of the energy of muscular work lies in the metabolism of the proteid constituents, and with increased muscular work there should be increased de- 1 Brandl : Zeitschrift fur Biologie, L892, Bd. 29, S. 277. 2 Chittenden and Mendel : American Journal of the Medical Sciences, 1896. :i Chittenden, Mendel and Jackson: American Journal of Physiology, 1898, vol. i. p. 164. 4 Schuniberg: Archiv fur Physiologic, 1899, Suppl. Bd. S. 289. 360 AN AMERICAN TEXT- BOOK OF PHYSIOLOGY. struction of proteid and an increase in the nitrogenous excretions. That the total energy of muscular work is not derived from the oxidation or metabolism of proteid alone was clearly demonstrated by the famous experiment of Fick and Wislicenus. These physiologists ascended the Faulhorn to a height of 1956 meters. Knowing the weight of his body, each could estimate how much work was done in ascending such a height. Kick's weight, for example, was 66 kilograms, therefore in climbing the mountain he performed 66 X 1956 = 129,096 kilogrammeters of work. In addition, the work of the heart and the respiratory muscles, which could not be determined accurately, was estimated at 30,000 kilogrammeters. There was, moreover, a certain amount of muscular work performed in the movements of the arms and in walking upon level ground that was omitted entirely from their calculations. For seventeen hours before the ascent, during the climb of eight hours, and for six hours afterward their food was entirely non-nitrogenous, so that the urea eliminated came entirely from the proteid of the body. Nevertheless, when the urine was collected and the urea estimated it was found that the potential energy contained in the pro- teid destroyed wasentirely insufficient to account for the work done. Although later estimates would modify somewhat the actual figures of their calculation, the margin was so great that the experiment has been accepted as showing conclusively that the total energy of muscular work does not come necessarily from the oxidation of proteid alone. Later experiments made by Voit upon a dog working in a tread- wheel and upon a man performing work while in the respiratorv chamber (p. 344) gave the surprising result that not only may the energy of muscular work be far greater than the potential energy of the proteid simultaneously oxidized, but that the performance of muscular work within certain limits does not affect at all the amount of proteid metabolized in the body, since the output of urea is the same on working-days as during days of rest. Careful experiments by an English physiologist, Parkes, made upon soldiers while resting and after performing long marches showed also that there is no distinct increase in the excretion of urea after muscular exercise. It followed from these experiments thai Liebig's theory as to the source of the energy of muscular work is incorrect, and that the increase in the oxida- tions in the body that undoubtedly occurs during muscular activity must affect only the non-proteid material, that is, the fats and carbohydrates. More recently the question was reopened by experiments made under Pfluger by Argutinsky. ' In these experiments the total nitrogen excreted was deter- mined with especial care in the sweat as well as in the urine and the feces. The muscular work d consisted in long walks and mountain-climbs. Argutinsky found that work caused a marked increase in the elimination of nitrogen, the increase extending over a period of three days, and he estimated that the additional proteid metabolized in consequence of the work was suf- ficient to account for most of the energy expended in performing the walks and climbs. A number of objections have been made to Argutinsky 's work. It has been asserted that during his experiment he kept himself upon a ! Pfluger^ Archiv fur die gesammte Physiologie, 1890, vol. 46, p. 552. CHEMISTRY OF DIGESTION AND NUTRITION. 361 diet deficient in non-proteid material; that if the supply of this material had been sufficient, none of the additional proteid would have been oxidized. It must be admitted, however, that the experiments of A.rgutinsky compel us to state the proposition above as to the relation between muscular work and proteid metabolism in a more careful way. It is necessary to modify the statement generally made to the extent of saying that muscular work causes no increase in proteid metabolism, provided the supply of non-nitrogenous food is abundant. If now we compare the amounts of C0 2 eliminated during work and during rest, it will be found that there is a very decided increase during work. In the experiments made by Pettenkofer and Voit the 0O 2 given off by a man during a day of muscular work was nearly double that eliminated during a resting-day. Indeed, the same fact has been observed repeatedly upon isolated muscles made to contract by artificial stimuli. Assuming, then, that muscular work causes no increase in the nitrogen excreted, but a marked increase in the C0 2 eliminated, we are justified iu saying that the energy of muscular work under normal conditions comes mainly, if not exclusively, from the oxidation of non-proteid material. The machine that does the work, the muscle, is par excellence a proteid tissue, but the normal resting metabolism of its pro- teid substance is not increased by the chemical changes of contraction. Or, to put it in another way, the chemical changes that give rise to the energy lib- erated in contraction may involve only the non-proteid material. It is inter* >t- ing to remember in this connection that the consumption of glycogen, or of the sugar derived from it, is intimately connected with muscular work. The glycogen of the body in an animal deprived of food disappears much more rapidly if the animal is made to work his muscles than if he remains at rest. In an experiment by Kiilz upon well-fed dogs it was found that the glycogen was practically all used up in a single fasting-day during which the animals did a great deal of work. Morat and Dufourt have shown also that a muscle after prolonged contraction takes much more sugar from the blood than it did previous to the contraction, and Harley 1 finds that power to perform muscular work may be increased and susceptibility to fatigue be diminished by eating sugar in quantities. It is, in fact, generally agreed that glycogen i- used up in muscle-contractions, but the way in which the destruction of the glycogen is effected is not definitely known. After the glycogen has been con- sumed it is probable that the other constituents of the body, the fats and the proteids, are called upon to furnish the necessary energy. I'd- this reason we should expect, in a person performing excessive muscular work, that there would be an increased destruction of proteid when the supply of aon-proteid food is insufficient. Metabolism during Sleep. — It has been shown that during sleep there is no marked diminution of the nitrogen excreted, and therefore no distincl decrease in the proteid metabolism; on the contrary, the < '< > 2 eliminated and the oxygen absorbed are unquestionably diminished. This latter fact finds its 1 Journal ,,/ Physiology, 1894, vol. xvi. j>. '.'7. 362 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. simplest explanation in the supposition that the muscles are less active during sl< ep. The muscles do less work in the way of contractions, and, in addition, probably suffer a diminution in tonicity which also affects their total metab- olism. Effect of Valuations in Temperature. — In warm-blooded animals variations of outside temperature within ordinary limits do not affect the body-tem- perature. A full account of the means by which this regulation is effected will be found in the section upon Animal Heat. So long as the temper- ature of the body remains constant, it has been found that a fall of outside temperature may increase the oxidation of non-proteid material in the body, the increase being in a general May proportional to the fall in temperature. That the increased oxidation affects the non-proteid constituents is shown by the fact that the urea remains unchanged in quantity, other conditions being the same, while the oxygen-consumption and the C0 2 -elimination are increased. This effect of temperature upon the body-metabolism is due mainly to a reflex stimulation of the motor nerves to the muscles. The temperature-nerves of the skin are affected by the fall in outside temperature, and bring about reflexly an increased or a diminished innervation of the muscles of the body. Indeed, it is stated 1 that unless the lowering of the temperature is sufficient to cause shivering or muscular tension no increase in the C0 2 -excretion results. This fact suffices to explain, therefore, the physiological value of shivering and muscular restlessness when the outside temperature is low. The fact that variations in outside temperature affect only the consumption of non-proteid material falls in, therefore, with the conception of the nature of the metab- olism of muscle in activity, given above. When the means of regulating the body-temperature break down from too long an exposure to excessively low or excessively high temperatures, the total bodv-mPtabolism, proteid as well as non-proteid, increases with a rise in body-temperature and de- creases with a fall in temperature. In fevers arising from pathological causes it has been shown that there is also an increased production of urea as well as of C0 2 . Effect of Starvation. — A starving animal must live upon the material pres- ent in its body. This material consists of the fat stored up, the circulating and tissue proteid, and the glycogen. The latter, which is present in compara- tively small quantities, is quickly used, disappearing more or less rapidly according to the extent of muscular movements made, although in any case it practically vanishes in a few days. Thereafter the animal lives on its own proteid and fat, and if the starvation is continued to a fatal termination the body becomes correspondingly emaciated. Examination of the several tissues in animals starved to death has brought out some interesting facts. Voit took two cats of nearly equal weight, fed them equally for ten days, and then killed one to serve as a standard of comparison and starved the other for thirteen days: the latter animal lost 1017 grams in weight, and the loss was divided as follows among the different organs : 1 Johannson: Skandinavisehr* Archiv fiir Physioloyie, 1897, Kd. vii. S. 123. CHEMISTRY OF DIGESTION AND NUTRITION. 363 Supposed wt. of Actual loss of Loss to each 100 grams organs before organs in of fresh organ starvation. grams. (percentage loss). Bone 393.4 54.7 13.9 Muscle 1408.4 429.4 30.5 Liver 91.9 49.4 53.7 Kidney 25.1 6.5 25.9 Spleen 8.7 5.8 66.7 Pancreas 6.5 1.1 17.0 Testes 2.5 1.0 40.0 Lungs 15.8 2.8 17.7 Heart 11.5 0.3 2.6 Intestines 118.0 20.9 18.0 Brain and cord .... 40.7 1.3 3.2 Skin and hair .... 432.8 89.3 20.6 Fat 275.4 267.2 97.0 Blood 138.5 37.3 27.0 Remainder 136.0 50.0 36.8 According to these results, the greatest absolute loss was in the muscles (429 grams), while the greatest percentage loss was in the fat (97 percent.), which had practically disappeared from the body. It is very significant that the central nervous system and the heart, organs which we may suppose were in continual activity, suffered practically no loss of weight : they had lived at the expense of the other tissues. We must suppose that in a starving animal the fat and the proteid material, particularly that of the voluntary muscles, pass into solution in the blood, and are then used to nourish the tissues gen- erally and to supply the heat necessary to maintain the body-temperature. Examination of the excreta in starving animals has shown thai a greater quantity of proteid is destroyed during the first day or two than in the sub- sequent days. This fact is explained on the supposition that the body i> al first richly supplied with " circulating proteid " derived from its previous food, and that after this is metabolized the animal lives entirely, so far as proteid-consumption is concerned, upon its "tissue proteid." If the animal remains quiet during starvation, the amount of nitrogen excreted daily soon reaches a nearly constant minimum, showing that a practically constant amount of proteid (together with fat) is consumed daily to furnish body-heat, and probably to repair tissue waste in the active organs, such as the heart. Shortly before death from starvation the daily amount of proteid consumed may increase, as shown by the larger amount of nitrogen eliminated. This fact is explained by assuming that the body fat is then exhausted and the animal's metabolism is confined to the tissue proteids alone. The general fact that the loss of proteid is greatest during the firsl one or two days of starvation lias been confirmed recently upon men, in a number of interesting experiments made upon professional tasters. For the numerous details as to loss of weight, variations of temperature, etc., carefully r< rded in these latter experiments, reference must be made to original sources.' It may be added, in conclusion, that the fatter the body is to begin with, the longer will 1 Yirchow's Arehiv, lid. 131, supplement, 1893, and Luciani, Das ffungern, 1S90. 364 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. starvation be endured, and if water is consumed freely the evil effects of star- vation, as well as the disagreeable sensations of hunger, are very much reduced. Potential Energy of Food. — The chemical changes occurring in the body are accompanied by a transformation of chemical energy to different forms — for example, to heat, electricity, and mechanical work. By far the most of this energy takes the form, directly or indirectly, of heat Even when the muscles are apparently at rest we know that theyare undergoing chemical changeswhich give risetoheat. When :t muscle contracts, the greater part (four-fifths) of th< energy liberated by the chemical change takes the form of heat ; a much smallei part (al)ont one-fifth as a maximum) may perform mechanical work, which in turn, as in the case of the respiratory muscles and the heart, may be con- verted to heat within the body. Roughly speaking, an adult man gives off from his body in the course of twenty-four hours about 2,400,000 calories of heat (1 calorie = the heat uecessary to raise 1 cubic centimeter of water 1° C). This supply of heat is derived from the metabolism or physiological oxidation of the proteids, the fats, and the carbohydrates that we take into the body in our food. By means of the oxygen absorbed through the lungs these substances are burnt, with the formation of C0 2 , H 2 0, and urea or some similar nitrog- enous waste product. In the long run, then, the source of body-energy is found in the potential energy contained in our food. Our energy-yielding foods — proteids, fats, and carbohydrates — are more or less complex bodies that are built up originally by plant organisms with the aid of solar energy; when they are burnt or otherwise destroyed, with the formation of simpler bodies (such as C0 2 or H 2 0), their so-called potential energy is liberated in the form of heat, and this is what occurs in the body. From the standpoint of the law of conservation of energy it is easy to understand that the amount of available energy in any food-stuff may be determined by burning it outside the body and measuring the quantity of heat liberated. If a gram of sugar is burnt, it is converted to C0 2 and FLO and a certain quantity of heat is liber- ated ; if the same gram of sugar had been taken into the body, it would event- ually have been reduced to the form of C0 2 and H 2 0, and the total quantity of heat liberated would have been the same as in the combustion outside the body, although the destruction of the sugar in the body may not be a direct, but an indirect, oxidation; that is, the oxygen may first be combined with sugar and other food-stuffs to form a complex molecule which afterward dissociates into simpler compounds similar to those obtained by direct oxidation, or there may be first a dissociation or cleavage followed by oxidation of the dissociation products. In determining the total energy given to the body we need only consider the form in which a substance enters the body and the form in which it is finally eliminated. In the case of proteids the combustion in the body is not so complete as it is outside ; the chief final products are C0 2 , H 2 0, and urea. The urea, however, .-till contains potential energy which may be lib- erated by combustion, and in determining the energy of proteid available to the body, that which is lost in the urea must be deducted. As a matter of fact, it is possible that the proteid in the body is completely oxidized to C0 2 , CHEMISTRY OF DIGESTION AND NUTRITION. 365 H..O, and NH 3 ; but, since the XH,in this case is recombined to form an ammo- nium compound, and this in turn is converted into urea, the additional energy lib- erated in the first combustion is balanced by that absorbed in the synthetic produc- tion of the urea. Thepotential energy ofthe fats, carbohydrates, and proteids can be determined by combustion outside the body; the energy liberated is meas- ured in terms of heat by some form of calorimeter, and the quantity of heat so obtained, expressed in calories, is known usually as the "combustion equiva- lent." To be perfectly accurate, each particular form of fat, proteid, etc. should be burnt and its energy be determined, but usually average figures are employed, as the amount of heat given off by the different varieties of any one food-stuff — proteids, for example — does not vary greatly. According to Stoh- mann, 1 gram of beef deprived of fat = 5641 calories, while 1 gram of veal gives 5663 calories. For muscle extracted with water, Rubner obtained the following figures: 1 gram = 5778 calories. The combustion equivalent of urea (Rubner) is 2523 calories. Since 1 gram of proteid yields about one-third of a gram of urea, we should deduct 841 calories from the combustion equiva- lent of one gram of proteid to get its available energy to the body : 5778 — 841=4937 calories. Practically, however, this value is found to be too high. Direct determinations upon the body in a calorimeter gave to Rubner the fol- lowing values, which seem to be generally adopted by workers in this field: 1 gram of proteid=4100 calories, 1 gram of fat=9300 calories, 1 gram of carbo- hvdrate=4100 calories. Weight for weight, fat contains the most energy, and, as we know, in cold weather and in cold climates the proportion of fat in the food is increased. In dietetics, however, the use of fatis limited by thedifficulty attending its digestion and absorption as compared with carbohydrates. Fats and carbohydrates have the same general nutritive value to the body : they serve to supply energy. Since the amount of potential energy contained in each of these substances may be determined accurately by means of its com- bustion equivalent, it would seem probable that they might be mutually interchangeable in dietetics in the ratio of their combustion equivalents. Such, in fact, is the case. The ratio of interchange is known as the " i so- dynamic equivalent," and it is given usually as 1 : 2,4 or 2.2 ; that is, fats may replace over twice their weight of carbohydrate in the diet. It follows from the general principles just stated that if we wished to know the amount of heat produced in the body in a given time, say twenty-lour hours, we might ascertain it in one of two ways: In the first place, the animal might be placed in a calorimeter and the heat given off in twenty-four hours be measured directly. This method, which is that of direct calorimetry, is described more completely in the section treating of Animal Ileal. Secondly, one might feed the animal upon a diet containing known quantities of proteid, fats, and carbohydrates, and by collecting the total N and C excreta determine how much of each of these had been destroyed in the body. Knowing the combustion equivalent of each, the total quantity of heat liberated in the body could be ascertained. This latter method is known as indirect calorimetry. The two methods, if applied simultaneously to the same animal, should give identical results. It is very interesting to know that an experiment of this character 366 AX AMERICA X TEXT-BOOK OE PHYSIOLOGY has been successfully performed by Rubner; 1 his experiments were made with the greatest accuracy and with careful attention to all the possible sources of error, and it was found that the quantities of heat as determined by the two methods agreed to within less than 0.5 per cent. These experiments are note- worthy because they furnish us with the first successful experimental demon- stration of the accuracy of the general principles, stated above, upon which the available energy of foods is calculated. Dietetics. — The subject of the proper nourishment of individuals or col- lections of individuals — armies, inmates of hospitals, asylums, prisons, etc. — is treated usually in books upon hygiene, to which the reader is referred for practical details. The general principles of dieting have been obtained, how- ever, from experimental work upon the nutrition of animals. These principles have been stated more or less completely in the foregoing pages, but some additional facts of importance may be referred to conveniently at this point. In a healthy adult who has attained his maximum weight and size the main object of a diet is to furnish sufficient nitrogenous and non-nitrogenous food- stuffs, together with salts and water, to maintain the body in equilibrium — that is, to prevent loss of proteid tissue, fat, etc. In speaking of the nutritive value of the food-stuffs it was shown that in carnivora (dogs) this condition of equilibrium may be maintained upon proteid food alone, putting aside all consideration of salts and water, or upon proteids and fats, or upon proteids and carbohydrates, or upon proteids, fats, and carbohydrates. When proteids alone are used, the quantity must be increased far above that necessary in the case of a mixed diet, and it is doubtful whether, in the case of man or the herbivora, a healthy nutritive condition could be maintained long upon such a diet, owing to the largely increased demand upon the power of the alimentary canal to digest and absorb proteids, to the greater labor thrown on the kidneys, etc. The experience of mankind, as well as the results of experimental investiga- tion, shows that the healthy diet is one composed of proteids, fats, and carbo- hydrates. The proportion in which the fats and the carbohydrates should be taken — and, to a certain extent, this is true also of the proteids — may be varied within comparatively wide limits, in accordance with the law of " iso- dynamic equivalents/' provided that the total amount of potential energy repre- sented in the food does not fall below a certain amount, on the average about 10,000 calories per kilo, of body weight. This is illustrated by the fol- lowing "average diets" calculated by different physiologists to indicate the average amount of food-stuffs required by an adult man under normal conditions of Life : Average Diets. Molesehott. Ranke. Voit. Forster. Atwater. Fats Carbohydrates .... 130 grams. 40 " 550 " 100 grains. 100 " 240 " 118 grams. 56 " 500 " 131 grams. 68 " 494 " 125 grams. 125 " 400 " 1 ZriUrhnjt Jiir Jlmh./ie, 1893, Bd. XXX. S. 73. CHEMISTRY OF DIGESTION AND NUTRITION. 367 In Voit's diet, which is the one usually taken to represent the daily Deeds of the body, it will be noticed that the ratio of the nitrogenous to the non- nitrogenous food-stuffs is about as 1 : 5, and basing the estimate upon a man weighing 70-75 kilos., 118 grams of proteid per day would represent a consumption of proteid equal to 1.3 to 1.7 grams per kilo, of weight. Siven 1 has recently attempted to show that this proportion of proteid in food is unnecessarily high. In some experiments upon himself he was able to reduce his daily proteid food to about 0.2 gram per kilo, of body weight and still maintain his body in N-equilibrium, provided the non-proteid por- tions of his diet were so increased that the total energy of his daily diet remained unchanged. Whether or not so high an amount of proteid per day as 118 grams is most beneficial to the body, under normal conditions of mod- erate labor, is perhaps an open question. It seems certain that for short periods at least the average individual can keep his body in equilibrium on much smaller amounts. It must be remembered, in regard to these diets, that the amounts of food-stuffs given refer to the dry material: 118 grams of proteid do not mean 118 grams of lean meat, for example, since lean meat (flesh) contains a large proportion of water. Tables of analyses of food (one of which is given on page 278) enable us to determine for each par- ticular article of food the proportion of dry food-stuffs contained in it, and in how great quantities it must be taken to furnish the requisite amount of proteid, fats, or carbohydrates. There is, however, still another practical consideration that must be taken into account in estimating the nutritive value of articles of food from the analyses of their composition, and that is the extent to which each food-stuff in each article of food is capable of being digested and absorbed. Practical experience has shown that proteids in certain articles of food can be digested and absorbed nearly completely when not fed in excess, while in other foods only a certain percentage of the proteid is absorbed under the most favor- able conditions. This difference in usableness of the food-stuffs in various foods is most marked in the case of proteids, but it occurs also with the fats and the carbohydrates. Facts of this kind cannot be determined by mere analysis of the foods; they must be obtained from actual feeding experiments upon man or the lower animals. ft has usually been stated by those who have worked in this field that the proteids of meats are more completely util- ized than those of vegetables. Hut it is possible that as a generalization this statement is too sweeping, and rests upon the erroneous assumption that the nitrogen in \\'c<^ represents chiefly undigested proteid. Prausnitz 2 and others have given reasons for believing that the nitrogen inthefeces is derived mainly from the intestinal secretions, and that vegetable foods that do not contain much indigestible material, such as rice and bread, are practically completely digested and absorbed in the intestines, their proteids, therefore, being utilized as completely as in the case of meats. Munk' 1 gives an inter 1 Skandinavisehes Archivfiir Physiologic, 1899, Bd. 10, S. 91. 1 Zeitsehrifi fur Biologie, L897, Bd. 35, S. 835. 3 Wevl's Handbuch der Hygiene, L893, Bd. iii. Theil i. S. 69. 368 AN AM ERIC AX TEXT-BOOK OF PHYSIOLOGY. esting table showing how much of certain familiar articles of food would be necessary, if taken alone, to supply the requisite daily amount of proteid or non-proteid food ; his estimates are based upon the percentage composition of the fond-, and upon experimental data showing the extent of absorption of the food-stuffs in each food. In this table he supposes that the daily diet should contain 11<> grams of proteid = 17.5 grams of N, and non-proteids sufficient to contain 270 grains of C : Milk . . . . Meal ! lean) . Heu's eggs Wheat flour . Wheat bread Rye bread . . Rice . . . . Corn . . . . Peas . . . . Potatoes . . For 1K» grams proteid (17.5 grams N I. 2900 540 18 800 1650 1900 1870 990 520 4500 grams. grams. For 270 grams C. 3800 grams. 2000 37 eggs. 670 grams. 1000 " 1100 " 750 " 660 750 2550 As Munk points out, this table shows that any single food, if taken in quantities sufficient to supply the nitrogen, would give too much or too little C, and the re- verse; those animal foods which, in certain amounts, supply the nitrogen needed furnish only from one-quarter to two-thirds of the necessary amount of C. To live for a stated period upon a single article of food — a diet sometimes recom- mended to reduce obesity — means, then, an insufficient quantity of either N or C and a consequent loss of body-weight. Such a method of dieting amounts practically to a partial starvation. In practical dieting we are accustomed to get our supply of proteids, fats, and carbohydrates from both vegetable and animal foods. To illustrate this fact by an actual case, in which the food was carefully analyzed, an experimenter (Krummacher) weighing 67 kilograms records that he kept himself in N equilibrium upon a diet in which the pro- teid was distributed as follows : 300 grams meat 666. 3 c.c. milk 100 grams rice 100 " bread 500 c.c. wine 63.08 grains proteid 18.74 " 7.74 '• 11.32 " " 1.17 " 102.05 " For a person in health and leading an active normal life, appetite and experi- ence seem to be safe and sufficient guides by which to control the diet; but iu conditions of disease, in regulating the diet of children and of collections of individuals, scientific dieting, if one may use the phrase, has accomplished much, and will lie of greater service as our knowledge of the physiology of nutrition increases. VI. MOVEMENTS OF THE ALIMENTARY CANAL. BLADDER, AND URETER. Plain Muscle -tissue. The movements of the alimentary canal and the organs concerned in mic- turition are effected for the most part through the agency of plain muscle- tissue. The general properties of this tissue will be referred to in the section upon the Physiology of Muscle and Nerve, but it seems appropriate in this connection to call attention to some few points in its general physiology and histology, inasmuch as the character of the movements to be described depends so much upon the fundamental properties exhibited by this variety of muscle-tissue. Plain muscle as it is found in the walls of the abdominal and pelvic viscera is composed of masses of minute spindle-shaped cells whose size is said to vary from 22 to 560 p. in length and from 4 to 22 ju in width, the average size, according to Kolliker, being 100 to 200 fx in length and 4 to 6 u in width. Each cell has an elongated nucleus, and its cytoplasm shows a longitudinal fibrillation. Cross striation, such as occurs in cardiac and striped muscle, is absent. These cells are united into more or less distinct bundles or fibres, which run in a definite direction corresponding to the long axes of the cells. The bundles of cells are united to form flat sheets of muscle of varying thicknesses, which constitute part of the walls of the viscera and are distin- guished usually as longitudinal and circular muscle-coats according as the cells and bundles of cells have a direction with or at right angles to the long axis of the viscus. The constituent cells arc united to one another by cement- substance, and according to several observers 1 there is a direct protoplasmic continuity between neighboring cells — an anatomical fact of interest, since it makes possible the conduction of a wave of contraction directly from one cell to another. Plain muscle-tissue, in some organs at least, e. g. the stomach, intestines, bladder, and arteries, is under the control of motor nerves. There must be, therefore, some connection between the nerve-fibres and the muscle- tissue. The nature of this connection is not definitely established ; according to Miller, 2 the nerve-fibres terminate eventually in line nerve-fibrils that run in the cement-substance between the cells and send off small branches that end in a swelling applied directly to the muscle-cell. Berkley'' finds a similar 1 Sec I'xilicMiaii : A iiinisc/i< r .1 h-ci'i/it, I SKI, I'.d. 10, No. 10. 2 Archiv fur mikro8kopisclii' Atminmir, is, |'.<1. 40. 3 Anatomhcher Anzeigcr, 1893, Bd. 8. Voi,. I. —24 369 370 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. ending of the nerves, and in addition describes in the muscularis mucosae of the intestine a large globular end-organ which he considers as a motor plate. Perhaps the most striking physiological peculiarity of plain muscle, as compared with the more familiar striated muscle, is the sluggishness of its contrac- tions. Plain muscle, like striated muscle, is inde- pendently irritable. Various forms of artificial stimuli, such as electrical currents, mechanical, chemical, and thermal stimuli, may cause the tis- sue to contract when directly applied to it, but the contraction in all cases is characterized by the slowness with which it develops. There is a long latent period, a gradual shortening which may per- sist for some time after the stimulus ceases to act, and a slow relaxation. These features are repre- sented in the curve shown in Figui'e 68, which it is instructive to compare with the typical curve of a striated muscle (Vol. II.). The slowness of the con- traction of plain muscle seems to depend upon the absence of cross striation. Striped muscle as found in various animals or in different muscles of the same animal — e. g. the pale and red muscles of the rabbit — differs greatly in the rapidity of its contraction, and it has been shown that the more perfect the cross striation the more rapid is the contraction. The cross striation, in other words, is the expression of a mechanism or structure adapted to quick contractions and relaxations, and the relatively great slowness of movement in the plain muscle seems to result from the absence of this particular structure. It should be added, however, that plain muscle in different parts of the body exhibits considerable variation in the rapidity with which it contracts under stimulation, the ciliary muscle of the eyeball, for example, being able to react more rapidly than the muscles of the in- testines. The gentle prolonged contraction of the plain muscle is admirably adapted to its function in the intestine of moving the food-contents along the canal with sufficient slowness to permit normal digestion and absorption. Like the striated muscle, and un- like the cardiac muscle, plain muscle is capable of I ;<.. 68.— Contraction of a stri]> of plain muscle from tin- stomach of a terrapin. The bottom line gives the time-record in seconds ; tin- middle line shows the time of application of the stimulus, a tetan- izing current from an induction coil ; the upper line is the curve recorded by the contracting muscle. MOVEMENTS OF THE ALIMENTARY CANAL, ETC. 371 giving submaximal as well as maximal contractions; with increased strength of stimulation the amount of the shortening increases until a maximum is reached. This fact may be observed not only upon isolated strips of muscle from the stomach, but may be seen also in the different degrees of contraction exhibited by the intestinal musculature as a whole when acted upon by various stimuli. In his researches upon the movements of the ureter Engelmann l showed that a stimulus applied to the organ at any point caused a contraction that. starting from the point stimulated, might spread for some distance in either direction. Engelmann interprets this to mean that the contraction wave in the case of the ureter is propagated directly from cell to cell, and this possi- bility is supported by the fact, before referred to, that there is direct proto- plasmic continuity between adjoining cells. This passage of a contraction wave from cell to cell has, in fact, often been quoted as a peculiarity of plain muscle-tissue. In the case of the ureter the fact seems to be established, but in the intestines, where there is a rich intrinsic supply of nerve-ganglia, it is not possible to demonstrate clearly that the same property is exhibited. The wave of contraction in the intestine following artificial stimulation is, according to most observers, usually localized at the point stimulated or is propagated in only one direction, and these facts are difficult to reconcile with the hypothesis that each cell may transmit its condition of activity directly to neighboring cells. Upon the plain muscle of the ureter Engel- mann was able to show also an interesting resemblance to cardiac muscle, in the fact that each contraction is followed by a temporary diminution in irritability and conductivity ; but this important property, which in the case of the heart has been so useful in explaining the rhythmic nature of its contrac- tions, has not been demonstrated for all varieties of plain muscle occurring in the body. A general property of plain muscle that is of great significance in explain- ing the functional activity of this tissue is exhibited in the phenomenon of "tone." By tone or tonic activity as applied to muscle-tissue is meant a con- dition of continuous contraction or shortening that persists for long periods and may be slowly increased or decreased by various conditions affecting the muscle. Both striated and cardiac muscle exhibit tone, and in the latter at least the condition may be independent of any inflow of nerve-impulses from the extrinsic nerves. Plain muscle exhibits the property in a marked degree. The muscular coats of the alimentary canal, the blood-vessels, the bladder, etc., are usually found under normal circumstances in a condition of tone that varies from time to time and differs from an ordinary visiUe contraction in the slowness with which it develops and in its persistence for long periods. Such conditions as the reaction of the blood, for example, are known to alter greatly the tone of the blood-vessels, a less alkaline reaction than normal causing relaxation, while an increase in alkalinity favor- the development of tone. Tone may also be increased or diminished by the action of motor or 1 I'jliii/ir'x Archivfur die gesammte Physiologie, 1869, Bd. -', S 243. 372 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. inhibitory nerve-fibres, but the precise relationship between the changes underlying the development of tone and those leading to the formation of an ordinary contraction has not been satisfactorily determined. The mode of contraction of the plain muscle in the walls of some of the viscera, especially the intestine and meter, is so characteristic as to be given the special name of peristalsis. I>y peristalsis, or vermicular contraction as it is sometimes called, is meant a contraction which, beginning at any point in the wall of a tubular viscus, is propagated along the length of the tube in the form of a wave, each part of the tube as the wave reaches it passing slowly into contraction until the maximum is reached, and then gradually relaxing. In viscera like the intestine, in which two muscular coats are present, the longitudinal and the circular, the peristalsis may involve both layers, either simultaneously or successively, but the striking feature observed when watching the movement is the contraction of the circular coat. The contraction of this coat causes a visible constriction of the tube that may be followed by the eye as it passes onward. Mastication. Mastication is an entirely voluntary act. The articulation of the mandi- bles with the skull permits a variety of movements ; the jaw may be raised and lowered, may be projected and retracted, or may be moved from side to side, or various combinations of these different directions of movement may be effected. The muscles concerned in these movements and their innervation are described as follows: The masseter, temporal and internal pterygoids raise the jaw ; these muscles are innervated through the inferior maxillary division of the trigeminal. The jaw is depressed mainly by the action of the digastric muscle, assisted in some cases by the mylo-hyoid and the geniohyoid. The two former receive motor-fibres from the inferior maxillary division of the fifth cranial, the last from a branch of the hypoglossal. The lateral movements of the jaws are produced by the external pterygoids, when acting separately. Simultaneous contraction of these muscles on both sides causes projection of the lower jaw. In this latter case forcible retraction of the jaw is produced by the contraction of a part of the temporal muscle. The external pterygoids also receive their motor fibres from the fifth cranial nerve, through its inferior maxillary division. The grinding movements commonly used in masticating the food between the molar teeth are produced by a combination of the action of the external pterygoids, the elevators, and perhaps the depressors. At the same time the movements <r solar plexus and then to the stomach. These fibres probably reach the stomach as non-medullated or sympathetic fibres. The vagi where they are distributed to the stomach seem to consisl almosf entirely of non-medullated fibres also, and probably the fibres distributed to the muscular coat arc of this variety. The results of numerous experiments seem to show quite conclusively thai in general the fibres received along the vagus path arc motor, artificial stimula- tion of them causing mure or less well marked contractions of part or all of the musculature of the stomach. It has been shown that the sphincter pylori as well as the rest of the musculature is supplied by motor fibres from these 1 Zeitschrift filr Biologie, 1895, Bd. xxxii. 382 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. nerves. The fibres coming through the splanchnics, on the contrary, are mainly inhibitory. When stimulated they cause a dilatation of the contracted stomach and a relaxation of the sphincter pylori. Some observers have reported experiments which seem to show that this anatomical separation of the motor and inhibitory fibres is not complete; that some inhibitory fibres may be found in the vagi and some motor fibres in the splanchnics. The anatomical courses of these fibres are insufficiently known, but there seems to lie no question as to the existence of the two physiological varieties. Through their activity, without doubt, the movements of the stomach may be regu- lated, favorably or unfavorably, by conditions directly or indirectly affect- ing the central nervous system. Wertheimer 1 has shown experimentally that stimulation of the central end of the sciatic or the vagus nerve may cause reflex inhibition of the tonus of the stomach, and Doyon 2 has confirmed this result in cases where the movements and tonicity of the stomach were first increased by the action of pilocarpin and strychnin. Cannon in his observa- tions upon cat- found that all movements of the stomach ceased as soon as the animal showed signs of anxiety, rage, or distress. It must be borne in mind, however, that the action of these extrinsic fibres under normal conditions is probably only to regulate the movements of the stomach. As we have seen, even the extirpated stomach under proper conditions seems to execute movements of the normal type. Normally the movements are provoked by a stimulus of some kind, usually the presence of food material in the interior of the stomach. How the stimulus acts in this case, whether directly upon the muscle-fibres or indirectly through the intrinsic ganglia of the stomach, has not been determined, and the evidence for either view is so insufficient that a discussion of the matter at this time would scarcely be profitable. We musl wait for more complete investigations upon the physiology as well as the his- tology of the muscle- and nerve-tissue in this and in other visceral organs constructed on the same type. Movements op the Intestines. The muscles of the small and the large intestine are arranged in two layers, an outer longitudinal and an inner circular coat, while between these coats and in the submucous coat there are present the nerve-plexuses of Auerbach and Meissner. The general arrangement of muscles and nerves i< similar, there- fore, to that prevailing in the stomach, and in accordance with this we find that the physiological activities exhibited are of much the same character, only, per- haps not quite so complex. Forms of Movement. — Two main forms of intestinal movement have been distinguished, the peristaltic and the pendular. Peristalsis. — The peristaltic movement consists in a constriction of the walls of the intestine which beginning at a certain point passes downward away from the stomach, from segmenl to segment, while the parts behind the advancing /.one of constriction gradually relax. The evident effect of such a movement 1 .i PhysiologU normak et pathologique, 1S92. p. 379. 2 Ibid., 1895, p. 374. MOVEMENTS OF THE ALIMENTARY CANAL, ETC 383 would be to push onward the contents of the intestines in the direction of the movement. It is obvious that the circular layer of muscles is chiefly involved in peristalsis, since constriction can only be produced by contraction of this layer. To what extent the longitudinal muscles enter into the movement is not definitel v determined. The term " anti-peristalsis" is used to describe the same form of movement running in the opposite direction — that is, toward the stomach. Anti-peristalsis is usually said not to occur under normal conditions; it has been observed sometimes in isolated pieces of intestine or in the exposed intes- tine of living animals when stimulated artificially, and Griitzner 1 reports a number of curious experiments which seem to show that substances such as hairs, animal charcoal, etc., introduced into the rectum may travel upward to the stomach under certain conditions. The peristaltic wave normally passes down- ward, and that this direction of movement is dependent upon some definite arrangement in the intestinal walls is beautifully shown by the experiments of Mall 2 and others upon reversal of the intestines. In these experiments a por- tion of the small intestine Mas resected, turned round and sutured in place again, so that in this piece what was the lower end became the upper end. In those animals that made a good operative recovery the nutritive condition gradually became very serious, and in the animals killed and examined the autopsy showed accumulation of material at the upper end of the reversed piece of intestine, and great dilatation. The peristaltic movements of the intestines may be observed upon living animals when the abdomen is opened. If the operation is made in the air and the intestines are exposed to its influence, or if the conditions of tempera- ture and circulation are otherwise disturbed, the movements observed are often violent and irregular. The peristalsis runs rapidly along the intes- tines and may pass over the whole length in about a minute; at the same time the contraction of the longitudinal muscles gives the bowels a peculiar writhing movement. Movements of this kind are evidently abnormal, and onlv occur in the body under the strong stimulation of pathological conditions. Normal peristalsis, the object of which is to move the food slowly along the alimentary tract, is quite a different affair. Observers all agree that the wave of contraction is gentle and progresses slowly. According to Bayliss and Starling, 3 the peristaltic movement is a complicated reflex through the intrinsic ganglia. When the intestine is stimulated by a bolus placed within its cavity, the musculature above the point stimulated is excited, while that below is in- hibited. In accordance with this law they find that in peristalsis the advanc- ing wave of constriction is preceded by a wave of relaxation or inhibition. The force of the contraction as measured by Cash ' in the dog's intestine is very small. A weighl of five to eight grains was sufficient to check the on- ward movement of the substance in the intestine and to set up violent colicky 1 Deutsche medicinische Wpchenschrift, 1894, No. 18. 2 The Johns Hopkins Hospital Reports, vol. i. p. 93. 8 Journal of Physiology, L899, vol xxiv. p. 99. 4 Proceedings of tin- Royal Society, London, 1887, vol. 41. 384 AN AMERICA X TEXT-BOOK OF PHYSIOLOGY. contractions which caused the animal evident uneasiness. We may suppose that under normal conditions each contraction of* the antrum pylori of the stomach, which ejects chyme into the duodenum, is followed by a peristalsis that beginning at the duodenum passes slowly downward for a part or all of the small intestine. According to most observers, the movement is blocked at the ileo-ca?cal valve, and the peristaltic movements of the large intestine form an independent group similar in all their general characters to those of the small intestine, but weaker and slower. Mechanism of the Peristaltic Movement. — The means by which the peri- staltic movement makes its orderly forward progression have not been deter- mined beyond question. The simplest explanation would be to assume that an impulse is conveyed directly from cell to cell in the circular muscular coat, so that a contraction started at any point would spread by direct con- duction of the contraction change. This theory, however, does not explain satisfactorily the normal conduction of the wave of contraction always in one direction, nor the fact that a reversed piece of intestine continues to send its waves in what was fir it the normal direction. Moreover, Bayliss and Starling state that although the peristaltic movements continue after section of the extrinsic nerves — indeed, become more marked under these conditions — the application of cocaine or nicotine prevents their occurrence. Since these substances may be supposed to act on the intrinsic nerves, it is probable that the co-ordination of the movement is effected through the local nerve- ganglia, but our knowledge of the mechanism and physiology of these peripheral nerve-plexuses is as yet quite incomplete. Pendular Movements. — In addition to the peristaltic wave a second kind of movement may be observed in the exposed intestines of a living animal. This movement is characterized by a gentle swinging to and fro of the different loops, whence its name of pendular movement. The oscillations occur at regular intervals, and are usually ascribed to rhythmic contractions of the longitudinal muscles. Mall, 1 however, believes that the main feature of this movement is a rhythmic contraction of the circular muscles, involving a part or all of the intestines. He prefers to speak of the movements as rhythmic instead of pendular contractions, and points out that owing to the arrangement of the blood-vessels in the coats of the intestine the rhythmic contractions should act as a pump to expel the blood from the submucous venous plexus into the radicles of the superior mesenteric vein, and thus materially aid in keeping up the circulation through the intestine and in maintaining a good pressure in the portal vein, in much the same way as happens in the case of the spleen (see p. 332). Bayliss and Starling corroborate this view, except that they find that both the circular and longitudinal layers of muscle are concerned in the movement. The rhythmic contractions, according to these observers, are entirely muscular in origin, since they persist after the application of nicotine or cocaine. Extrinsic Nerves of the Intestines. — As in the case of the stomach, the 1 The Johns Hopkins Hospital Reports, vol. i. p. 37. MOVEMENTS OF THE ALIMENTARY CANAL, ETC. 385 small intestine and the greater part of the large intestine receive visceromotor nerve-fibres from the vagi and the sympathetic chain. The former, according to most observers, when artificially stimulated cause movements of the intestine, and are therefore regarded as the motor fibres. It seems probable, however, that the vagi carry or may carry in some animals inhibitory fibres as well, and that the motor effects usually obtained upon stimulation aredue to the fad that in these nerves the motor fibres predominate. The fibres received from the sympathetic chain, on the other hand, give mainly an inhibitory effect when stimulated, although some motor fibres apparently may take this path. Bechterew and Mislawski 1 state that the sympathetic fibres for the small intestine emerge from the spinal cord as medullated fibres in the sixth dorsal to the first lumbar spinal nerves, and pass to the sympathetic chain in the splanchnic nerves and thence to the semilunar plexus, while the sympathetic fibres to the large intes- tine and rectum arise in the four lower lumbar and the three upper sacral spinal nerves. According to Langley and Anderson 2 the descending colon and rec- tum receive a double nerve-supply — first from the lumbar spinal nerves (second to fifth), the fibres passing through the sympathetic ganglia and the inferior mesenteric plexus and causing chiefly an inhibition ; second, through the sacral nerves, the fibres passing through the nervus erigens and the hypogastric plexus and causing chiefly contraction of the circular muscle. These extrinsic fibres undoubtedly serve for the regulation of the move- ments of the bowels from the central nervous system ; conditions which influ- ence the central system, either directly or indirectly, may thus affect the intesti- nal movements. The paths of these fibres through the central nervous system are not known, but there are evidently connections extending to the higher brain-centres, since psychical states are known to influence the movements of the intestine, and according to some observers stimulation of portions of the cere- bral cortex may produce movements or relaxation of the walls of the small and large intestines. As in the case of the stomach, the extrinsic fibres seem to have only a regulatory influence. When they are completely severed the tonicity of the walls of the intestine is not altered, and peristaltic and rhythmic movements still occur. The same results may be obtained even upon ex- cised portions of the intestines (Salvioli, Mall). It seems probable, there- fore, that normal peristalsis in the living animal may be effected independently of the central nervous system, although its character and strength is subject to regulation through the medium of the viscero-motor fibres, in much the same way, and possibly t<> as great an extent, as the movements of the heart are controlled through its extrinsic nerves. Effect of Various Conditions upon the Intestinal Movements. — Experi- ments have shown that the movements of the intestines may be evoked in many ways beside direct stimulation of the extrinsic nerves. Chemical stimuli may be applied directly to the intestinal wall. Mechanical stimulation, pinching, for example, or the introduction of a bolus into the intestinal cavity, will 1 Du Bois-Reymond' a Archiv fur Physiologic, 1889, Suppl. Bd. 1 Journal of Physiology, 1895, vol. xviii. p. 67. Vol.. I.— 25 386 AX AWERKAX TEXT-BOOK OF PHYSIOLOGY. start normal peristalsis. Violent movements may be produced also by shut- ting off the blood-supply, and again temporarily when the supply is re-estab- lished. A condition of dyspnoea may also start movements in the intestines or in some eases inhibit movements which are already in progress, the stimu- lus in this ease seeming to act upon the central nervous system and to stimu- late both the motor and the inhibitory fibres. Oxygen gas within the bowels tend- to suspend the movements of the intestine, while C0 2 , CH 4 , and H 2 S act as stimuli, increasing the movements. Organic acids, such as acetic, propionic, formic, and caprylic, which may be formed normally within the intestine as the result of bacterial action, act also as strong stimulants. 1 Defecation. — The undigested and indigestible parts of the food, together with some of the debris and secretions from the alimentary tract, are carried slowly through the large intestine by its peristaltic movements and eventually reach the sigmoid flexure and rectum. Here the nearly solid material stimu- lates by its pressure the sensory nerves of the rectum and produces a distinct sensation and desire to defecate. The fecal material is retained within the rectum by the action of the two sphincter muscles which close the anal opening. One of these muscles, the internal sphincter, is a strong band of the circular layer of involuntary muscles which forms one of the coats of the rectum. When the rectum contains fecal material this muscle seems to be thrown into a condition of tonic contraction until the act of defecation begins, when it is relaxed. The sphincter is composed of involuntary muscle and is innervated by fibres arising partly from the sympathetic system, and in part through the nervus erigens, from the sacral spinal nerves. The external sphincter ani is composed of striated muscle-tissue and is under the control of the will to a certain extent. When, however, the stimulus from the rectum is sufficiently intense, voluntary control is overcome and this sphincter is also relaxed. The act of defecation is in part voluntary and in part involuntary. The involuntary factor is found in the contractions of the strongly developed mus- culature of the rectum, especially the circular layer, which serves to force the feces onward, and the relaxation of the internal sphincter. It seems that these two acts are mainly caused by reflex stimulation from the lumbar spinal cord, although it is probable that the rectum, like the rest of the alimentary tract, i- capable of automatic contractions. The rectal muscles receive a double nervous supply, containing physiologically both motor and inhibitory fibres. Some of these fibres come from the nervus erigens by way of the hypogastric plexus, and some arise from the lumbar cord and pass through the correspond- in.: sympathetic ganglia, inferior mesenteric ganglion, and hypogastric nerve. It has been asserted that stimulation of the nervus erigens causes contrac- tion of the longitudinal muscles and inhibition of the circular muscles, while stimulation of the hypogastric nerve causes contraction of the circular muscles and inhibition of the longitudinal layer. This division of activity is not confirmed by the recent experiments of Langley and Anderson. 2 The voluntary factor in defecation consist- in the inhibition of the external 1 Buk;ii : Archivfiir exper. PaihoLogie und Pharmakologie, L888, lid. 24, S. 153. 2 Op. eit. MOVEMENTS OF THE ALIMENTARY CANAL, ETC 387 sphincter and the contraction of the abdominal muscles. When these latter muscles are contracted and at the same time the diaphragm is prevented from moving upward by the closure of the glottis, the increased abdominal pressure is brought to bear upon the abdominal and pelvic viscera, and aids strongly in pressing the contents of the descending colon and sigmoid flexure into the rectum. The pressure in the abdominal cavity is still further increased it' a deep inspiration is first made and then maintained during the contraction of the abdominal muscles. Although the act of defecation is normally initiated by voluntary effort, it may also be aroused by a purely involuntary reflex when the sensory stimulus is sufficiently strong. Goltz 1 has shown that in dogs in which the spinal cord had been severed in the lower thoracic region defe- cation was performed normally. In later experiments in which the entire spinal cord was removed, except in the cervical and upper part of the thoracic region, it was found that the animal after it had recovered from the operation had normal movement once or twice a day, indicating that the rectum and lower bowels acted by virtue of their intrinsic mechanism. A curious result of these experiments was the fact that the external sphincter eventually regained its tonic activity. It would seem that the whole act of defecation is at bottom an involuntary reflex. The physiological centre for the movement probably lies in the Lumbar cord, and has sensory and motor connections with the rectum and the muscles of defecation, but this centre is in part at least provided with connections with the centres of the cerebrum through which the act may be controlled In- voluntary impulses and by various psychical states, the effect of emotions upon defecation being a matter of common knowledge. In infants the essen- tially involuntary character of the act is well seen. Vomiting. — The act of vomiting causes an ejection of the contents of the stomach through the oesophagus and mouth to the exterior. It was long debated whether the force producing this ejection comes from a strong contrac- tion of the walls of the stomach itself or whether it is due mainly to the action of the walls of the abdomen. A forcible spasmodic contraction of the abdominal muscles takes place, as may easily be observed by any one upon himself, and it is now believed that the contraction of these muscles is the principal factor in vomiting. Magendie found that if the stomach was extir- pated and a bladder containing water was substituted in its place and connected with the oesophagus, injection of an emetic caused a typical vomiting movement with ejection of the contents of the bladder. Giauuzzi showed, on the other hand, that upon a curarized animal vomiting could not be produced by an emetic — because, apparently, the muscles of the abdomen were paralyzed by the curare. There are on record, however, a number of observations which tend to show thai the stomach is not entirely passive during the act. < >n the contrary, it may exhibit contractions, more or less violent in character, which while insufficient in themselves to eject its contents, probably aid in a normal act of vomiting. According to < )penchowski, 2 the pylorus is closed and the pyloric end of the 1 Archiv fiir die gesammte Physiologie, 1874, Bd. viii. 8. 460; also Bd. lxiii. S. 362 2 Archivfur Physiologie, 1889, S. 552. 388 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. stomach firmly contracted so as to drive the contents toward the dilated cardiac portion. The act of vomiting is in fact a complex reflex movement into which many muscles enter. The following events are described : The vomiting is usually preceded by a sensation of nausea and a reflex How of saliva into the mouth. These phenomena are succeeded or accompanied by retching movements, which consist essentially in deep spasmodic inspirations with a closed glottis. The effect of these movements is to compress the stomach by the descent of the diaphragm, and at the same time to increase decidedly the negative pressure in the thorax, and therefore in the thoracic portion of the oesophagus. During one of these retching movements the act of vomiting is effected by a convulsive contraction of the abdominal wall that exert- a sudden additional strong pressure upon the stomach. At the same time the cardiac orifice of the stomach is dilated, possibly by an inhibition of the sphincter, aided it is supposed by the contrac- tion of the longitudinal muscle-fibres of the oesophagus and the oblique fibres of the muscular coat of the stomach. The stomach contents are, therefore, forced violently out of the stomach through the oesophagus, the negative pressure in the latter probably assisting in the act. The pas- sage through the oesophagus is effected mainly by the force of the contrac- tion of the abdominal muscles; there is no evidence of antiperistaltic move- ments on the part of the oesophagus it-elf. During the ejection of the contents of the stomach the glottis i- kepi closed by the adductor muscles, and usually the nasal chamber is likewise shut off from the pharynx by the contraction of the posterior pillars of the fauces on the palate and uvula. In violent vomit- ing, however, the vomited material may break through this latter barrier aud be ejected partially through the nose. Nervous Mechanism <>f Vomiting. — That vomiting is a reflex act is abun- dantly shown by the frequency with which it is produced in consequence of the stimulation of sensory nerves or as the result of injuries to various [tarts of the central nervous system. After lesions or injuries of the brain vomiting often results. Disagreeable emotions and disturbances of the sense of equi- librium may produce the same result. Irritation of the mucous membrane of various parts of the alimentary canal (as, for example, tickling the back of the pharynx with the finger), disturbances of the urogenital apparatus, artificial stimulation of the trunk of the vagus and of other sensory nerves, may all cause vomiting. Under ordinary conditions, however, irritation of the sensory uerves of the gastric mucous membrane is the most common cause of vomiting. This effecf may result from the product- of fermentation in the stomach in cases of indigestion, or may be produced intentionally by local emetics, such as mustard, taken into the stomach. The afferent path in this case is through the sensory fibres of the vagus. The efferent paths of the reflex are found in the motor nerves innervating the muscles con- cerned in the vomiting, namely, the vagus, the phrenic-, and the spinal nerves supplying the abdominal muscles. Whether or not there is a definite vomit- in- centre in which the afferent impulses are received and through which 3IOVE3IEXTS OF THE ALIMENTARY CANAL, ETC. 389 a co-ordinated series of efferent impulses is sent out to the various muscles, has not been satisfactorily determined. It has been shown that the portion of the nervous system through which the reflex is effected lies in the me- dulla. But it has been pointed out that the muscles concerned in the act are respiratory muscles. Vomiting in fact consists essentially in a simul- taneous spasmodic contraction of expiratory (abdominal) muscles and inspi- ratory muscles (diaphragm). It has therefore been suggested that the reflex takes place through the respiratory centre, or some part of it. This view seems to be opposed by the experiments of Thumas, 1 who has shown that when the medulla is divided down the mid-line respiratory movements con- tinue as usual, but vomiting can no longer be produced by the use of emetics. Thumas claims to have located a vomiting centre in the medulla in the imme- diate neighborhood of the calamus scriptorius. Further evidence, however, is required upon this point. The act of vomiting may be produced not only as a reflex from various sensory nerves, but may also be caused by direct action upon the medullary centres. The action of apomorphia is most easily explained by supposing that it acts directly on the nerve-centres. Micturition. — The urine is secreted continuously by the kidneys, is car- ried to the bladder through the ureters, and is then at intervals finally ejected from the bladder through the urethra by the act of micturition. Movements of the Ureters. — The ureters possess a muscular coat consisting of an internal longitudinal and external circular layer. The contractions of this muscular coat are the means by which the urine is driven from the pelvis of the kidney into the bladder. The movements of the ureter have been carefully studied by Engelmann. 2 According to his description the musculature of the ureter contracts spontaneously at intervals of ten to twenty seconds (rabbit), the contraction beginning at the kidney and progressing toward the bladder in the form of a peristaltic wave and with a velocity of about twenty to thirty milli- meters per second. The result of this movement should be the forcing of the urine into the bladder in a series of gentle rhythmic spirts, and this method of filling the bladder has been observed in the human being. Suter and Maver 3 report some observations upon a boy in whom there was ectopia of the bladder with exposure of the orifices of the ureters. The flow into the bladder was intermittent and was about equal upon the two sides for the time the child was under observation (three and a half days). The causation of the contractions of the ureter musculature is not easily explained. Engelmann finds that artificial stimulation of the ureter or of a piece of the ureter may start peristaltic contractions which move in both direc- tions from the point stimulated. lb' was not able to find ganglion-cells in the upper two-thirds of the ureter, and was led to believe, therefore, that the con- traction originates in the muscular tissue independently of extrinsic or intrinsic nerves, and that the contraction wave propagates itself directly from muscle- 1 Virchovfs Archiv fur pathologische Anatornie, etc., L891, Bd. 123, S. II. " PfiUger l 8 Archivfiir diegesammte Physiologie, 1869, Bd. ii. B. 243; Bd. iv. S. 33. 3 Archiv fiir exper. Patholog'x- vmd Pharmakologie, 1893, Bd. 32, S. 241. 390 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. cell to muscle-cell, the entire musculature behaving as though it were a single, colossal hollow muscle-fibre. The liberation of the stimulus which inaugurates the normal peristalsis of the ureter seems to be connected with the accumulation of urine in its upper or kidney portion. It maybe supposed that the urine that collects at this point as it flows from the kidney stimulates the muscular ti~-ue to contraction, either by its pressure or in some otherway, and thus leads to an orderly sequence of contraction waves. It is possible, however, that the muscle of the ureter, like that of the heart, is spontaneously contractile under normal conditions, and does not depend upon the stimulation of the urine. Thus, according to Engelmann, section of the ureter near the kidney does not materially affect the nature of the contractions of the stump attached to the kidney, although in this case the pressure of the urine could scarcely act as a stimulus. Moreover, in the case of the rat, in which the ureter is highly con- tractile, the tube may be cut into several pieces and each piece will continue to exhibit periodic peristaltic contractions. It does not seem possible at present to decide between these two views as to the cause of the contractions. The nature of the contractions, their mode of progression, and the way in which they force the urine through the ureter seem, however, to be clearly established. Efforts to show a regulatory action upon these movements through the central nervous system have so far given only negative results. Movements of the Bladder. — The bladder contains a muscular coat of plain muscle-tissue, which, according to the usual description, is arranged so as to make an external longitudinal coat and an internal circular or oblique coat. A thin longitudinal layer of muscle-tissue lying to the interior of the circular coat is also described. The separation between the longitudinal and circular layers is not so definite as in the case of the intestine ; they seem, in fact, to form a continuous layer, one passing gradually into the other by a change in the direction of the fibres. At the cervix the circular layer is strengthened, and has been supposed t<> act as a sphincter with regard to the urethral orifice — the so-called sphincter vesicae internus. Round the urethra just outside the blad- der is a circular layer <>f striated muscle that is frequently designated as the external sphincter or sphincter urethra'. The urine brought into the bladder accumulates within its cavity to a certain limit. It is prevented from escaping through the urethra at first by the mere elasticity of the parts at the urethral orifice, aided perhaps by tunic contraction of the internal sphincter, although this function of the circular layer is disputed by some observers. When the accumulation becomes greater the external sphincter is brought into action. If the desire to urinate is strong the external sphincter seems undoubt- edly to be controlled by voluntary effort, but whether or not, in moderate filling of the bladder, it is brought into play by an involuntary reflex is not definitely determined. Back-flow of urine from the bladder into the ureters is effectually prevented by the oblique course of the ureters through the wall of the bladder. Owing to this circumstance pressure within the bladder serves to close the mouths of the ureters, and indeed the more completely the higher the pres- sure. At some point in the filling of the bladder the pressure is sufficient to MOVEMENTS OF Till-: ALIMENTARY CANAL, ETC. 391 arouse a conscious sensation of fulness and a desire to micturate. Under nor- mal conditions the act of micturition follows. It consists essentially in a strong contraction of the bladder with a simultaneous relaxation of the external sphincter, if this muscle is in action, the effect of which is to obliterate more or less completely the cavity of the bladder and drive the urine out through the urethra. The, force of this contraction is considerable, as is evidenced by the height to which the urine may spirt from the end of the urethra. According to Mosso the contraction may support, in the dog, a column of liquid two meters high. The contractions of the bladder may be and usually are assisted by contractions of the walls of the abdomen, especially toward the end of the act. As in defecation and vomiting, the contraction of the abdominal muscles, when the glottis is closed so as to keep the diaphragm 'fixed, serves to increase the pressure in the abdominal and pelvic cavities, and is thus used to assist in or complete the emptying of the bladder. It is, however, not an essential part of the act of micturition. The last portions of the urine escaping into the urethra are ejected, in the male, in spirts produced by the rhythmic contractions of the bulbo-cavernosus muscle. Considerable uncertainty and difference of opinion exists as to the physio- logical mechanism by which this series of muscular contractions, and especially the contractions of the bladder itself, is produced. According to the frequently quoted description given by Goltz 1 the series of events is as follows : The dis- tention of the bladder by the urine causes finally a stimulation of the sensory fibres of the organ and produces a reflex contraction of the bladder musculature which squeezes some urine into the urethra. The first drops, however, that enter the urethra stimulate the sensory nerves there and give rise to a conscious desire to urinate. If no obstacle is presented the bladder then empties itself, assisted perhaps by the contractions of the abdominal muscles. The emptying of the bladder may, however, be prevented, if desirable, by a voluntary con- traction of the sphincter urethra, which opposes the effect of the contraction of the bladder. If the bladder is not too full and the sphincter is kept in action for some time, the contractions of the bladder may cease and the desire to micturate pass off. According to this view the voluntary control of the process is limited to the action of the external sphincter and the abdominal muscles; the contraction of the bladder itself is purely an unconscious reflex taking place through a lumbar centre. The experiments of Goltz and others, upon dogs in which the spinal cord was severed at the junction of the lumbar and the thoracic regions, indicate that micturition is essentially a reflex acl with it.- centre in the lumbar cord, although the same observer has shown that in dogs whose spinal cord has been entirely destroyed, except in the cervical and upper thoracic region, the bladder empties itself normally without the aid of external stimulation. MoSSO and Pellacani 2 have made experiments upon women which ><'r\\\ to 1 Archiv fur die gesammte Physiologie, IsTt, Bd, viii. S. 17s 2 Archives it.< ,h Biologie, L882, tome i. 392 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. show thai the bladder may be emptied by a direci voluntary act. Tn these experiments a catheter was introduced into the bladder and connected with a r< rding apparatus to measure the volume of the bladder. It was found that, in some cases at least, the woman could empty the bladder at will without using the abdominal muscles. The same authors adduce experi- mental evidence to show that the sensation of fulness and desire to mic- turate come from sensory stimulation in the bladder itself caused by the pressure of the urine. They point out that the Madder is very sensitive to reflex stimulation ; that every psychical act and every sensory stimulus is apt to cause a contraction or increased tone of the bladder. The Madder is, therefore. subject t<> eoiitiiiual changes in size from reflex stimulation, and the pressure within it will depend not simply on the quantity of urine, but ■ m the condition of tone of the bladder. At a certain pressure the sen- sorv nerves are stimulated and under normal conditions micturition ensues. We may understand, from this point of view, how it happens that we have sometimes a strong desire to micturate when the bladder contains bui little urine — for example, under emotional excitement. In such cases if the micturi- tion is prevented, probably by the action of the external sphincter, the bladder may subsequently relax and the sensation of fulness and desire to micturate pass away until the urine accumulates in sufficient quantity or the pressure is again raised by some circumstance which causes a reflex contraction of the bladder. \< rvous Mechanism. — According to a recent paper by Langley and Anderson, 1 the bladder in cats, dogs, and rabbits receives motor fibres from two sources: (1) From the lumbar nerves, the fibres passing out in the second to the fifth lumbar nerves and reaching the bladder through the sympathetic chain and the infe- rior mesenteric ganglion and hypogastric nerves. Stimulation of these nerves causes comparatively feeble contraction of the bladder. (2) From the sacral spinal nerves, the fibre- originating in the second and third sacral spinal nerves, or in the rabbit in the third and fourth, and being contained in the so-called nervus erigens. Stimulation of these nerves, or some of them, causes strong contractions of the bladder, sufficient to empty its contents. Little evidence was obtained of the presence of vaso-motor fibres. According to Nawrocki and Skabitschewsky a the spinal sensory fibre- to the bladder are found in part in the posterior roots of the first, second, third, and fourth sacral spinal nerves, particularly the second and third. When these fibres are stimulated they excite reflexly the motor fibres to the bladder found in the anterior roots of the second and third sacral spinal nerves. Some sensory fibres to the bladder pass by way of the hypogastric nerves. When these are stimulated they produce, according to these authors, a reflex effect upon the motor fibres in the other hypogastric nerve, causing a < traction of the bladder, the reflex occurring through the inferior mesenteric ganglion. This observation has been confirmed by several authorities, and is the best example of a peripheral ganglion serving as a reflex '- Journal of Phyxiolgy, 1895, vol. xix. p. 71. - Archivfur gesamnUe Physiologic, 1891, Bd. 49, S. 141. MOVEMENTS OF THE ALIMENTARY (ANAL, ETC. 393 centre. Langley and Anderson, 1 who also obtained this effect, give it a special explanation, contending that it is not a true reflex. The immediate spinal centre through which the contractions of the bladder may be reflex ly stimulated or inhibited lies, according to the experiments of Goltz, in the lumbar portion of the cord, probably between the second and fifth lumbar spinal nerves. In dogs in which this portion of the cord was isolated by a cross section at the junction of the thoracic and lumbar regions, micturi- tion still ensued when the bladder was sufficiently full, and could be called forth reflexly by sensory stimuli, especially by slight irritation of the anal region. This localization has been confirmed by others. 2 Movements of other Visceral Organs. — For the characteristics of the move- ments of other viscera reference must be made to the appropriate sections. The movements of the arteries are described under Circulation, those of the uterus under Reproduction. 1 Journal of Physiology, 1894, vol. xvi. p. 410; see also Justschenko : Archives des Sciences biologiques, 1898, t. 6, p. 536. 2 See .Stewart: American Journal of Physiology, 1899, vol. ii. p. 182. VII. RESPIRATION. A study of the phenomena of animal life teaches us that a supply of oxygen and an elimination of carbon dioxide are essential to existence. Oxy- gen is indispensable to life; carbon dioxide is inimical to life. One serves for the disintegration of complex molecules whereby energy is evolved, while the other is one of the main effete products of this dissociation. We therefore find an intimate relationship between the ingress of the one and the egress of the other. During the entire life of the individual there is this continual inter- change, which we term respiration. This term embraces two acts which, while different, are nevertheless co-operative — first, the interchange of O and C0 2 ; second, the movements of certain parts of the body, having for their object the inflow and outflow of air to and from the lungs. The former, properly speak- ing, is respiration ; the latter, movements of respiration. Respiration is spoken of as internal and as external respiration. In the very lowest forms of life the interchange of gases takes place directly between the various parts of the organism and the air or the water in which the organ- ism lives ; but in higher beings a circulating fluid becomes a means of exchange between the bodily structures and the surrounding medium, so that in these beings there is first an interchange between the air or the water in which the animal lives and the circulating medium, and subsequently an inter- change between the circulating medium and the tissues. Therefore in the most primitive forms of life respiration is a single process, while in higher organ- isms it is a dual process, or one consisting of two stages, the first being the interchange between the atmosphere or the water surrounding the body and the circulating medium, and the second between the circulating medium and the bodily structures. In man, external respiration is the interchange taking place between the blood and the gases in the lungs and. to a very small extent, between the blood and the air through the skin ; while internal res- piration is the interchange between the blood and the tissues. In external respiration O is absorbed and ( '( )_, is given off by the blood : in internal res- piration the blood absorbs ( '()._, and gives off O. A. The Respiratory Mechanism in Man. The respiratory apparatus in man consists (1) of the lungs and the air- passages loading to them, the thorax and the mnsenlar mechanisms by means of which the lungs are inflated and emptied, and the nervous mechanisms con- nected therewith ; and (2) the skin, which, however, plays a subsidiary part in man, and need not here be considered. 395 396 IV AMERICAN Tl 'XT-BOOK OF PHYSIOLOGY. The lungs may be regarded as two large bags broken up into saccular divisions and subdivisions which ultimately consist of a vast number of little pouches, or infundibuli, each of which is, as the name implies, funnel-shaped, the walls being hollowed out into alveoli, or air- vesicles. These alveoli vary in size from 120 ju to 380 /i, the average diameter being about 250// (y^ inch). Each infundibulum communicates by means of a small air-passage with a bronchiole, which in turn communicates with a smaller air-tube or bronchus, and finally, through successive unions, with the common air-duct or trachea. It i< estimated that the alveoli number about 725,000,000, and that the total superficies exposed by them to the gases in the lungs is about 200 square meters, or from one hundred to one hundred and thirty times greater than the surface of the body ( L.5 to 2 square meters). The wall of each alveolus forms a delicate partition between the air in the lungs and an intricate net- work of blood-vessels; this network is so dense that the spaces between the capillaries an;, as a rule, smaller than the diameters of the vessels. The lungs, therefore, are exceedingly vascular, and it is estimated that the vessels contain on an average about 1.5 kilograms of blood. Owing to the minute- ness of the capillaries and the density of the network, the air-cells may be said to be surrounded by a film of blood which is about 10/v in thickness and has an area of about 150 square meters. The lungs are highly elastic, and their elasticity is perfect, as is shown by the fact that they immediately regain their passive condition as soon as the dilating or distending force has been removed. Before birth the lungs are air- less (iihlci-l(tt'ic) and the walls of the bronchioles and the infundibuli are in contact, yet in the child before birth, as in the adult, the lungs are in apposi- tion with the thoracic walls, being separated only by two layers of the pleurae. As soon as the child is born a few respiratory movements are sufficient to inflate them, and thereafter they never regain their atelectatic condition, since after the most complete collapse, such as occurs when the thorax is opened, some air remains in the alveoli, owing to the fact that the walls of the bron- chioles come together before all of the air can escape. As the child grows the thorax increases in size more rapidly than the lungs, and becomes too large, as it were, for the lungs, which, as a consequence, become permanently distended because of their being in an air-tight cavity. If the chest of a cadaver be punctured, the lungs immediately -brink so that a considerable air-space will be formed between them and the walls of the thorax. This collapse is due to the condition of elastic ten-ion which exists from the moment air is introduced into the alveoli, and which increases with the degree of expansion. Therefore, after the lungs are inflated they exhibit a persistent tendency to collapse; con- sequently they musl exercise upon the thoracic walls and diaphragm a constant traction or "pull" which is in proportion to the amount of tension. It is therefore obvious that there musl exisl within the thorax, under ordinary circumstances, a state of ncr/utive pressure (pressure below that of the atmo- sphere). This can be proven by connecting a trocar with a manometer and then forcing the trocar into one of the pleural sacs. BESPIRA TION 397 Donders found that the pressure at the end of quiet expiration was —6 mil- limeters of Hg, and at the end of quiet inspiration —9 millimeters. Accord- ing to these figures, the pressure on the heart, great blood-vessels, and other thoracic structures lying between the lungs and the thoracic walls would be 754 millimeters of Hg (one atmosphere, 760 millimeters, —6 millimeters) at the end of quiet expiration, and 751 millimeters of Hg at the end of quiet inspiration. Corresponding values by Hutchinson are —3 millimeters and —4.5 millimeters. Arron x found in a case of a woman with emphysema that the pressure at the end of expiration ranged from —1.9 to —3.9 millimeters, and at the end of inspiration from —4 to —6.85 millimeters, according to the position of the body, the pressure being lowest in the lying posture, higher when sitting in bed, still higher when sitting on a chair, and highest when sit- ting and when inspiration on the well side was hindered, thus throwing a larger portion of the work on the diseased side, on which the measurements were made. During inspiration negative pressure increases in proportion to the depth of inspiration — or, in other words, in relation to the amount of expan- sion of the lungs — while during expiration it gradually falls to the standard at the beginning of inspiration. During forced inspiration it may reach —30 to —40 millimeters or more. The pressure thus observed within the thorax (out- side of the lungs) is known as intrathoracic pressure, and must not be con- founded with intrapulmonary or respiratory pressure, which exists within the lungs and the respiratory passages (see p. 408). The thorax is capable of enlargement in all directions. It is cone-shaped, the top of the cone being closed in by the structures of the neck ; the sides, by the vertebral column, ribs, costal cartilages, sternum, and intercostal sheets of muscular and other tissues; and the bottom, by the arched diaphragm. It is obvious that, since the thorax is an air-tight cavity and completely filled by various structures, enlargement in any direction must cause a diminution of pressure within the lungs, while a shrinkage would operate to bring about an opposite condition of increased pressure. Since the trachea is the only means of communication between the lungs and the atmosphere, it is evident that such alterations in pressure must encourage either the inflow or the outflow of air, as the case may be; consequently, when the thoracic cavity is expanded the pres- sure within the lungs is less than that of the atmosphere, and air is forced into the lungs; and when the thorax is decreased in size the reverse of the above pressure relation exists, and the air is expelled. In fact, the thorax and the lungs behave as a pair of bellows — just as air is drawn into the expanding bellows, so is air drawn into the lungs by the enlargement of the thorax ; similarly, as the air is forced from the bellows by compression, so is air forced from the lungs by the shrinkage of the lungs and the thorax. During the expansion of the thorax the lungs are entirely passive, and by virtue of their perfect elasticity merely follow the thoracic walls, from which they are separated only by the two layers of the pleura?, which, being moist- ened with lymph, slide over each other without appreciable friction. That 1 Virchow's Archiv, 1891, Bd. 126, 8. 523. AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. tlif lungs are entirely passive is shown by the fact that when the thorax is punctured, so as to allow a tree communication with the atmosphere, expan- sion of the chest is no longer followed by dilatation of the lungs. During the shrinkage of the thorax the clastic reaction of the lungs plays an active part. Respiration, Inspiration, and Expiration. — Each respiration or respiratory act consists of an inspiration (enlargement of the thorax and inflation of the lungs) and an expiration (shrinkage of the thorax and the lungs). Accord- ing to some observers, a 'pause exists after expiration {expiratory pause), but during quiet breathing no such interval can be detected. A pause mav be present when the respirations are deep and infrequent. Under certain abnor- mal circumstances a pause may exist between inspiration and expiration (inspiratory pa use). Inspiration is accomplished by the contraction of certain muscles which are designated inspiratory muscles. Expiration during quiet breathing is essen- tially a passive act, but during forced breathing various muscles are active; these muscles are distinguished as expiratory muscles. During inspiration the thorax is enlarged in the vertical, transverse, and antero-posterior diameters. During quiet breathing the vertical diameter is increased by the descent of the diaphragm, and during deep inspiration it is further increased by the backward and slightly downward movement of the floating ribs, and by the extension of the vertebral column, which raises the sternum with its costal cartilages and ribs. The transverse diameter is in- creased by the elevation and eversion (rotation outward and upward) of the ribs. The antero-posterior diameter is increased by the upward and outward movement of the sternum, costal cartilages, and ribs. During quiet inspiration in men the sternum is not raised to a higher level, but the low^er end is rotated forward and upward. It is only during deep inspiration in men and in quiet or deep inspiration in women that the sternum as a whole is elevated. The movements of the anterior and lateral walls constitute costal respira- tion, and those of the diaphragm diaphragmatic or, as it is sometimes called, abdominal respiration, since the descent of the diaphragm causes protrusion of the abdominal walls. Both types coexist during ordinary respiratory move- ments, but one may be more prominent than the other. The costal type is well marked in women, and the diaphragmatic type in men. These peculiarities are not, however, due to inherent sexual differences, but to dress. Young children of both sexes exhibit, as a rule, the diaphragmatic type, and it is only later, and owing to constricting dress, that the costal type is developed in the female. The chief muscles of inspirit ion are the diaphragm, the quadrat! lumborum, the serrati postici inferiores, the scateni, the serrati postici superiores, the leva- tores cost, i mm lonai t intercartilaginei. Movements of the Diaphragm. — The diaphragm is attached by its two crura to the first three or four lumbar vertebrae, to the lower six or seven cos- tal cartilages and adjoining parts of the corresponding ribs, and to the poste- rior surface of the ensiform appendix. It projects into the thoracic cavity in RESPIRATION. 399 the form of a flattened dome, the highest part being formed by the central tendon. The tendon consists of three lobes which are partially separated by depressions. The right lobe, or largest, is the highest portion and lies over the liver ; the left lobe, which is the smallest, lies over the stomach and the spleen ; while the central lobe is situated anteriorly, the upper surface blending with the pericardium. The central tendon is a common point of insertion of all the muscular fibres of the diaphragm. In the passive condition the lower portions of the diaphragm are in apposition to the thoracic Malls. During contraction the whole dome is drawn downward, while the parts of the muscle in contact with the chest are pulled inward. According to Hult- kranz, the cardiac part of the diaphragm descends from 5.5 to 11.5 millimeters during quiet inspiration, and as much as 42 millimeters during deep inspira- tion. Not only is the height of the arch lessened, but there is also a tendency, owing to the points of attachment of the diaphragm, toward the pulling of the lower ribs with their costal cartilages and the lower end of the sternum inward and upward ; this traction, however, is counterbalanced by the pressure of the abdominal viscera, the latter being forced downward and outward against the thoracic and abdominal walls. If this counterbalancing pressure be removed by freely opening the abdominal cavity, especially after removing the viscera, the lower lateral portions of the thorax will be seen during each inspiration to be drawn inward. It is during labored inspiration only that this movement occurs in the intact individual. When the diaphragm ceases to contract, the elastic recoil of the distended lungs is sufficient to draw the sunken dome upward into the passive position. This upward movement of the diaphragm is aided by the positive intra- abdominal pressure exerted by the elastic tension of the abdominal walls through the medium of the abdominal viscera. In forced expiration the contraction of the abdominal muscles (p. 407) adds additional force. The quadrati lumborum are believed to assist the diaphragm by fixing the twelfth ribs, or even lowering and drawing them backward duringdeep inspira- tion. Each of these muscles arises from the ilio-lumbar ligament and the iliac- crest, and is inserted into the transverse processes of the first, second, third, and fourth lumbar vertebrae and the lower border of one-half of the length of the last rib. These muscles are regarded by some physiologists as expiratory agents. The serrati postici inferloj-es similarly assist the diaphragm by drawing the lower four ribs backward, and in deep inspiration also downward. They not only thus oppose the tendency of the diaphragm to pull the lower ribs upward and forward, which would lessen its effectiveness in enlarging the vertical diameter of the thorax, but they contribute to this enlargement by their backward and downward traction upon the rib- and the attached por- tions of the diaphragm. These muscles pass from the spines of the eleventh ami twelfth dorsal and first two or three lumbar vertebrae and the supraspi- nous ligament to the lower borders of the ninth, tenth, eleventh, and twelfth ribs, beyond their angles. Simultaneously with the contraction of the diaphragm the thoracic walls 400 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. are drawn upward and outward by the contractions of other inspiratory mus- cles, thus enlarging the thorax in the antero-posterior and lateral diameters. Movements of the Ribs. — The movements of the ribs during inspiration arc, as a whole, essentially rotations upward and outward upon axes which are directed obliquely outward and backward, each axis being directed through the costo-vertebral articulation and a little anterior to the costotransverse articulation. The vertebral ends of the ribs lie higher than their sternal extremities, so that when the ribs are elevated the anterior ends are advanced forward and upward. The arches of the ribs are inclined downward and outward, and, owing to the obliquity of the axes of rotation, the convexities are rotated upward and outward, or everted. Thus both the antero-posterior and lateral diameters are increased. The degree of obliquity of the axes of rotation of the different ribs varies. The axis of the first rib is almost transverse (Fig. 69), while that of each succeeding rib to the ninth, inclusive, becomes more oblique (Fig. 70). The Fig. 69.— First dorsal vertebra and rib. Fig. 70.— Sixth dorsal vertebra and rib. more oblique the axis, the greater the degree of eversion ; consequently the first rib is capable of but .-light eversion, while the lower ribs may be everted to a relatively marked extent. Moreover, the peculiarities or the absence of the costo-transverse articulations materially affect the character of the move- ments of the differenl ribs. Thus, the facets on the transverse processes of the first and second dorsal vertebrae are cup-shaped, and into them are inserted the conical tuberosities of the ribs, thus materially limiting the rotation of the ribs; while the facets for the articulations of the third to the tenth ribs, inclu- sive, assume a plane character which admits of larger movement. The facets for the third to the fifth ribs are almost vertical, thus allowing a free move- ment upon the oblique axis; while the facets for the sixth to the ninth ribs, inclusive, are directed obliquely upward and backward, and admit of a move- RESPIRA TION. 40 1 ment upward and backward as well as a rotation upon the oblique axis. Finally, the eleventh and twelfth ribs (and generally the tenth) have no costo- transverse articulations, allowing a movement backward and forward as well as rotation upon their oblique axes. While, therefore, the movements of the ribs are essentially rotations upward, forward, and outward upon oblique axes directed through the eosto-vertebral articulations and a little anterior to the costo-trans verse articulation, they are more or less modified by reason of the motion permitted by the nature or the absence of the costo-transverse articu- lations. Thus, the essential character of the movement of the first to the fifth ribs is a rotation upward, forward, and outward ; that of the sixth to the ninth ribs, a rotation upward, forward, and outward combined with a movement upward and backward; that of the tenth and eleventh ribs, a rotation upward, forward, and outward with a rotation backward ; that of the twelfth rib, chiefly a rotation backward and rather downward. The character of the movement of each rib differs somewhat as we pass from the first to the twelfth ribs. During forced inspiration the sternum and its attached costal cartilages with their ribs are pulled upward and outward, while the ninth, tenth, eleventh, and twelfth ribs are drawn backward and downward. During expiration these movements are of course reversed. The intercostal spaces during inspiration, except the first two, are widened. 1 The reason for this opening out must be apparent when we remember that the ribs are arranged in the form of a series of parallel curved bars directed obliquely downward, and the fact may be demonstrated by means of a very sim- ple model (Fig. 71) consisting of a vertical support and two parallel bar-, a, b, placed obliquely. If, after measuring the distance c, d, we raise the bars to a horizontal position, the distance c,J will be found to be greater than c, d, since the bars rotate around fixed points placed in the same vertical line. This widening of the intercostal spaces is readily accomplished because of the elasticity of the costal cartilages. The muscles which may be involved in the movements of the ribs during quiet inspiration include the scaleni, the serrati postid superiores, the levatores eostarum longiet breves, and the intercostales externi ei intercartilaginei. The Hcaleni are active in fixing the first and second ribs, iustrat< the widening thus <■stal.lisl.ing, as it were, a firm basis from which the '; r,h " i " , " r ' : . 08 a ^ 1 ft s n pace9 ~' during Inspiration. external intercostal muscles may act. The scalenus anticus pusses between the tubercles of the transverse processes of the third, fourth, fifth, and sixth cervical vertebrae to the scalene tubercle on the firsl rib. The scalenus medius passes from the posterior tubercles of the transverse processes of the lower six cervical vertebra 1 to the upper surface of the first rib, extending from the tubercle to just behind the groove for the subclavian artery. The scalenus posticus passes from the transverse pro- 1 Elmer: Arehivjur Anatomie vmd Physiologic, Anatomiscbe Abtheilung, L886, 8. L99. Vol. I.— 2fi 11. Model to [1- 402 AN AMERICAN TEXT- BO OK OF PHYSIOLOGY. cesses of the two or three lower cervical vertebrae to the outer surface of the second rib. The serrati postid mperiorea aid in fixing the second ribs and raise the third, fourth, and fifth ribs. The muscles )>a>s from the ligamentum nuchae and the spines of theseventh cervical and first two or three dorsal vertebrae to the upper borders of the second, third, fourth, and fifth ribs, beyond their angles. The levatores costarum breves consist of twelve pairs which pass from the tips of the transverse processes of the seventh cervical and first to the eleventh dorsal vertebrae downward and outward, each being inserted between the tubercle and the angle of the next rib below. Those arising from the lower ribs send fibres to the second vertebra below [levatores costarum longiores). They assist in the elevation and eversion of the first to the tenth ribs, inclusive, and co-operate with the quadrati lumborum and the serrati postici inferiores to draw the lower ribs backward. The functions of the intercostales have been a matter of dispute for centu- ries, and the problem is still unsettled. For instance, Galen looked upon the external intercostals as being expiratory. Vesalius asserted that both the external and the internal intercostals are expiratory, while Haller expressed the opposite belief. Hamberger and Hutchinson regarded the external inter- costals and the intcrchondrals as being inspiratory, and the interosseous portion of the internal intercostals as being expiratory. Finally, Landois believes that while the external intercostals and the intcrchondrals are active during inspira- tion, and the interosseous portion of the internal intercostals during expiration, their chief actions are not to enlarge nor to diminish the volume of the thoracic cavity, but to maintain a proper degree of tension of the intercostal spaces. Each view still has its adherents. The actions of the intercostal muscles are generally demonstrated by means of rods and clastic bands arranged in imitation of the ribs and the origins and insertions of the muscles, or by geometric diagrams. The well-known model of Bernouilli consists of a vertical bar representing the vertebral column, upon which bar move two parallel straight rods in imitation of the ribs (Fig. 72). If the rods be placed at an oblique angle and a tense rubber band (a, b) be affixed to represent the relations of the external intercostals, the rods will be pulled upward and the space between them will be widened. The interchon- dral portion of the internal intercostal- bears the same oblique relation to the costal cartilages, and theoretically should have the same action. The action of the interosseous portion of the internal intercostals is demonstrated in this way: If the rubber band be placed at right angles to the rods (Fig. 73, a, b) and the rods be raised to a horizontal position, the rubber is put on the stretch (c, d), so that when the rods are released they will be pulled downward by the elastic reaction of the rubber. This last demonstration has been held to indi- cate that during inspiration the interosseous portion of the internal intercostals i- put on the stretch and in an oblique position, and therefore in a relation favorable tor effective action during contraction. The ribs, however, differ essential Iv from such a model in the fact that they are curved bars, that their RESPIRATJOX. 403 ends are not free, and that the movement of rotation is materially different. In fact, the mechanical conditions are so complex that deductions from phe- nomena observed in such gross demonstrations or by means of geometric figures such as suggested by Rosenthal and others must be accepted with caution. There is no doubt that stimulation of any of the intercostal fibres causes an elevation of the rib below if the rib above be fixed, and that if the excita- tion be sufficiently strong and the area be large, the effect may extend from rib to rib, and thus a large part of the thoracic cage will be elevated. Conse- quently, it has been assumed that, should the upper ribs be fixed, the contrac- tions of both sets of intercostals would elevate the system of ribs below. But the experiments of Martin and Hartwell l show that during forced inspiration the internal intercostals contract alternately with the diaphragm and the exter- nal intercostals, and therefore are expiratory. Moreover, Ebner 2 has found, as a result of elaborate measurements, that the intercostal spaces, excepting the first two, are, instead of being narrowed, actually widened during inspiration. Fig. 72. — Model to illustrate the action of the external intercostals and interchondrals. Fig. 73.— Model to illustrate the action of the inter- osseous portion of the internal intercostals. An examination of the origins and insertions of the external intercostals and the interosseous portion of the internal intercostals, and of their actions during contraction, renders it apparent that it is possible for the externi to elevate the ribs and to widen the intercostal spaces, but that such effects are impossible in the case of the interosseous portion of the internal intercostals. Thus, if we take the model described above (Fig. 72), project a line a, 6 in imitation of the relation of the external intercostals to the ribs, and raise the parallel bars to a horizontal position, the distance between c, d is shorter than that between a, l>. It is but a logical step from this demonstration to assume that, should a strip of muscle be placed between «, b, the muscle in shortening would pull the bars upward, at the same time widening the intercostal spaces. 1 1" now the upper ribs be fixed, it is obvious that the external intercostals must raise the ribs and open up the intercostal spaces during contraction. This same reason- ing applies to the interchondrals, and the experiments of Hough 3 show that they contract synchronously with the diaphragm, and therefore with the exter- nal intercostals. 1 Journal of Physiology, 1S79-80, vol. 2, p. 24. 2 Lnr. ril. 3 Studies from the Biological Laboratory, Johns Hopkins University) March, 1894. 404 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. In considering the interosseous portion of the internal intercostals we find that during the passive condition they are placed nearly at right angles to the ribs. H' contraction takes place, it is obvious that the mechanical response must be an approximation of the ribs and a lessening of the width of the inter- costal spaces. It must also be apparent that during the movement of inspira- tion these fibres are put on the stretch, which can be demonstrated in the above model. Thus, if we put a rubber band at right angles to the parallel rods (Fig. 73), we will find that when the rods are in the horizontal position, in imitation of the position of the ribs at the beginning of expiration, the distance between c, '/ is greater than that between a, b ; therefore if we lessen the dis- tance between e, r/, as when the muscle-fibres contract, the mechanical result of contraction must be approximation, the opposite to that which occurs during inspiration. While the whole subject of the actions of the intercostal muscles must still be regarded as in an unsettled condition, yet there is no reasonable doubt that the externi and the intercartilaginei contract during inspiration, and the inter- osseous portion of the internal intercostals during expiration. Admitting this to be true, it is, however, by no means clear whether or not these muscles are for the purpose of altering the volume of the thorax. It is probable, as sug- gested by Landois, that their chief function is to maintain, during all phases of the respiratory movements, a proper degree of tension of the intercostal tissues. If this view be correct, the external intercostals and interchondrals con- tract during inspiration chiefly for the purpose of causing greater tension of the intercostal tissues, so as to counteract the influence of the increase of negative intrathoracic pressure ; while during expiration, when their relax- ation occurs, a substitution for this relaxation is provided by the contraction of the interosseous portion of the internal intercostals, so that the tension of the intercostal tissues is maintained. The internal intercostals must prove most effective during forced expiratory efforts — for example, in coughing, when the intercostal tissues are subjected to high positive intrathoracic pres- sure, and there is a consequent tendency to outward displacement, which is met and counteracted by the internal intercostals. During forced inspiration the scaleni and the serrall j>ostiel superiores con- tract vigorously, so that the sternum and the first five ribs are elevated, thus raising the thoracic cage as a whole. At the same time the serrati postid inferiores, the quadraii lumborum, and the sacro-lumbaies are active in pulling the lower ribs downward and backward. Besides these muscles there are a number of others which directly or indirectly affect the size of the thorax and which may be brought into activity ; chief among these are the slerno-chi- mastoidei, the trapezei, the pectorales minores, the perforates majores (costal portion), the rhomboidei, and the erectores s/)ince. The xfenio-cteido-mastoid passes from the mastoid process and the superior curved line of the occipital bone to the upper front surface of the manubrium and the upper bolder of the inner third of the clavicle. These muscles ele- vate the upper part of the chest when the head and neck are fixed. The RESPIRA TIOX. 405 trapezius passes from the occipital bone, the ligamentum nucha?, the spines of the seventh cervical and of all the dorsal vertebra, and the supraspinous liga- ment to the posterior border of the outer third of the clavicle, the inner border of the acromion process, the crest of the spine of the scapula, and to the tubercle near the root. The trapezei help to fix the shoulders. The rhomboid- eus minor passes from the ligamentum nucha? and the spines of the seventh cervical and first dorsal vertebrae to the root of the spine of the scapula. The rhomboideus major passes from the spines of the first four or five dorsal vertebrae and the supraspinous ligament to the inferior angle of the scapula. The trapezei and rhomboidei fix the shoulders, affording a base of action from which the pectorales act. The pectoralis major passes from the pectoral ridge of the humerus to the inner half of the anterior surface of the clavicle, the corre- sponding half of the anterior surface of the sternum, the cartilages of the first six ribs, and the aponeurosis of the external oblique muscle. The pecto- ralis minor passes from the coracoid process of the scapula to the upper margin and outer surface of the third, fourth, and fifth ribs close to the cartilages and to the intercostal aponeuroses. The pectorales minores and the costal portion of the pectorales majores raise the ribs when the shoulders are fixed. The erectorcs spina? are composite muscles extending along each side of the spinal column, each consisting of the sacro-lumbalis, the musculus accessorius, the cervicalis ascendens, the longissimus dorsi, the transversalis cervicis, the trachelo- mastoid, and the spinalis dorsi. The erectores spinae straighten and extend the spine and the neck, and thus tend to raise the sternum, the costal cartilages, and the ribs. The infrahyoidei may also be included among the muscles engaged in forced inspiration, since they may aid in the elevation of the sternum. Summary of the Actions of the Chief Muscles of Inspiration. — Dur- ing quiet inspiration the diaphragm contracts, thus increasing the vertical diam- eter of the thorax, its effectiveness being augmented by the associated actions of the quadrati lumborum and the serrati postici inferiores, the tinnier fixing the twelfth ribs, and the latter fixing the ninth, tenth, eleventh, and twelfth ribs, and thus preventing the muscular slips of the diaphragm attached to these ribs from drawing them inward and upward and thus diminishing the cavity of the thorax. Coincidcntly with the contractions of these muscles the seal ni fix the first and second ribs, and the serraU postici superiores aid in fixing the second ribs and elevate the third, fourth, and fifth ribs ; the intercostales extemi et intercartilaghiei and the levatores costarum tongi > I bn ves elevate and evert the first to the tenth ribs, inclusive, throwing the lower end of the sternum for- ward; and the levatorcs, in conjunction with the quadrati lumborum and the 8t ■rrati postici inferiores, aid in fixing the lower ribs and even draw them buck- ward. The intercostales extern/ also serve to maintain a proper degree of tension of the intercostal tissues. During forced inspiration the scaieni and the serrati postici superiores act more powerfully and thus raise the sternum with its attached costal cartilages and ribs, being assisted by the sterno-cleido-Tnastoidei and the infrahyoidei when the head and neck are fixed, and by the pectorales majores et minores 406 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. when the shouldersare fixed by thetrapezei and the rhomboidei. The erectores spina- further assist this action by extending the spinal column. Movements of Expiration. — During quiet breathing; expiration is effected mainly or solely by the passive return of the displaced parts. Normal expi- ration is therefore essentially a passive act, although it may be assisted by the contraction of the interosseous portion of the internal intercostals. The most important factors are unquestionably the elastic tension of the lungs, costal cartilages, intercostal spaces, and abdominal walls, together with the weight of the chest. The lungs after quiet expiration are in a state of elastic tension equal to a pressure of +1.9 to +3.9 millimeters of mercury (see p. 397), which pressure during inspiration is increased in proportion to the depth of the movement. As soon, therefore, as the inspiratory muscles cease to contract, this tension comes into play, and, aided by elastic and mechanical reactions below noted, forces air from the lungs. This elasticity, and the facility with which the air is expelled, may be demonstrated by inflating a pair of excised lungs and then suddenly allowing a free egress of the air : collapse occurs with remarkable rapidity, with a force proportionate to the degree of distention. The elastic costal cartilages are similarly put on the stretch : the lower borders are drawn outward and upward and are thus twisted out of position, so that as soon as the inspiratory forces are withdrawn they must untwist themselves, further aiding the elastic reaction of the lungs. The intercostal spaces, excepting the first two, are widened and the tissues are stretched, and the diaphragm during its descent presses upon the abdominal viscera, rendering the abdominal walls tense. When, therefore, inspiration ceases the reaction of the tense and elastic intercostal tissues aids in bringing the chest into the position of rest, while the stretched abdominal walls press upon the abdominal viscera and thus force the diaphragm upward. Finally, the chest-walls by their weight tend to fall from the position to which they have been raised, adding thus another factor toward the elastic reaction of the lungs, costal cartilages, intercostal tissues, and abdominal walls. Whether or not the interosseous portion of the internal intercostal muscles assists in expiration cannot be stated with positiveness. The fact that these muscles contract during the expiratory phase and that the contraction results in an approximation of the ribs leads to the belief that they are expiratory., lint, as before stated (p. 1»>1), this activity may be primarily for the purpose of maintaining a proper degree of tension of the intercostal tissues. In the doe- these muscles are not active until dyspnoea appears, while in the cat they do not come into play until extreme dyspnoea has set in (Martin and Hartwell). These facts certainly militate against regarding them as active expiratory fac- tors during quiel breathing, while during forced expiration they may with accuracy be considered as being in part at leas! expiratory in function. We are therefore justified in concluding thai normal quiet expiration is essentially a passive act due to elastic reaction and to the mechanical replacement of dis- placed parts. RESPIRATION. 407 During forced expiration certain muscles may be active, the chief being the intercostales intend interossei, the triangulares sterni, the museuli abdominales, and the levatores ami. The intercostales intend interossei are probably active expiratory muscles during forced expiration, but they can prove effective only when the lower part of the thoracic cage is fixed or drawn down — an act which is accomplished chiefly by the abdominal muscles. The triangulares sterni pass outward and upward from the lower part of the sternum, the inner surface of the ensiform cartilage, and the sternal ends of the costal cartilages of the two or three lower sternal ribs, to the lower and inner surfaces of the cartilages of the second to the sixth ribs, inclusive. They draw the attached costal cartilages downward during expiration. The abdominales during quiet expiration are passive, and aid in the expul- sion of air from the lungs simply by their elasticity ; but during forced expi- ration, by contraction, they are active expiratory factors. The obliquus externus arises by slips on the outer surface and lower borders of the lower eight ribs, and is inserted into the outer lip of the anterior half of the crest of the ilium and into the broad aponeurosis which blends with that of the opposite side in the linea alba. The obliquus internus passes from the outer half or two-thirds of Poupart's ligament, the anterior two-thirds of the middle lip of the crest of the ilium, and the posterior layer of the lumbar fascia to the cartilages of the last three ribs and the aponeurosis of the anterior part of the abdominal wall. The rectus abdominis passes from the crest of the pubes and the ligaments in front of the symphysis pubis to the cartilages of the fifth, sixth, and seventh ribs, and usually to the bone of the fifth rib. The transversalis abdominis passes from the outer third of Poupart's ligament, the anterior three-fourths of the inner lip of the iliac crest, by an aponeurosis from the transverse and spinous processes of the lumbar vertebrae, and from the inner surface of the sixth lower costal cartilages to the pubic crest and the linea alba. The fibres for the most part have a horizontal directi< >n. The pyram- idcdls passes from the anterior surface of the pubes and the pubic ligament to the linea alba. It is obvious from the points of origin and insertion of the abdominal muscles that during contraction they co-operate toward diminishing the volume of the thorax in three ways: (1) By offering a base of action for the internal intercostals, and thus aiding in the approximation of the ribs; (2) by depressing and drawing inward the lower end of the sternum and the lower costal cartilages and ribs; (3) by forcing the abdominal viscera against the diaphragm, thrusting it upward. The abdominales are unquestionably the chief expiratory muscles. The levatores ani converge from the pelvic wall to t ho inner part of the rec- tum and the prostate gland. They form the largest part of the muscular floor of the pelvic cavity. The levatores ani are important during forcible expi- ration by resisting the downward pressure of the pelvic viscera caused by the powerful contractions of the abdominal muscles, but they must be regarded rather as associated in the act of expiration, and not as true expiratory muscles. Summary of the Actions of the Chief Muscles of Expiration. — During 408 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. quiet expiration no muscular factors are involved, unless it be the contraction of the intercostales intemi interossei, in which event they are more probably engaged in maintaining the tension of the intercostal tissues than in actually diminishing the capacity of the thorax. During/orced expiration the abdominales flex the thorax upon the pelvis, force the abdominal viscera against the diaphragm, thrusting it upward, and by pulling upon the lower margins of the thoracic cage draw them inward and at the same time offer a base from which the intercostales intemi inter- ossei act to pull the ribs downward; the triangulares stemi contract at the same time and pull downward the cartilages of the second to the sixth ribs, inclusive. Associated Respiratory Movements. — Associated with the thoracic and abdominal movements of respiration are movements of the face, pharynx, and larynx. The nostrils arc slightly dilated during inspiration and passively return to their condition of rest during expiration ; the soft palate moves to and fro with the inflow and outflow of air, and the glottis is widened during inspiration and narrowed during expiration. During labored inspiration, besides the above movements, the mouth is usually opened; the muscles con- cerned in facial expression may be active, giving the individual an appearance of distress; the soft palate is raised, and the larynx descends. The widening of the nares and the glottis, the opening of the mouth, the elevation of the soft palate, and the descent of the larynx during inspiration are obviously for the purpose of lessening the resistance to the inflow of air. Intrapulmonary or Respiratory Pressure and Intrathoracic Pressure. — The tidal flow of air to and from the lungs during the respiratory move- ments is due, as already stated, to the differences between the pressure within the lungs and that outside the body. During inspiration the enlargement of the thorax causes an expansion of the lungs and a consequent diminution of pressure within them, so the air is forced through the air-passages until the pressure within the lungs equals that of the atmosphere; during expiration there occur elastic and mechanical reactions whereby the pressure within the lungs is greater than that of the atmosphere, consequently air is expelled until an equilibrium is again established. It is apparent, then, that during inspira- tion there exists within the lungs a condition of negative pressure, and that during expiration the pressure is positive. If a manometer be so arranged as in do way to interfere with the ingress and egress of air, it will be found that during inspiration the column of mercury sinks, while during expiration it rises. Donders found by connecting a manometer with the nasal passage that the pressure during quiet inspiration was — 1 millimeter of ITg, and during expiration +2 to 3 millimeters. Ewald gives as corresponding values — 0.1 millimeter and -f-0.13 millimeter, and Mundhorst, — 0.5 millimeter and +5 millimeters. During deep inspiration Donders noted a pressure of — 30 milli- meter-, and when the mouth and nose were closed, — 57 millimeters. During forced expiration, with respiratory passage closed, it was +87 millimeters; but these figures have been exceeded. RESPIRA TIOF. 409 It will l>e observed that during quiet respiration intrapulmonary pressure (pressure vnthin the lungs) oscillates between negative and positive and rice versd, whereas intrathoracic pressure (pressure outside the lungs) is persistently negative, the amount by which it differs from atmospheric pressure becoming greater during inspiration and diminishing to the previous level during expi- ration (p. 397). Under forced expiration, however, when the air-passages are obstructed intrathoracic pressure may become positive. This may be demon- strated in this way: If a manometer be connected with the mediastinum of a cadaver, and the chest be pulled upward in imitation of deep inspiration, intrathoracic pressure will be found to be about — 30 millimeters. If now a second manometer be connected with the trachea, and air be forced into the lungs through a tracheal tube, as intrapulmonary pressure rises intrathoracic pressure falls, so that when the former reaches +30 millimeters the intratho- racic negative pressure exerted by the elastic traction of the lungs is counter- balanced and the pressure within and outside the lungs is equal. If intra- pulmonary pressure now rise above this limit, intrathoracic pressure must proportionately become positive. During violent coughing, when the expira- tory blast is obstructed and the muscular effort is powerful, intrapulmonary pressure may rise to -(-80 millimeters or more. The intercostal tissues tend to be drawn inward as long as negative intra- thoracic pressure exists, and to be forced outward when there is positive intra- thoracic pressure; hence during inspiration the traction becomes more marked with the rise of intrathoracic pressure, and during expiration the reverse ; while during forced expiration with obstructed air-passages the pressure exerted by the effort of the expiratory muscles, together with the weight of the chest and the elastic reaction of the costal cartilages, etc., may be, as above stated, far more than sufficient to counterbalance the traction exerted by the distended elastic lungs, and thus cause positive intrathoracic pressure. The influences exerted by changes in intrathoracic and intrapulmonary pressure upon the circulation are marked and important, and may be so pro- nounced as to cause an obliteration of the pulse. Respiratory Sounds.— During the respiratory acts characteristic sounds are heard in the lungs. A study of these sounds, however, properly belongs to physical diagnosis. The Value of Nasal Breathing. — Nasal breathing h;is a value above breathing through the mouth, inasmuch as the air is warmed and moistened and thus rendered more acceptable t<> the lungs, mure or less of the foreign particles in the air are removed, and noxious odors may be detected. B. The Gases in the Lungs, Blood, and Tissues. Alterations in the Gases in the Lungs. — The object of respiratory movements is t<> renew the air within the lungs, which air is constantly being vitiated, and thus supply () and remove CO, and other ell'ete substances. The lungs of the average adult man after quiet expiration contain about 2800 cubic centimeters (170 cubic inches) of air. During quiet respiration there is an 410 AX AMEIUCAX TEXT- BOOK OF PHYSIOLOGY. inflow and outflow of about 500 cubic centimeters (30 cubic inches), therefore from one-sixth to one-tilth of the air in the lungs is renewed by each act. Since the respirations occur at so frequent a rate as 16 to 20 per minute, it seems apparent that there must be a rapid loss of O and a gain of C0 2 . This is proven by analyses of inspired and expired air. Inspired air is under normal circumstances atmospheric air, composed of oxygen, nitrogen, argon, and carbon dioxide, with more or less moisture, traces of ammonia and nitric acid, dust and micro-organisms, etc. The essential differences between inspired and expired air are shown by the following table, the figures for the gases being in volumes per cent. Nitrogen and argon are omitted because they play no important role in respiration, there being neither absorption nor discharge of either to any noteworthy extent. They take no part, as far as known, beyond that of a mere diluent of the inspired and expired air. Inspired air . . Expired air . . 20.x l 1 1 ;.<>:; 4.78 < ■( >, (Mil 138 4.34 Water Vapor. Variable. Saturated. Temperature. Average about 20° Average, about 30.3° Volume (Actual). Diminished i .i to Expired air is therefore 4.78 volumes per cent, poorer in O, 4.34 volumes per cent, richer in 0O 2 ; it is saturated with water vapor, and is of higher tem- perature and of less actual volume. In addition, expired air contains various effete bodies, such as organic matter, hydrogen, marsh-gas, etc. The relative quantities of O absorbed and of 0O 2 given off are not constant, and the ratio is known as the respiratory quotient. This is obtained by dividing the volume of CO, given offby that of ( ) absorbed/ f~^.= 0.908. Hence, O, 4. i 8 for each volume of <) that is lost 0.908 volume of C0 2 is gained. Various conditions affect the quotient (p. 436). The quantity of watery vapor lost by the lungs varies inversely with the amount contained in the atmosphere and with the volume of air respired. The less the moisture in the atmospheric air and the larger the volume of air respired, the greater the loss. Valentine, in experiments on eight young men, records a daily loss varying from 319.'.) to 773.3 grams, or an average of 540 grams. Vierordl records a loss of 330 grams, while Aschenbrandt estimates a daily loss of 526 grams. 'flie temperature of the expired air varies directly with the temperature and volume of the inspired air and with the temperature of the body. Valentine and Bruner found that when the temperature of inspired air was from 15° to 20°, that iif expired air was 37.3° ; when that of inspired air was — 6.3°, expired air had a temperature of 29.8° ; while when the inspired air was at 41.9°, that of expired air was 38.1°. When the air is respired through the nose the expired air is warmer than when respiration occurs through the mouth. Bloeh 1 1 ZeUschrifl fur Ohrenheilhtnde, 1888, Bd. xviii. S. 215. R ESPIRA TION. 4 1 1 records a difference of 1.5° to 2°. The figures by other observers vary from 0.5° to 1.5°. The larger the volume of air respired, other things being equal, the less the increase of temperature. The volume of expired air is from 10 to 12 per cent, greater than that of inspired air, this increase being due to expansion caused by the increase of tem- perature. When dried and proper deductions made for temperature and baro- metric pressure, the actual or corrected volume is less by about ^ to -£$. Lossen estimated that 0.0204 gram of ammonia is eliminated per diem in the expired air. Bergey also found small quantities of ammonia, yet Voit's investigations indicate that expired air usually does not contain even a trace of ammonia. Alterations in the Gases in the Blood. — The blood in the pulmonary artery is of the typical venous color — that is, deep bluish-red. During its passage through the lungs it becomes scarlet-red, or, commonly speaking, arte- rialized or aerated. If we take arterial blood and deprive it of oxygen, the color changes to a venous hue ; if now we shake the bluish-red blood in air or O, the scarlet-red color is restored. We have here the suggestion that the blood while passing through the lungs absorbs O. Analyses show that not only does absorption of O occur, but that there is simultaneously with this an elimination from the blood of C0 2 . A rterial and venous blood each contains approximately 60 volumes per cent, of O and C0 2 ; that is, for about every 100 volumes of blood 60 volumes of gas will be obtained. Such analyses demonstrate also that while the total volumes per cent, of O and CO, are about the same, the proportions are different. The following table, compiled from various sources, gives the volumes per cent, of gases in the arterial blood of various animal- : Animal. Total. O. CO-,. N. Dog 59.38- 18.65 38.93 1.8 Cat 43.2 13.1 28.8 1.3 Sheep 57.6 10.7 45.1 1.8 Rabbit 49.3 13.2 34.0 2.1 Man 63.4 21.6 40.3 1.5 Fowl 58.8 10.7 48.1 Pflviger obtained as averages of analyses of arterial blood of dogs 58.3 volumes per cent., consisting of 22.2 volumes per cent, of O, 34.3 volumes per cent, of C0 2 , and 1.8 volumes per cent, of N. Venous blood, according to estimates by Zuntz based on a large number of analyses, contains 7.15 vol- umes per cent, less of O and 8.2 volumes per cent, more of C< I,. The quantity of N is practically the same in both arterial and venous blood. The proportions of O and CO a in arterial blood vary but little in speci- mens taken at random from the arterial system, while those of venous blood, on the contrary, differ considerably according to the locality of the vessel as well as to the degree of activity of the structures whence the Mood come-. Thus, venous blood from an active secreting gland differs very little in its composition, gaseous and otherwise, from typical arterial blood, whereas when 412 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. the gland is inactive the blood is typically venous. The arterial character of the venous blood in the former ease is due to the considerable increase in the quantity of blood passing through the gland during activity, the result being that the loss and gain of substances are not so noticeable although the total quantities of O and 0O 2 and other substances exchanged are actually greater than when the gland is at rest and the blood coming from it has the typical venous characters. The venous blood during its passage through the lungs acquires O and loses C0 2 . After the blood is arterialized it parses from the lungs into the left side of the heart, from which it is forced to the aorta and its ramifications and ulti- mately into the capillaries. Here it undergoes a retrograde change, parting with some of its O and taking in exchange C0 2 ; consequently the gaseous interchange between the blood and the tissues is the reverse of that occurring between the blood and the air. Thus we find that the interchange of O and C0 2 occurs in a distinct series of events: (1) Oxygen is carried as a constituent of the atmospheric air to the alveoli ; (2) here it is absorbed by the venous blood, which at the same time gives off C0 2 to the air in the alveoli; (3) O is now in major part conveyed to the tissues, in which it is taken up and utilized in pro- cesses of oxidation, CO, being the chief effete product, which is formed immedi- ately or ultimately and given to the blood (a part of the O is consumed by the blood, C0 2 being one of the results) ; (4) the venous blood is now conveyed to the lungs, C0 2 is given off and O is received iu exchange, and the series of events is repeated. The Forces Concerned in the Diffusion of O and C0 2 in the Lungs. — If the air expired be collected in a number of parts, each successive portion will be found to contain a smaller percentage of O and a larger percentage of C0 2 . The air in the beginning of the respiratory tract (nose and mouth) varies from atmospheric air but little in composition, while that in the alveoli contains con- siderably less O ami much more C0 2 . With each quiet act of inspiration the quantity of air breathed is from three to four times greater than the capacity of the trachea and bronchi, so that with each respiratory act two-thirds or more of the fresh air is carried into the alveoli. When expiration occurs a similar volume of the vitiated air within the alveoli is driven into the bronchi and trachea, and thus a certain percentage is expelled from the body. Thus the mere volume and force of the air-currents must obviously be of great value in equalizing the composition of the air in the different parts of the respiratory tract. The contractions of the heart exert similar mechanical influences. With each contraction intrathoracic pressure is lessened, so that there is a slight expansion of the lungs, just as would lie caused had the thorax been slightly enlarged, and consequently there is a movement of air toward and into the alveoli. Dur- ing diastole intrathoracic pressure returns to the previous level, the volume i if the lungs is diminished, and the air is driven from the alveoli. Thus each heart-beat causes a to-and-fro movement of the air. These oscilla- tions, which are termed cardio-pneumatic movements, are of more importance than mighf seem at first sight, for it has been shown that in cases of suspended BESPIMA TION. \\:\ animation and in hybernating animals they aid materially in pulmonary ven- tilation. Besides these mechanical factors there is present the important factor of the diffusion of gases, O diffusing toward the alveoli and CG 2 toward the anterior nares. The rapidity with which diffusion occurs, other things being equal, depends upon the differences in the " partial pressure " of the gas at various regions. Each gas forming part of a mechanical mixture exerts a partial pressure proportional to its percentage of the mixture. Thus, atmospheric air contains 20.81 volumes per cent, of O, 0.04 volumes per cent, of C0 2 , and 79.15 volumes per cent, of N. If the air exists at 760 millimeters barometric pressure, each gas will exert apart of the total pressure, or a " partial pressure," equivalent to its respective volume. Should we wish to find the partial pressure of O, it may be ascertained simply by taking ^jjL of the total pressure = IM^pO = 158.15 millimeters; similarly, the partial pressure of C0 2 would be 0.04 X 760 noA .... . . „ AT 79.15X760 nn , c t r-^j = 0.30 millimeter; and that of JN, r-r^r — — = 601.54 millimeters. Knowing, then, the composition of any mixture of gases and the total pressure under which it exists, it is a matter of very simple calculation to determine the partial pressure of each of the various gases constituting the atmosphere. Expired air is poorer in O and richer in C0 2 than inspired air, and alveolar air is altered even to a greater extent than expired air ; hence the partial pressures must be affected similarly. The first portion of the air expired contains a maximum amount of inspired air and a minimum amount of the air contained in the air-passages previous to the inspiratory act ; but as expiration continues the mixture becomes poorer and poorer in inspired air and similarly richer in the vitiated air from the smaller air-passages and the alveoli; in fact, the last portion of expired air is very similar to, if not identical in its composition with, that in the alveoli. The following partial pressures of O and C0 2 in inspired air and alveolar air indicate the extent to which the composition varies in different parts of the respiratory tract : Gas. Inspired Air. Alveolar Air. O 158.15 millimeters. 100 millimeters. 1 C0 2 0.30 millimeter. 23 millimeters. Since the partial pressure of O in inspired air is about 158.15 millimeters, and as it is but about 100 millimeters in the alveoli, and as the air is poorer in ( > as we pass from the nares to the alveoli, it is obvious thai a force musi be exerted constantly to cause a diffusion of O from the larger air-passages to the bron- chioles and from the bronchioles to the alveoli — that the () must diffuse from the region of highest pressure to tliat of lowest pressure. During life an equilibrium can never be established, because of the constant supply of fresh air and the continual passage of () from the alveoli to the blood. The 1 The exact per cent, composition of alveolar air is not known ; these Bgures are estimates. 414 AN AMERICAN TEXT- BOOK OF PHYSIOLOGY. same relations of partial pressure are observed in connection with C0 2 , except thai the air in the alveoli is incessantly acquiring this gas from the blood, causing the per cent, composition of C0 2 to be much in excess of that found in the atmosphere. The partial pressure of CO a in the alveolar air is about 23.00 millimeters, while in inspired air it is only 0.30 millimeter ; hence C0 2 must diffuse from the alveoli outward. There are, therefore, three important factors concerned in the admixture and purification of the air in the lungs: (1) The tidal movements caused by inspiration and expiration, which movements by the mere force of air-cur- rents cause a partial mixture of the air; (2) the smaller wave-movements (car- dio-pneumatie) produced by the heart-beats, and similar in effect to, but much less effective than, the first ; (3) the diffusion of O and CO z , depending upon dif- ferences in their partial pressures in the various parts of the respiratory tract. The first is by far the most important. The Forces Concerned in the Interchange of O and CO., between the Alveoli and the Blood. — The gases in the lungs are in the form of a mechanical mixture, while in the blood they are in solution or in chemical combination ; hence we now have to deal with conditions quite different, involv- ing the consideration of the relations of gases to liquids — a relationship of twofold nature, inasmuch as the gas may be found not only in solution, but in chemical association. When an atmosphere consisting of O, C0 2 , and N is brought in contact with water, each gas is absorbed independently not only of the others, but of the nature and quantity of all other gases which may happen to be in solution. The quantity of each gas dissolved depends upon its relative solu- bility as well as upon the temperature and the barometric pressure. The coefficient of absorption of any fluid is the quantity of gas dissolved at a given temperature and pressure, and is in inverse relation to temperature and in direct relation to pressure. The following absorption-coefficients of water for O, C0 2 , and N at 760 millimeters of Hg have been obtained by Winkler: 1 Temperature. O. C0 2 . N. 0° 0.04890 1.7967 0.02348 15° 0.03415 1.0020 0.01682 40° 0.02306 • . 01183 Thus, at 0° ( ! and 7f>() millimeters pressure each volume of water absorbs 0.0489 volume of O; at 15°, 0.03415 volume; and at 40°, 0.02306 volume. The absorption-coefficienl falls, it will be observed, with the increase of temperature. Comparing the solubilities of the three gases, it will be seen that at the same temperature and pressure a considerably larger quantity of CO, is absorbed than ofO — Dearly forty times more — whereas the quantity of N absorbed is less than one-half as mneli as thai of O. The quantity of a gas absorbed bya given liquid at a given temperature is proportionate to its coefficient of solubility and to the pressure, and is the same 1 Zeittschrift fur physikalischi Chemie, 1892, Rd. 9, S. 173. BESPIRA TION. 41 5 whether the gas exist free or as a constituent of a complex atmosphere, pro- vided that the pressure exerted by the gas in both cases be the same. Thus, atmospheric air consists of 20.81 volumes per cent, of O, 0.04 volume per cent, of C0 2 , and 79.15 volumes per cent, of N. Each gas exerts a partial pressure in proportion to its percentage of the mixture. Assuming that the air is at standard atmospheric pressure, the partial pressure of O is 20.81 per cent, of 760 millimeters of Hg, or 158.15 millimeters. The quantity of O absorbed from the air at 0° C and 760 millimeters pressure is therefore the same as when the atmosphere consists of pure O at a pressure of 158.15 millimeters. ti i m • , .11 20.81 X 0.0489 _ .. _ Ihe absorption-coemcieut must consequently be - — — = 0.01 vol- ume. Therefore 100 volumes of water at 0° C. and 760 millimeters pressure absorb from the air 1 volume of O. If the partial pressure of O be increased or decreased, the quantity absorbed will rise or fall accordingly. From this it is obvious that O must exist under a certain degree of pressure to prevent its passing out of solution, which is expressed by the term tension of solution, meaning, in a word, the pres- sure required to keep the gas in solution. If the partial pressure of the gas diminishes, the gas in solution is given off until the partial pressure of the gas in the air and the tension of the gas in solution are equal. Conversely, as the partial pressure of the gas in the air increases, the gas in solution will be under correspondingly higher tension. Tension of O. — The absorption-coefficient of blood for O is nearly the same as that of water, so that blood at 0° should absorb from the atmosphere about 1 volume per cent, of O, but less than one-half as much at the temperature of the body. The results of experiments show, however, that blood contains considerably more than this (see table, p. 411), and very much more than can be accounted for by the laws of partial pressures and tensions. Moreover, when the blood is subjected to a vacuum pump there is evolved a small amount of gas consistent with the diminution of pressure, but the greal bulk of it does not come off until the pressure has been reduced to -fa to -,- 1 ,, of an atmosphere. Finally, the quantity absorbed is affected but little by changes in pressure above or below a certain standard. These facts indicate that almost all of the O must be in chemical combination. This combination Is with haemoglobin in the form of oxyhemoglobin. This chemical union i> readily dissociated at a constant minimal pressure which is termed the tension of dissociation. There is a persistenl tendency of the gas in such a compound to become disengaged, so that when oxyhemoglobin is placed under circum- stances where the tension or the partial pressure of <> is less than that in the compound dissociation occurs ; conversely, when haemoglobin is brought in contact with Oat a pressure above the minimal constanl of dissociation (..'.. to ] \ t of an atmosphere), the two unite to form oxyhemoglobin. One gram of haemoglobin from ox blood combines, according to Kufner,' with 1.34 cubic centimeters of O at 0° and 760 millimeters pressure. Assuming 1 Arehiv fiir Anatomie und Physiologie, 1894, S. L30, 416 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. that 100 cubic centimeters of blood contain 1 5 grams of haemoglobin (p. 37), the quantity of gas which would combine with this amount of haemo- globin would be equal to 20.1 cubic centimeters ; in other words, arterial blood should contain, if the haemoglobin be saturated with oxygen, 20.1 volumes per cent, of ( >. The plasma ami the serum absorb hut very small quantities of O — accord- ing to PHiiger, only 0.26 volume per cent. ( hving to the relatively low absorp- tion-coefficient of the plasma compared with the ( ^capacity of the haemoglobin, as well as to the fact that the haemoglobin is nearly saturated at a relatively low pressure, the quantity of O absorbed is not materially affected by an increase of pressure above the level of the tension of dissociation. The tension of O in arterial and venous blood must be ascertained separ- ately, inasmuch as each contains a different percentage. Following this method, Strassburg 1 records the following averages: Arterial blood, 29.64 millimeters of Hg, or 3.9 per cent, of an atmosphere ; and venous blood, 22.04 millimeters, or 2.9 per cent, of an atmosphere. The figures obtained by Bohr and by Ilaldane and Smith 2 are, however, much higher (see p. 418). Tension of ( '0 2 . — Venous blood contains about 45 volumes per cent, of CO.,. The results of experiments prove that only about 5 per cent, of this ( '( )., is in simple solution, that from 10 to 20 per cent, is in firm chemical combination, and that from 75 to 85 per cent, is in loose combination. When the blood at the temperature of the body is subjected to a vacuum, all of the C0 2 is given off; but if the blood-corpuscles be removed and the plasma and corpuscles each in turn be submitted to the pump, both will give off CO,, the plasma yielding a larger volume than the corpuscles, but not so much as when they are together. Plasma and serum in vacuo give off only a portion of their C0 2 ; the remainder may, however, be dissociated by adding acid or red corpuscles. The red corpuscles therefore act as an acid and cause the disengagement of all the gas from the plasma; consequently, not only do the corpuscles yield up the C0 2 contained in them, but they are also active agents in bringing about the dissociation of CO z which is in chemical combination in the plasma. The dissociation is due in part, perhaps, to the presence of phos- phates in the stromata of the red corpuscles, and to certain proteids, but the observations of Preyer and Hoppe-Seyler lead to the conviction that it is due chiefly to oxyhemoglobin and haemoglobin. While phosphates, proteids, haemoglobin, and oxyhemoglobin all may have the power of expelling C0 2 from sodium carbonate in solution in vacuo, this fact leaves us none the wiser as to which, if any, is active in this way in the blood. Arterial blood gives oil' its CO., more readily than venous blood. Of the total quantity of 0O 2 , about 5 per cent, is in simple solution and from 10 to 20 per cent, is in firm chemical combination in the plasma, the latter requiring the addition of acid or of haemoglobin, etc. to cause its dissociation in vacuo; while the remainder, constituting much the larger proportion, is in 1 Archivfiir Physiologic, Bd. vi. S. 65. 2 Journal of Physiology, 1/ Physiology, 1*07, vol. xxii. p. 231. BESPIRA TION. 4 1 9 that the transmission of O between the alveoli and the blood cannot be satis- factorily explained by mere diffusion. Moreover, about twice as much argon exists in solution in the blood plasma as can be accounted for by physical laws. Facts of this kind are explicable on the hypothesis that the living tissues are, as contended by Ludwig, Bohr, and others, actively engaged in the proc- ess, but our knowledge is as yet too incomplete and contradictory to justify its acceptance. Until, therefore, we are in possession of the results of further research we are justified in the belief that the interchange of and ( !< ). between alveoli and blood is due to physical and chemical factors, diffusion being most important, and that it may be possible that the living tissues take some active part. The Forces Concerned in the Interchange of O and C0 2 between the Blood and the Tissues. — Innumerable facts show that the chief seat of the chemical processes in the body is in the tissues, and that the decompositions are essentially of an oxidizing character whereby C0 2 is formed as one of the most important effete products ; consequently the blood as it is carried through the capillaries gives up O and receives C0 2 . Experiments show that the tissues exert a strong reducing action, and that their avidity for O is so great that they will take it up at extremely low pressures. Moreover, never more than mere traces of O can be obtained from the tissues, because the gas upon its absorption immediately enters into chemical combination. The tension of 0O 2 in the tissues is considerably higher than in blood. Strassburg, 1 in a loop of intestine into which he injected atmospheric air, found that the tension was 58.52 millimeters of Hg, which is considerably greater than in either arterial or venous blood. Thus we find that the tension of O in the tissues is nil, owing to the avidity with which substances of the tissues combine with the gas, and its chemical fixation; while that of ( ( ), is very high. Comparing the tensions of these two gases in the blood and the tissues, it will be observed that there are present conditions which arc highly favorable to the passage of () to the tissues and of CO a in the reverse direction : o. CO,. Tensions in arterial blood 29.64 21.28 Blood-vessel walls Tensions in tissues 0.00 y.b4 S5J.28 f i 0.00 58125 It is manifest from the above that O should pass from the blood to the tissues, and C0 2 from the tissues to the blood. The lymph is probably merely a passive medium in this interchange. It contains, according to Ham marsten, only traces of O, from 37.5 to 17.1 vol- umes per cent, of C0 2 , and from 1.1 to 1.63 volumes per cent, of N. The mean percentage of C0 2 is lower than in serum, but Gaule has shown that the tension is higher. Doubtless the same relations hold good for the plasma and 1 Lor. cit. 420 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. the bloodj so that, notwithstanding a smaller volume per cent, of C0 2 in the lymph, CO a passes to the 1>1< ►< >tl because of the higher tension in the lymph. Extraction of Gases from the Blood. — We have found that in the blood both O and C0 2 exist partly in solution and partly in chemical combination. The portion in solution comes off regularly with a diminution of pressure, but that which is in chemical i bination remains so until the pressure is reduced to the level of the tension of dissociation. Since there are several of these combinations, such as O in oxyhemoglobin and C0 2 in carbonates, bicarbonates, etc., portions of each of these gases come oil' at different press- ure- in accordance with their different tensions in the several chemical combinations. The portions in solution may be removed by the use of an ordinary air-pump, but those in chemical combination are held so firmly that the more powerful mer- curial pump is recpiired. A con- venient pump of this kind has been devised by Dr. Geo. T. Kemp, the description of which he gives as follows : " To use the pump the reservoir bulb Bb (Fig. 74), the bulb /, the , cylinder SR and S'R f , and the ves- sel Pare filled with mercury. When the bulb Bb is raised the mercury rises in the tube AC and tills B, driving the air out by the path FHOP, the stopcock Q being closed. When Bb is lowered again the mer- cury flows back from B into Bb, creating a Torricellian vacuum in B. As soon as the mercury has fallen below the joint D, this vacuum in B becomes connected by the path DEG with the tubes TGUG'T' and the tube VWYX, and thence, when the stopcock is open, with the vessel to be exhausted. The air in this then diffuses to fill the vacuum in II, and becomes rarefied, so that the mercury rises from the cylin- ders SR and S'R' in the outer tubes TO and T'G'. The small inner tubes RQ and R'G' are made so high that even when there is a complete vacuum in the outer tubes TG and T'G' the mercury will not rise high enough to cover them. "On raising Bb again the mercury rises in AC, and as soon as the joint D is covered, all the air which has been caught in B is forced out by the path FHOP. Each time the bulb Bb is raised and lowered a certain amount of air is ex- aa pump. RESPIRATION. 421 tracted from the receiver, until finally a vacuum is produced. In a similar way, when the receiver connected with the pump at Z contains any gas which we wish to analyze — as, for example, the gases given off by the blood in a vacuum — we put a eudiometer (Eu) over the bend of the tube at P, which, of course, is always under the mercury, and collect the gases as they are forced out. " The extraction of the last traces of gas by raising and lowering Bb is a very tedious and laborious process, so that the final extraction of the gases can best be accomplished by the Sprengel pump. IJKLMNHOP. The bulb and stop- cock UK are made separate, as shown in the figure, and are connected with LMN by a piece of rubber tubing, the whole being under mercury. This is accomplished by the bend JKLM, which is made so as to allow a narrow wooden box filled with the mercury to be slipped up over the bend high enough to cover the stopcock and thus prevent leakage of air. The same arrangement is shown at X, and is indicated by a dotted line in each instance. When the stopcock K is opened the mercury flows in, drops down the tube NHOP, and extracts the gases at H in the well-known manner of the Sprengel pump. The large bulb is for rapid exhaustion down to the last few millimeters of pressure, the rest being accomplished more slowly but more perfectly by the Sprengel. In extracting blood-gases the oxygen is given off suddenly and the C0 2 slowly. The great desideratum is to keep the tension of the gases in the blood-chamber down as near zero as possible — certainly below 20 millimeters of Hg. This is readily done with the large bulb when the O is evolved, while the Sprengel is able to remove the C0 2 as it is given off, thus obviating the continued rais- ing and lowering of the reservoir bulb." The gases collected are driven through the tube P into a eudiometer previously filled with mercury and inverted. The eudiometer (Fig. 75) is a calibrated tube in which the gases are measured. In the upper part of it are two plati- num wires by means of which an electric spark is brought in contact with the gases. Hydrogen is introduced into the eudiometer in definite quantity (more than sufficient to com- bine with all of the O to form H 2 ()), and a spark is gen- erated between the ends of the platinum wires, causing the Oandthe II to combine. The diminution in volume is now noted, one-third of which diminution is equal to the total volume of O obtained from the sample of blood. The quan- tity of CO a may be estimated by introducing into the eudi- ometer a piece of moistened fused potassium hydrate, which absorbs the C() 2 , forming potassium carbonate. The loss in volume is the volume of C0 2 obtained from the blood. The residual gas consists of X and II, the latter being the excess not combined with (). The total quantity of II introduced Fiq. 75.-Eudiometer. being known, and also the quantity which combined with (), the difference is deducted from the volume N and II, the remainder being the volume N. Accurate analysis necessitates correction- for temperature, for > I! , 422 AN AMERICAN TEXT- IK >< >K OF PHYSIOLOGY. tension "I' aqueous vapor, and for atmospheric pressure, as well as attention to the many details connected with gas-analysis. Cutaneous Respiration. — In frogs the skin is a more important respi- ratory organ than the lungs, as is illustrated by the fact that asphyxia is more rapidly produced by dipping the animal in oil, and thus preventing the interchange of () and CO a through the skin, than by ligature of the trachea; moreover,the investigations of Regnault and Reiset show that in these animals Dearly the same quantities of O are absorbed and C0 2 eliminated after the lungs are excised as in the intaet animal. In man the reverse is the case, the cutaneous interchange being insignificant as compared with that in the lungs. The quantity of CO., exhaled through the skin during twenty-four hours has been estimated by different observers from 2.23 grams to as much as 32.08 grams. Compared with pulmonary interchange, the ratio of O absorbed is probably about 1 : 100-200, and of C0 2 eliminated, 1 : 200-250. ( utaneous respiration is, as a rule, subject to the same circumstances that affect the interchange in the luugs, and is accomplished, moreover, in the same way. In some instances, however, it is influenced in the opposite direction ; for instance, it is increased by circumstances that hinder pulmonary respiration. Cutaneous respiration is favored by moist skin, and Ronchi found that it was increased by higher external temperature. Internal or Tissue-respiration. — The main object of the respiratory mech- anism is to supply the organism with O and to remove the C0 2 resulting from ti->ue-activitv. The organism may be regarded as an aggregation of living cells, each of which during life consumes O and gives off CO z . Activity depends essentially upon processes of oxidation ; consequently, not only is oxi- dation necessary for existence, but the quantity of O absorbed must bear a direct relation to the degree of activity. The avidity of the different tissues for O varies greatly, and the differences are doubtless expressions, broadly speaking, of the relative intensities of their respiratory processes. Quinquaud 1 records the following absorption-capacities of 100 grams of each tissue, submitted for three hours to a temperature of 38° : Muscle 23 c.c. I hart 21 " Brain 12 " Liver 10 " Kidney 10 " Spleen 8 Lungs 7.2 Adipose tissue 6 Bone 5 Blood 0.8 The quantity of ('()_, formed in each case was approximately proportional to the quantity of < ) absorbed. The respiratory value of blood is doubtless too low. The blood is not merely a carrier of O aud C0 2 to and from the tissues, but is itself th'' -eat of active disintegrations which involve the consumption of O and the production of C0 2 and other effete matters. Ludwig and his pupils Ion- ago showed that when readily-oxidizable substances, such as lactate of sodium, are mixed with the blood, and the blood is transfused through the lung- or other living tissues, more < > is consumed and C0 2 given off than by 1 Complet rendua de /« Societe de biohgu (9), 1890, 2, pp. 29, 30. RESPIRATIOX. 423 blood free from them. These results have been substantiated by the recent researches of Bohr and Henriquez 1 on dogs, whose experiments have further shown that a considerable portion of O may disappear as a result of processes occurring in the blood during its passage through the lungs, and a large amount of C0 2 be formed as one of the products. Thus they found that con- siderably more O was absorbed from the lungs than could be pumped from the blood, and that more C0 2 was given to the air in the lungs than was lost by the venous blood. They believe that the tissues deliver to the blood par- tially-oxidized substances which undergo a final splitting up when the blood reaches the lungs. If this be so, the respiratory capacity of the blood, apart from its capacity as a carrier of and C0 2 to and from the tissues, must be considerably greater than indicated by Quinquaud's figures. The chief chemical product of the oxidative decompositions in the blood and tissues is C0 2 ; but the quantity of O absorbed is not necessarilv related to the amount of C0 2 eliminated ; that is, during a given interval the quantity of O may be out of proportion to the elimination of C0 2 , and vice versd. Thus, in a muscle during rest, at normal bodily temperature, the consumption of O is greater than the elimination of C0 2 , while during activity the propor- tion of C0 2 to O increases and may exceed that of O. Rubner's 2 experiments on the resting muscle at various temperatures accentuate the fact that the for- mation of C0 2 may be independent of the quantity of O absorbed. Thus, at 8.4° the respiratory quotient was 3.28 ; at 28.2°, 1.01 ; at 33.8°, 1.18 ; and at 38.8°, 0.91. The high respiratory quotient at low temperatures is to be explained partly by direct oxidation and partly by intramolecular splitting, which is independent of oxidation. It is probable that during rest O is util- ized to some extent in oxidations which are not at once carried to their final stage and in which relatively little C0 2 is formed; hence during activity com- paratively little O is required to cause a final disintegration of the now par- tially broken-down substances, and thus to give rise to a relatively large formation of C0 2 . (See Effects of Muscular Activity on Respiration and Metabolism of Muscle, etc.) C. The Rhythm, Frequency, and Depth of the Respiratory Movements. The Rhythm of the Respiratory Movements. — During normal breathing the respiratory movements follow each other in regular sequence or rhythm. Various instruments have been devised for the study of these movements in man; the form most commonly used is the stethograph or pneumo- graph of Marey. The respiratory movements are communicated by a system of levers to a tambour, thence through a rubber tube to a second tambour having attached a lever which records upon a moving surface. In animals :i trachea] cannula or tube (p. I 16) Is usually Inserted into the trachea, and a tube is led from it to a recording tambour. In case the movements 1 Comptes rendus, 1892, t. Ill, pp. 1496-99. 2 DtiBois-Rfijmond's Archiv fur Physiologie, 1885, S. 38-66. I-Jl AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. of the ribs are especially to be studied, the stethograph maybe employed; if the movements of the diaphragm, a long probe may be inserted through the abdominal walls so that one end rests between the liver and the diaphragm and the other end connects with a recording lever, the abdominal walls serving as a fulcrum. A tracing obtained by one of the above methods shows: (1) That inspiration passes into expiration without an appreciable in- tervening pause; (2) that inspiration is shorter than expiration; (3) that the curves of inspiration and expiration differ in certain characters. The relative periods of inspiration and expiration vary with age, sex, and other conditions. The inspiratory phase is shorter relatively in women than in men. and in chil- dren and the aged than in those of middle life. The length of inspiration as compared to expiration is subject to variations, but these relations are affected chiefly by disease and by other abnormal conditions. After section of the pneumogastric nerves, and in diseased conditions which narrow any part of the air-passages, inspiration is longer than expiration, while in emphysema the expiratory phase is prolonged. The relative periods occupied by inspiration and by expiration in the adult differ according to various observers; at one extreme, the ratio according to Vierordt and Ludwig is 10 : 19-20, and at the other extreme, according to Ewald, 11:12. A mean ratio is 5:6. Rennebaum found that the expiratory phase is relatively prolonged by an increase in the respiration-rate, the ratio being 9 : 10 at 13 respirations per minute, and 9 : 13 at 46 per minute. In the new-born the ratio is 1 : 2-3. Mosso found that during sleep the inspiratory phase is lengthened one-fourth. Inspiration is more abrupt than expiration, the lever moving more rapidly during inspiration than during expiration; consequently the curves differ in character. We may volitionally affect the rhythm and the various phases of each respiratory act. A pause may exist between expiration and inspiration (expiratory pause) when the respirations are abnormally infrequent. In certain diseases an inter- val may be observed between inspiration and expiration (inspiratory pause). Some observers look upon the nearly horizontal part of the respiratory curve a- a record of a pause, but an examination of tracings of normal respirations shows that one phase passes into the other without an appreciable interval. The respiratory acts while we are awake and quiet are rhythmical, but this rhythm is more or less disturbed during sleep, especially in young children ami in the aged. In the latter there may not only be an irregularity in the time-intervals between successive acts, but occasionally long expiratory pauses, giving the movements a peculiar periodical character. In the so-called " Cheyne-Stokes respiration " the rhythm is . greatly disturbed. This type is characterized by groups of respiratory movements, each group being separated from the preceding and succeeding ones by more or less marked pauses. The fir>t respiration in each group is very shallow and is followed by movements which successively become deeper and deeper until a maximum is reached; then the successive movements become more and more shallow and finally <•< ase. Bach group commonly consists of about 10 to 30 respirations, and is BESPIBA TION. A 2 5 separated from the preceding and succeeding groups by a variable interval, usually 30 to 45 seconds. This form of respiration is frequently observed in uraemia, after severe hemorrhage, and in certain diseases of the heart and brain. Periodical alterations in the respiratory rhythm may be observed in the last stages of asphyxia, in poisoning by chloral, opium, curare, and digitalis, in cer- tain septic fevers, in certain animals during hybernation, ete. In the human organism, excepting during sleep and in the aged and the very young, such non-rhythmical respirations are always indicative of abnormal conditions. In warm-blooded animals the movements are generally of a much more rhythmical character than in cold-blooded animals. The Frequency and Depth of the Respiratory Movements. — The respiratory rate is affected by a number of conditions, chiefly species, age, posture, time of day, digestion, activity, internal and external temperature, season, barometric pressure, emotions, the composition of the air, the composi- tion of the blood, the state of the respiratory centres and nerves, etc. The following figures, compiled from various sources, indicate the wide differences in various species, the rates being per minute : Horse 6-10 Ox 10-15 Sheep 12-20 Pig 15-20 Man 16-24 Cat 20-30 Dog 15-25 Pigeon 30 Kabbit .... 50-60 Sparrow ... 90 Guinea-pig . . 100-150 Rat 100-200 The average rate in man varies according to different investigators, from 11.9 by Vierordt to 19.35 by Ruef. Hutchinson noted 16-24 per minute as a mean of 2000 observations. There is a general, but not an absolute, rela- tionship between the rate and the size of the body, as regards both different species and different individuals of the same species : as a rule, the smaller the species the more frequent the respirations ; the same holding good for indi- viduals of the same species. The marked influence of age is illustrated by the records of the observa- tions by Quetelet on 300 individuals : Rate per Minute. Age. New-born 70 1- 5 years . . . 15-20 " 20-25 25-30 30-50 cimum. Minimum. Mean. 70 23 44 32 26 24 16 20 24 14 18.7 21 15 16 23 11 18.1 Posture exerts a marked influence, especially in those enfeebled by disease. Guy records, in normal individuals, 13 while lying, 19 while sitting, and 22 while standing. The diurnal changes are in close accord with those of the pulse-rale (p. 1 21 i. The rate is less frequent by about one-fourth during the night than during the day, and more frequent after meals, especially alter the mid-day meal. Vier- ordt noted the following variations: 9 a.m., 12.1 ; 12 m., 11.5; 2 P.M., 13 J 126 AX AMERICAS TEXT-BOOK OF PHYSIOLOGY. 7 P.M., 11.1. Guy gives the mean rate in the morning as 17 and in the evening as 18. The rate increases with an increase in muscular activity (p. 121). Changes in external (surrounding) temperature have very little influence. Vierordt noted a rate of 12.16 at f internal temperature are associated with marked changes, as is well illustrated in the increase in the ■ rate observed in lexers, which increase, in turn, is closely related to the rise in the pulse-rate and the body temperature. Season is not without its influence. In the spring the rate, according to E. Smith, is 32 per cent, greater than at the end of summer. Ordinary changes in atmospheric pressure exert no influence, but under con- siderable variations the rate rises and falls inversely with the pressure. The frequency of the respirations may be profoundly affected by our emo- tions and by our will. Mental excitement may increase or decrease the rate, and, as is well known, we may greatly modify not only the rate, but also the depth and the rhythm of the movements by volitional effort. If the composition of the inspired air becomes so altered that O falls below 13 volumes per cent., the respirations are increased in frequency and in depth. In the same way, if the blood becomes deficient in O or overcharged with C0 2 , movements of respiration are increased. Excitation and depression of the respiratory centres and nerves through the agency of operations, disease, poisons, etc. effect changes in the respiratory rate. The rate and the depth of the respirations bear generally an inverse relation to each other : the greater the rate the less the depth, and vice versa ; but the quantity of air respired during a given period does not necessarily bear any direct relation to either the rate or the depth alone, but rather to both. A general relationship exists between the frequency of the respirations and the pulse-rate. Comparisons of a large number of observations by different investigators give a ratio at twenty-five to thirty-five years, 1 : 4-4.5 ; at fifteen to twenty years, 1 : 3.5 ; at six weeks, 1 : 2.5. D. The Volumes of Air, O, and CO.. Respired. During quiet respiration there occurs an inflow and outflow of air, desig- nated tidal air, equal to about 500 cubic centimeters, or 30 cubic inches. The volume of expired air is a little in excess of inspired air, owing to the expan- sion caused by the increase of temperature, although the actual volume is less (p. 410). The volume of air respired during each respiration bears generally an inverse relation to the respiration-rate, and is affected by the position of the body; thus, if in the lying posture the volume be 1, when sitting it will be 1.11, and when standing 1.13 (Hutchinson). Besides the term tidal air, others are used to express definite volumes associated with the capacity of the lungs under certain circumstances. Thus, Hutchinson distinguishes RESPIBATIOX. 127 complemented air, or the volume that can be inspired after the completion of an ordinary inspiration (1500 cubic centimeters); reserve or supplemental air, or the volume that can be expelled after an ordinary expiration (1240-1800 cubic centimeters); residual air, or the volume remaining in the lungs after the most forcible expiration (1230-1(340 cubic centimeters); and stationary air, or the volume remaining in the lungs after ordinary expiration, and equal to reserve air plus residual air (2470-3440 cubic centimeters). The volume of residual air is different according to various observers, the estimates ranging within wide limits. Hermann and Berenstein 1 record from observations on sixteen living male subjects a maximum of 1250 cubic centimeters, a minimum of 440 cubic centimeters, and a mean of 796 cubic centi- meters. Lung-capacity is the total quantity of air the lungs contain after the most forcible inspiration, and is equal to the vital capacity plus the residual air. Bronchial capacity is the capacity of the trachea and bronchi, and is equal to about 140 cubic centimeters. Alveolar capacity is the volume of air in the smallest air-passages and alveoli, and is greater during inspiration than during expira- tion, and, of course, is altered in proportion to the depth of these movements. After quiet expiration it is equal to about 2000 to 3000 cubic centimeters ; during quiet inspiration it is increased about 500 cubic centimeters, and during forced inspiration about 2000 cubic cen- timeters; during forced expiration it is dimin- ished about 1500 cubic centimeters. Between the extremes of forced inspiration and forced expiration the volume differs about 3J times. Vit muscular activity of the gastro-intestinal walls. Zuntz and Mering ' endeavored to 1 MoUschottia Untersuch. z. Natwrl., L887, Bd. 1 I. S. 623 629. 2 Ibid., L8S6, Bd. 13, S. 563. 3 Archiv fiir die gesammle Physiologic, 1888, Bd. 4:'.. S. 515 532. * Complex rend us, 1887, t. 105, pp. 390, 675. * AvchlV fiir die gexftnunte I'hysiologie, 1883, ltd. '.VI, S. 173-221. 432 IV AMERICAN TEXT-BOOK OF PHYSIOLOGY. settle this point by making three series of experiments : in one they injected certain readily oxidizable substances into the blood; in another the substances were injected into the stomach; and in another sulphate of sodium or other purgative was given. When the substances were injected into the blood, Zuntz and Mering found as a general result that the absorption of O was not increased, while the formation of C0 2 was slightly increased ; when injected into the stom- ach, no marked increase in respiratory activity occurred unless the substances were given in large quantities. When, however, in addition to the readily oxidiz- able substances, a purgative was injected, or when the purgative was given alone, the absorption of O and the elimination of 0O 2 were considerably in- creased. They were therefore led to conclude that the increased respiratory interchange during digestion is due chiefly to the muscular activity of the intestinal walls. Loewy 1 has confirmed this conclusion, and has clearly shown that the increase in respiratory activity is chiefly related to the intensity of peristalsis, the most marked increase being associated with excessive peristaltic activity. There can be no reasonable doubt, however, that a portion of the increase is due both to glandular activity and to the breaking down of the absorbed products of digestion. The volumes of O absorbed and of CO, produced rise with an increase of body temperature. This fact has been illustrated by the experiments of Pfluger and Colasanti on guinea-pigs, in which they found that the quantity of O absorbed at a body temperature of 37.1° was 948.17 cubic centimeters; at 38.5°, 1137.3 cubic centimeters; at 39.7°, 1242.6 cubic centimeters, per kilo per hour. Similar results have been obtained by other investigators in experiments both upon the human subject and upon the lower animals under the pathological conditions of fever. A fall of body temperature is accom- panied by a decrease in the intensity of respiration, unless the fall is accom- panied by muscular excitement, such as shivering. Speck 2 lias seen shiver- ing cause the consumption of O to rise from 302 to 496 cubic centimeters, and the exhalation of CCX, from 287 to 439 cubic centimeters. The primary and fundamental effect of lowering the body temperature is to diminish respi- ratory activity, but this may be more than compensated for by involuntary or voluntary excitement of the muscles (p. 433; see also Tissue-respiration). The effects of cricrinil fem/icrature upon warm- and cold-blooded animals are different: Molesohotl found that frogs produced three times more C0 2 at 38.7° than at 6°, while in warm-blooded animals the opposite is the case — that is, three times more CO a is formed at the lower temperature. The frog's tem- perature rises and falls with changes in the temperature of the surroundings, while that of warm-blooded animals remains at a fairly constant standard; he 'ee the respiratory intensity in the frog increases with the rise of external temperature, while in warm-blooded animals it decreases, owing to diminished heat-production. But in warm-blooded animals the alterations in respiratory activity caused by changes of external temperature are not always in inverse relation. Thus, Voit has shown, as a resull of studies in man, that the exhala- 1 Lor. tit. ' Deutsche* Archiv /. klin, Med., 1889, Bd. 33, S. 375, 424. RE8PIRA '/'/ox 133 tion of C0 2 diminishes with the rise of external temperature from 4.4° until the temperature reaches 14.3°, when it rises slowly. Those results have been substantiated by the more recent investigations of Page, 1 who found in experi- ments on dogs that the discharge of C0 2 was at a minimum at about 2o° ; that below this temperature the quantity increased as the temperature fell; ami that above this temperature the discharge increased, and became greatly augmented at temperatures of 40° to 42°. At the latter temperatures the increase may reach Sh times the normal, but the bodily temperature is also increased. If the elimination of C0 2 at 23° to 24° be represented by 100 as a standard, at 13° it will be about 128; at 10°, 141 ; and at 8°, 177. The researches of Speck, 2 of Loewy, 3 of Quinquaud, 4 and of Johansson 5 all show that external cold increases respiratory activity, chiefly or solely by causing involuntary muscular excitement (shivering). If shivering and other forms of muscular activity be absent, the exchange of O and C0 2 is unaffected or even diminished, but when present the increase of respiratory activity may amount to 100 per cent, notwithstanding a fall of bodily temperature below the normal. Muscular activity is one of the most important of all the circumstances affecting the quantities of O and C0 2 exchanged. Involuntary excitement, such as shivering, may of itself double the consumption of O and increase two and a half times the elimination of C0 2 , but volitional muscular effort may increase the interchange even beyond these limits. Hirn, in investiga- tions on four men, noted during rest an hourly absorption of 30.2 grams of O, and during work 120.9 grams; and Pettenkofer and Voit, in similar studies, found an increase of O from 867 grams during rest to 1006 grams during moderate work, and from 930 grams of C0 2 to 1137 grams. In experiments on the horse Zuntz and Lehmann 6 obtained the following results, which show to what a marked extent the respiratory interchange may be increased by muscular activity : Liters per Minute. COj o O. CO, Kesting 1.722 1.570 0.92 Walking 4.766 4.342 0.90 Trotting 8.093 7.516 <>.'.':; Speck 7 has added some interesting facts to our knowledge of the effects of muscular activity on the respiratory interchange. Thus, he found that the increase of O and CG 2 reaches a maximum before exertion reaches its maxi- mum ; that the increase for the same amount of work can be varied by chang- ing the position of the body; that if a given amount of work be divided into two equal parts, the increase of respiratory activity during the first period is greater than during the second ; that the greater the increase of ( '< >,. the less, i Journal of Physiology, 1879-80, vol. 2, p. 228. 2 Lor. at. 1 Archiv fur die gesammte Physiologie, 1890, Bd. 46, S. 189-224. * Oompies rendvs, 1887, t. 104, pp. 1542 1544 5 Skandinavisches Archiv fur Physiologie, 1897, Bd. 7, S. 123-177. 6 Journal of Physiology, 1890, vol. 2, p. 396. 7 Deutsche* Archiv f. Win. Med., 1889, Bd. 45, S. 460-528. Vol. I.— 28 434 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. proportionately, is the increase of O, so that the respiratory quotient rises more and more, and to such an extent that the C0 2 contains more O than is at the time absorbed; and that the quantity of air respired is so intimately related to the amount of C0 2 given off that he regards the quantity of this gas formed as the regulator, as it were, of the degree of activity of the respiratory movements. Griiber 1 states that while respiratory activity is proportional to the inten- sity of muscular activity, "training" diminishes the quantity of C0 2 given oil* for the same amount of work. Thus, taking 1 as a standard of the amount of C0 2 eliminated during rest, he obtained the following ratios in two series of observations : Climbing hills Climbing hills Resting. Walking. when not used when used to to it. it. Fire! series 1 1.89 4.1 3.3 .Second series _1_ L75 3^05 2A2 Mean 1 1.82 3.57 2.86 Training therefore reduces the output about 20 per cent. The elimination of C0 2 is about one-fifth less during sleep than while awake and quiet ; from one-fifth to one-half greater during ordinary exertion ; from two to two and a half times greater during violent exercise; and about three times greater during tetanus. During hybernation the absorption of O falls to -^j and the elimination of ( '( )., to -^ of the normal for the period of activity (Valentine). Relatively more O is absorbed than C0 2 given off, hence the respiratory quotient falls, reaching as low as 0.50 to 0.75. A diminution of the barometric pressure increases the respiration-rate and the volume of air respired, but both Mosso and Marcet have shown that if allowance- be made for the increase of volume of the air at the lower pressure, the actual volume respired is less. Conversely, an increase of pressure lowers the rate and the volume of air respired. Extremes of pressure severely affect the respiratory and other functions (p. 451). The integrity of the nervous apparatus which governs the metabolic pro- cesses in the tissues is obviously of fundamental importance. If the efferent nerve-fibres of a muscle be cut, the interchange of O and C0 2 at once sinks, as illustrated by the following results obtained by Zuntz : O consumed. C0 2 given off. Before section 13.2 c.c. 14.4 c.c. After section 10.45 c.c. 10-1 c.c. After section less] 2.75 c.c. 4.3 cc. The consumption of O was therefore lessened about 20 per cent., and the formation of C0 2 about 30 per cent. After secti< f the spinal cord in the dorsal region Quinquaud 2 obtained 1 Zeitschrifi f. Biokgie, 1891, Bd. 28, S. 466-491. ' Compt. rend. Soc. Bioloyie, 1887, pp. 340 -342. BESPIBA TION. \ • ! 5 similar results. Before the section the blood in the crural vein contained 9.5 per cent, of O and 60 per cent, of C0 2 ; after section it contained 13.5 per cent, of O and 40 per cent, of C0 2 , showing that the consumption of O by the tissues and the formation of C0 2 were considerably lessened. After de- struction of the spinal cord respiratory activity falls to a minimum. The study of the effects of alterations in the composition of the inspired air on the absorption of O and the elimination of C0 2 are of great importance. Nitrogen is merely a mechanical diluent of the inspired air, and may be replaced by H or by other inert gas, so that alterations in its percentage do not, per se, affect the respiratory phenomena ; but changes in the percentages of O and C0 2 may cause marked disturbances both of the respiratory move- ments and of the gaseous interchange. When the percentage of O in the inspired air is increased up to 40 volumes per cent., Bert found that there occurred an increase in the quantity absorbed, and both Speck and Fredericq have noted merely a transient increase under similar circumstances; but the results of most experimenters, on the contrary, seem to show quite conclusively that an increase of the per cent, of O above the normal does not affect the quantity absorbed. Lukjanow 1 in a large number of experiments could not detect any increase, and Saint-Martin, 2 in researches on guinea-pigs and rats with an atmosphere containing from 20 to 75 volumes per cent, of O, noted the same result. Even in an atmosphere of pure O animals breathe as though they were respiring normal atmospheric air. A decrease in the percentage of O is without influence until the proportion falls below 13 volumes per cent. Worm-Miiller long ago showed that animals breathe quietly in air containing 14.8 volumes per cent, of O, and that if the proportion fell to 7 volumes per cent., respiration became slow, deep, and diffi- cult; with 4.5 volumes per cent, marked dyspnoea occurred; and when there was but 3 volumes per cent, asphyxia rapidly supervened. The more remit results of Speck 3 not only confirm the main facts of Worm-Midler's observa- tions, but furnish other important data. He has shown that when the atmosphere contains 13 volumes per cent, of (), respiration is quiet and the quantity of O absorbed is but slightly, if at all, diminished, and that even when the proportion falls to 9.65 volumes per cent, breathing is carried mi for a long time without inconvenience, the amount of () absorbed, however, being diminished. He shows, moreover, that when the volume of in the atmo- sphere falls to s per cent, the respiratory movements are deep and are but slightly accelerated, the quantity of O absorbed being very much diminished, and that the animal subjected to such an atmosphere succumbs in a few moments. The quantity of O taken into the lungs falls proportionately with the diminution of O in the inspired air until the reduction reaches 11.26 vol- umes per cent., but further diminution is compensated for by an Increase in the volume of air respired. As the volume per cent. <-i in the inspired air 1 Zeitschrift f. physiolog. Chemie, 1883-1884, Bd. 8, S. 313-335. •-' Compt. rend., 1885, t. 98, pp. 241-243. * Zeitschrift f. Mm. Med., 1887, Bd. 12, S. 117 532. 436 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. diminishes the relative percentage of O absorbed increases, and this continues until the volume in the inspired air is reduced to 11.26 per cent., 27 per cent, of which is absorbed; below this point no further increase of absorption occurs. As the quantity of O absorbed is reduced the respiratory quotient becomes greater, and may reach as high as 2.218. When the quantity of O remains al the normal standard and the percentage of C0 2 is much increased, the elimination of the latter is interfered with ; and Pfluger has shown thai if the percentage of C0 2 be high, dyspnoea ensues, notwithstanding the fact that the blood contains a normal amount of O. When air contains 3 to 4 volumes per cent, of C0 2 , the quantity of C0 2 given off is diminished about one-half. Speck 1 and others have found that the elimination of CG 2 during a given period may be independent of both the percentage of O in the inspired air and the quantity absorbed. An atmo- sphere containing 10 volumes per cent, of C0 2 is generally believed to be toxic, but Wilson's 2 investigations show that air having even as much as 25 to 30 volumes per cent, may be inhaled with impunity. It is quite probable that in those cases in which small percentages of C0 2 in the inspired air have proven poisonous the gases were contaminated with CO (carbon monoxide). Respiration of an atmosphere of pure 0O 2 is followed within two or three minutes by death. Worm-Muller found that when animals breathe atmospheric air in a large closed chamber O disappears and C0 2 accumulates, and death finally occurs, not from a lack of O, but from the increase of C0 2 , as is shown by the fact that at the time of death the quantity of O in the air is sufficient to sustain life. He has shown that animals placed in a closed atmosphere of pure O die from an accumulation of ('( )_, in the blood, rabbits succumbing after the reten- tion of a volume of CO, equal to one-half the volume of the body, and at a time when the atmosphere contained as much as 50 volumes per cent, of O. The dyspnoea occurring in an animal confined in an air-tight chamber of small size is due to the lack of O, nearly all of the gas being absorbed before the animal dies, li' a cold-blooded animal, such as a frog, be similarly ex- posed, the attraction of haemoglobin for O is so strong that almost every par- ticle of gas will pass into the blood long before death occurs; and even after the total disappearance of O the elimination of C0 2 is said to continue at the normal rate. Animals placed in a confined space become accustomed, as it were, to the vitiated air, and survive longer than a fresh animal suddenly thrust into the poisonous atmosphere. The Respiratory Quotient. — The relation between the quantities of O absorbed and C0 2 given off during a given period is expressed as the respira- tory quotient The air during its sojourn in the lungs loses 4.78 volumes per cent, of O and acquires 4.34 volume- per cent, of C0 2 , hence the respiratory quotient is — ~ ''^ = 0.901. This quotient is subject to considerable 1 Loc. cit. 2 American Journ. Pharmacy, 1893, p. 561. RESPIRA TION. 437 variations not only in different species, but in different individuals under varied circumstances. The chief reasons for the differences are : First, the production of C0 2 is in a measure independent of the O absorbed, as is proven by the records of various investigators, showing that C0 2 results both from oxidation-processes and from intramolecular splitting (analogous to fermentation-processes) which may be entirely independent of each other; that the quantity of 0O 2 eliminated may continue under certain circumstances at the normal standard even after the absorption of O has ceased ; and that the quantity of O contained in the C0 2 eliminated during a given time may be larger than the actual quantity absorbed. This may be understood in a general way when we remember that the CC) 2 formed in the body is not the result of an immediate oxidation of the carbon-containing material of the body ; on the contrary, some of the O absorbed may be stored, as it were, in the form of complex compounds, which at some later time may undergo disin- tegration, with the formation of C0 2 ; or the complex materials introduced as food may undergo a similar disintegration and splitting of the molecules, with the formation of C0 2 independently of the direct action of the O upon them. Second, a larger quantity of 0O 2 is formed per unit of oxygen from the disintegration of certain substances than from others, consequently the quotient must be affected by the nature of the substances broken down. Thus, in the formation of C0 2 from carbohydrates all of the O consumed in the disinte- gration of the molecules is used in forming C0 2 , the H already having suffi- cient O to satisfy it ; but in the case of fats and proteids a portion of the O is utilized in the oxidation of H to form H 2 0. 6 molecules of O will oxidize 1 molecule of grape-sugar (C 6 H 12 6 ) into 6C0 2 + 6H 2 ; hence the quotient is n 2 =1. In regard to fat, if we take olein, C 3 H 5 (C^H^O^, as an ex- ample, 80 molecules of O are required to reduce each molecule of the fat to 5 7 CO 57 molecules of C0 2 and 52 molecules of H 2 ; hence the quotient is - Qnr . 2 80 (J 2 = 0.712. In the disintegration of proteid only a part of the C is oxidized into C0 2 , the remainder being eliminated as a constituent of various complex effete bodies; but it is estimated that the quotient for proteids (albumin) is from 0.75 to 0.81, depending upon the completeness of disintegration. The respiratory quotient varies with species, food, age, the time of day, internal and external temperature, muscular activity, the composition of the inspired air, etc. In regai'd to species, the quotient is higher in warm-blooded (0.70 to LOO) than in cold-blooded animals (0.G5 to 0.75) ; in herbivora (0.90 to 1.00) than in carnivora (0.75 to 0.80) ; and in omnivora (0.80 to 0.90) than in carnivora, but lower than in herbivora. These differences are due essentially to diet, herbivora feeding largely upon carbohydrates, omnivora using carbohydrates to a less extent, and carnivora practically not at all. These observations are substantiated by the fact that during lasting, when the animal is feeding upon its own tissues, the respiratory quotient in all species is the same (0.7 to 0.75). 138 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. The quotient is lowered by an animal diet and increased by a vegetable diet, the ratio approximating unity if the diet be sufficiently rich in carbohydrates. Ilaiuiot and Richet l in observations on man noted that before feeding the quo- tient was 0.84 to 0.89; when meat or fat was given the consumption of O was increased, but there was no increase in C0 2 , and the quotient fell to 0.76 ; when given potatoes it was ().!»:', ; and when the diet was of glucose it reached 1.03. During fasting the quotient falls rapidly. The experiments of Zuntz and Lehmann - show that in dogs it falls as low as 0.65 to 0.68 on the second day of lasting, and that on the resumption of food it rises to 0.73 to 0.81. The influence of age is manifest in the fact that in children the quotient is lower than in the adult, more O being absorbed in proportion to the 0O 2 given otf than after full growth has been reached. The quotient undergoes a diurnal variation. The day-time is more favor- able than the night for the discharge of C0 2 , as well as for the absorption of O, owing mainly to greater muscular activity luring the day, but the C0 2 is more affected than theO; hence the respiratory quotient is higher during the day. In the recent experiments by Saint-Martin 3 on birds, the mean quo- tient during the day was 0.83 and during the night 0.72 ; the ratio for C0 2 for the day and night was 1 : 0.78, and for O 1 : 0.9. During the night the elimination of CC) 2 was diminished about 20 per cent., while the absorption of O fell only about 10 per cent. The quotient is increased by a rise of external temperature. Thus, Pfliiger and Finkler found in guinea-pigs that the quotient was 0.83 at 3.64° and 0.94 at 2ii. 21°. When the bodily temperature is increased, as in fever, the respira- tory quotient remains practically unaltered. When the temperature falls below the normal the respiratory quotient increases. Muscular activity is also an important factor. During rest the consumption of O by muscles is greater than the production of CO,, while during contrac- tion the difference becomes less and less in proportion to the degree of activity, until finally more 0O 2 may be given off than there is O consumed. Sczelkow found in experiments on muscles of rabbits at rest and in tetanus that the respiratory quotient was decidedly increased. A mean of six experiments gives as the quotient during rest 0.543 and during tetanus 0.933; in one-half of the experiments it went above 1, and in one instance to 1.13. During sleep the output of C0 2 is diminished more than the consumption of O (p. 434), so that the respiratory quotient is less than when awake and quiet. During hybernation the quotient falls to a minimum — in the marmot as low as '). 49. This is due chiefly to the more decided falling off in the quantity of ( '< >,. the C< )., being reduced to J 7 , and the O to only ^j-; the animal, however, i- not only in a state of muscular quiet, but fasting, which, it will be remem- bered, i> an important factor in lowering the quotient. 1 Com,,i. rend., 1888, t. 106, pp. 496-498. * Berliner klin. Woch., 1887, S. 128. ■'Compi. rend., 1887, t. L05, pp. 1124-1128. BESPIRA TION. I J I '. I When the percentage of O in the inspired air falls so low as to cause marked dyspnoea, the respiratory quotient rapidly rises. This is owing on the one hand to the diminished quantity of O absorbed, and on the other hand to the increased production of CQ 2 as a consequence of excessive activity of the muscles of respiration. Speck (p. 435) found that when the proportion of was very low the quotient rose as high as 2.258. E. Principles op Ventilation. Breathing within a confined space, as in a small unventilated room or in a large room in which a considerable number of persons are assembled, causes a gradual diminution in the quantity of O and an accumulation of CO.,, moist- ure, and organic matter. In regard to O, even in the worst ventilated rooms the atmosphere seldom contains as little as 15 volumes per cent,, which is suffi- cient to permit of undisturbed respiration. When the proportion of C0 2 exceeds 0.07 volume per cent, the air becomes disagreeable, close, and stuffy — offensive characters which are due neither to the increase of C0 2 nor to a deficiency of O, but to the presence of odorous principles given off chiefly by the body and clothing. Air from which this organic exhalation is absent may contain considerably more C0 2 without causing any unpleasant effects. In well-ventilated rooms the proportion of C0 2 does not exceed 0.05 to 0.07 volume per cent. ; in badly-ventilated rooms it may reach 0.25 to 0.30 volume per cent. ; while when a large number of individuals are crowded together, as in lecture-rooms, it may be as high as 0.70 to 0.80 volume per cent. This vitiation is further increased by the burning of gas or oil, 150 liters of ordinary coal-gas (enough to supply a large burner for about an hour) consuming all the O in 120O liters of air, or as much () as is required by the average individual in eight hours, besides loading the air with various deleterious products of combustion. While the accumulation of C0 2 even in the worst ventilated rooms is not in itself pernicious, its percentage is a practical working index of the degree of vitiation. It has long been recognized that the atmosphere of crowded, badly-ventilated rooms gives rise to discomfort, and by sonic the expired air has been erroneously asserted to be toxic. Tims Brown-S6quard and d'Ar- sonval condensed the moisture of the expired air and found thai from 20 to 40 cubic centimeters would kill a guinea-pig; but their results have been contradicted positively by Dastre" and Love. Lehmann, Geyer, and others. The vitiation of the air of badly-ventilated rooms cannot be said to be due to any particular poison, but to an accumulation of odorous principles arising from uncleanly bodies, clothes, and surroundings, and also to an accumula- tion of C0 2 , and to a deficiency of O in extreme instances. The quantity of fresh air required during a given period depends upon the size of the individual, the degree of activity, and the size of the air-space. Assuming that an individual eliminates 900 grams, or 158 liters, of C0 2 per diem, and that the percentage of C0 2 is to be kept at a standard not exceeding 440 AN AMERICAN TEXT-HOOK OF PHYSIOLOGY. 0.07 volume percent., there would be required at least 1,440,000 liters of fresh air during twenty-four hours, or about 60,000 liters (2000 cubic feet) per hour. All circumstances, such as muscular activity, which increase the output of C0 2 augment the demand for fresh air. When confined in rooms, every person should have an air-space equal to about 28,000 liters, or 1000 cubic feet, the floor-space should not be less than ^ of the cubic capacity of the room, and the air should be renewed as often as twice an hour. In lecture- rooms, school-rooms, etc. the air-space per individual is usually very small, so that the renewal must be more frequent and in proportion to the limitation of space per individual. Ventilation i> accomplished by natural and artificial means. The forces of the wind, the differences in temperature within and without the building, the natural diffusion of gases owing to variations in composition, etc., all cause more or less circulation. Artificial ventilation is effected by the use of proper appliances for the forced introduction of air into and expulsion from apartments. F. The Effects of the Respiration of Various Gases. The respiration of pure () takes place without disturbance of the respira- tory processes. Lorrain Smith 1 has shown that O at the tension of the atmosphere stimulates the Lung-cells to active absorption, at a higher tension acts as an irritant, or pathological stimulant, and produces inflammation. Dyspnoea is developed when the inspired air contains less than 13 volumes per cent. (p. 435). Respiration of pure CO a (p. 436) is fatal within two or three minutes, but an atmosphere containing as much as 25 to 30 per cent, may be respired for a few minutes without ill effect (p. 436). Nitrogen, hydrogen, and carburetted hydrogen (CH 4 ) may be inhaled with impunity if they contain not less than 13 volumes per cent, of O. The respiration of nitrous oxide or of air containing much ozone rapidly produces aiuesthesia, unconsciousness, and death. Carbon monoxide (CO) and cyanogen are decid- edly toxic, combining with haemoglobin and displacing oxygen. Sulphuretted hydrogen, phosphoretted hydrogen, arseniuretted hydrogen, and antimoniu- retted hydrogen are all poisonous and are all destructive to haemoglobin. An atmosphere containing 0.4 volume per cent, of sulphuretted hydrogen is said to be toxic Air containing 2 volumes per cent, of CO (carbon monoxide) is quickly fatal. Certain gases and vapors — as, for instance, ammonia, chlorine, bromine, ozone, etc. — produce serious irritation of the respiratory passages, and may in this way cause death. G. Effects of the Gaseous Composition of the Blood on the Respiratory Movements. Certain terms are employed to express peculiarities in the respiratory phe- nomena: Ewpnoea is normal, quiet, and easy breathing. J yy/ma is a suspen- sion of the respiratory movements. Hyperpnoea is a condition of increased 1 Journal of Physiology, 1899, vol. 24, |>. 19. RESPIRA TIOX. 441 respiratory activity. Polypncea } thermopolypncea, and heat-dyspnoea are forms of hyperpnoea duo to heating the blood or the skin. Dyspnoea is distinguished by deep and labored breathing; the respiratory rate is usually less than the normal, but in some forms it may be higher. Asphyxia (suffocation) is cha- racterized by convulsive respirations which arc followed in the final stage by infrequent, feeble, and shallow respirations. Eupnoea is the condition of respiration observed during bodily and mental quiet, the quantities of O and C0 2 in the blood being within the normal mean limits. Apncea may be produced by rapidly repeated respirations of atmospheric air, under which circumstances the respiratory movements may be arrested for a period varying from a few seconds to a minute or more. This condition is produced most easily upon animals which have been tracheotomized and con- nected with an artificial respiration apparatus. If under these conditions the lungs are repeatedly inflated with sufficient frequency, and the blasts are then suspended, the animal will lie quietly for a certain period in a condition of apncea. The respirations after a time begin, usually with very feeble move- ments which quickly increase in strength and depth to the normal type. The ultimate cause of apncea is still a mooted question, and the heretofore prevalent belief that it is due to hyperoxygenation of the blood is almost entirely dis- carded. The connection between the quantity of O in the blood and apncea is, however, suggested by several facts : thus, apncea is more marked after the respiration of pure O than after that of atmospheric air, ami less marked if the air is deficient in O; moreover, Ewald states that the arterial blood of apnoeic animals is saturated with O. These tacts naturally lead to the inference that the blood is surcharged with (), and that the respiratory movements are arrested until the excess of O is consumed or until sufficient CO a accumulates in the blood to excite respiratory movements. But Head 1 has shown that apncea can be caused by the inflation of the lungs with pure hydrogen as well as by infla- tion with air or with pure O, although the apnoeic pause after the cessation of the inflations is not so long- or may be absent altogether; while Ewald's asscr- tion as to the saturation of the blood with O is contradicted by Iloppe-Seyler, Gad, and others. The tact that the apnoeic pause exists lor a longer period when O is respired lends confirmation to Gad's theory that it is due in part to the large amount of O carried into and stored up, as it were, in the alveoli — an amount sufficient to supply the blood for a certain period and thus to dis- pense with respiratory movements, (tad found that even when apnoea follows the inflation of the lungs with air, the air in the lungs contain- enough () fo supply the blood during the period occupied by the blood in making a com- plete circuit of the system. The fact, however, thai apmca can be caused by the inflation of the lungs by an indifferent gas such as hydrogen, by which every particle of <) may be driven from the lungs, certainly show- that then 1 exists some important factor apart from the Oj and this assump- tion receives support in the observation that after section of the pneumo- 1 Journal of Pin/sin!,,,,,/, 1SS<), vol. Id. pp. 1. -J7'.». 442 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. gastric nerves (the channels for the conveyance of sensory impulses from the lungs to the respiratory centre) it is very difficult to cause apnoea by in- flation of the lungs with air, while if pure hydrogen is used violent dyspnoea results. Tt seems, then, that apnoea cannot be produced after division of the vagi unless there he an accumulation of () in the lungs. These facts suggest that the frequent forced inflations of the lung- excite the pulmonic peripheries of the pneumogastric nerve-, thus generating impulses which inhibit the inspi- ratory discharges from the respiratory centre. This view receives further sup- port in several facts: first, that the same Dumber of inflations, whether of pure (). of air, or of H, causes apnoea, the only difference being the length of the apnoeic pause after the cessation of artificial respiration, which pause lasts for the longest period when O is used, and for the shortest period, or not at all, when II is employed; second, that apncea cannot be caused by inflation of the lungs with H if the pneumogastric nerves be previously divided ; third, that the arrest of respiration which occurs during swallowing (" deglutition-apnoea") i- due to an inhibition of the respiratory centre by impulses generated in the terminations of the glosso-pharyngeal nerves (p. 462). It therefore seems evi- dent that apncea may be due to either gaseous or mechanical factors, or to both, the former being effective, not because of the blood being saturated with O, but because of the increased amount of O in the alveoli — a quantity sufficient for a time to aerate the blood ; while the mechanical factors give rise to inhibi- tory impulses which suspend for a longer or shorter period the rhythmical inspiratory discharges from the respiratory centre, doubtless by depressing the irritability of this centre (p. 455). From the experiment quoted it seems that the first of these factors may alone be sufficient to cause apncea, but that apncea is more easily produced, and lasts longer, when both factors act together, as is usually the case. The form of hyperpncea due to museular activity is owing to the action upon the respiratory centre of certain substances which are formed in the muscles during contraction and are given to the blood. Muscular activity, as is well known, is accompanied by an increase in the rate and depth of the respiratory movements, and when the exercise is violent more or less marked dyspnoea may occur. Some physiologists have been led to the belief that the respiratory centre is connected directly or indirectly with the muscles by means of afferent nerve-fibres which convey impulses to the centre and thus excite it to activity; while other- have regarded a diminution of O and an increase ofCO a in the blood a- the cause, the active muscles rapidly consum- ing tin () in the blood and giving off C0 2 in great abundance. But Mathieu and I'rbain. and (leppert and Zunt/..' have found that the volumes percent, in the blood of O may be increased, and the volume per cent, of C0 2 decreased, during muscular activity. It i- probable that the hyperpncea is due to prod- ucts of muscular activity which are given to the blood and which act as powerful excitant- to the respiratory centre. The precise nature of the bodies is unknown, but it i- probable that they are of an acid character, for 1 Arehivftlr du gesammle I . 1 — , Bd. 42, S. 189. RESPIRA TION. 443 Lehmann 1 found that there was a distinct lessening of the alkalinity of* the blood after muscular exercise. It is likely that the bodies arc broken up in the system, because the results of Loewy's 2 investigations indicate that they are not removed by the kidneys. Polypncea, tiwrmopolyjmoea, and heat-dyspnoea are due to a direct excitation of the respiratory centres through an increase of the temperature of the blood, or reflexlv by excitation of the cutaneous nerves by external heat. This con- dition may be produced, as was done by Goldstein, by exposing the carotids and placing them in warm tubes, thus heating the blood ; or, as was done by Richet and others, by subjecting the body to high external heat. Richet in employing this latter method found that dogs so exposed may have a respira- tory rate as high as 400 per minute. Ott records marked polypncea as a result of direct irritation of the tuber cinereum. This form of hyperpnoea is entirely independent of the gaseous composition of the blood ; moreover, an animal in heat-dvspncea cannot be rendered apnoeic, even though the blood be so thor- oughly oxygenated that the venous blood is of a bright arterial hue. Dyspnoea is generally characterized by slow, deep, and labored respiratory movements, although in some instances the rate may be increased. Several distinct forms are observed: " O-dyspnoea," due to a deficiency of O; " C0 2 -dyspnoea," due to an excess of C0 2 in the blood; and cardiac aud hemorrhagic dyspnoeas, belonging to the O category. Dyspnoeas due to the gaseous composition of the blood may be caused either by a deficiency of O or by an excess of C0 2 , but are generally due to both. Dyspnoea from a deficit of O is observed when an animal is placed within a small closed chamber, or when an indifferent gas, such as pure hydrogen or nitrogen, is respired. Under the latter circumstances dyspnoea occurs even though the quantity of C0 2 in the blood be below the normal. If, on the contrary, the animal be compelled to breathe an atmosphere containing 10 vol- umes per cent, of CG 2 , dyspnoea occurs, notwithstanding an abundance of O (p. 436) both in the air and in the blood; indeed, the quantity of O in the blood may be above the normal. Fredericq 3 in ingenious experiments has directly demonstrated the influence of the quantity of C0 2 in the blood upon the respiratory movements. He took two rabbits or dogs, A and B, ligated the vertebral arteries in each, exposed the carotids, and ligated one in each animal. The other carotid in each was cut, and the peripheral end of the vessel of one was connected by means of a cannula with the central end of the vessel of the other, so that the blood of animal a supplied the head (respiratory centre) of animal B, and vice versd. When the trachea of animal A was ligated or com- pressed the animal B showed signs of dyspnoea, because its respiratory centre was now supplied with the venous blood from a. On the contrary, animal a exhibited quiet respirations, almost apnoeic, because its centre received the thoroughly arterialized blood from b, in which the respiratory movements were augmented. In a second series of experiments blood was transfused through 1 Archivfur die gesammte Physiologic, L888, BU 42, S. 284. : Ibid., S. 281 8 Hull. Acad. roy. Mid. Belgique, t. 13, pp. 417-421. 444 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. the head: when the blood was laden with C0 2 marked dyspnoea resulted; when arterial blood was transfused the normal respirations were restored. While dyspnoea may be caused by the respiration of an atmosphere either deficient in O (" O-dyspnoea ") or containing an excess of C0 2 (" 0O 2 -dysp- Doea "), the phenomena in the two cases are in certain respects different : When an animal breathes pure N, thus causing O-dyspncea, the dyspnoea is character- ized especially by frequent respiratory movements with vigorous inspirations, whereas if the atmosphere be rich in O and contain an excess of C0 2 the respirations are especially marked by a slower rate and by the depth and vigor of the expirations ', O-dyspnoea continues for a longtime before death ensues, and is more severe; in O-dyspnoea the absorption of () is diminished, but the excretion of C< l, is practically unaffected ; in O-dyspnoea the attendant rise of blood-pressure (p. 447) is more marked and lasting; in O-dyspnoea death is I hvii 'dcd by violent motor disturbances which are absent in C< ),-dvspnoea. Blood poor in O (O-dyspnoea) affects chiefly the inspiratory portion of the respiratory centre (p. 457), while blood rich in C0 2 (C0 2 -dvspnoea) affects chiefly the expiratory portion; hence in the former the dyspnoea is manifest especially in an increase in the frequency of the respirations (hyperpnoea) and in the vigor of the inspirations, while in the latter it is manifest in a lessened rate, strong expirations, and expiratory pauses. fhe marked increase in the depth of the respiratory movements in C0 2 - dvspncea is not solely due to the direct action of C0 2 upon the respiratory • '•litre, for Gad and Zagari ' have shown that C0 2 in abundance in inspired air acts upon the terminations of the sensory nerves of the larger bronchi and thus reflexly excites the respiratory centre. In a research on dogs these ob- servers opened the trachea and passed glass tubes through the trachea and the larger bronchi to the smaller bronchi. Before the tubes were inserted the inhalation of C0 2 caused a considerable deepening of the respiratory move- ments, but after the insertion of the tubes, by means of which the gas was carried directly to the smaller bronchi, the characteristic action of the C0 2 was no longer observed. From the results of these experiments we may con- clude that the marked increase iu the depth of the respiratory movements in ( '< )_, -dyspnoea is due in part to the irritation of the sensory nerve-fibres of the mucous membrane of the larger bronchi. ( urdiac and hemorrhagic dyspnoeas are chiefly due to the deficiency in the supply of O — the former, to the poor supply of blood due to the enfeebled action of the heart ; and the latter, both to this and to the reduced quantity of blood (haemoglobin). All circumstances which enfeeble the circulation or lessen the quantity of haemoglobin therefore tend to cause dyspnoea ; hence individuals with heart troubles or weakened by disease or with certain forms of anaemia are apt to suffer from dyspnoea upon the least exertion. All circumstances which interfere with the interchange of O and the elimination of CO, in the lungs are favorable to the production of dyspnoea, 1 Dii Bois-Reymond'a Archiv fur Physiologie, 1*90, S. 588. RESPIRATION. 445 as in pneumonia, pulmonary tuberculosis, growths of the larnyx, abdominal tumors, etc., especially so upon exertion. Asphyxia is literally a state of pulselessness, but the term is now used to express a series of phenomena caused by the deprivation of air, as by placing an animal in a closed chamber of moderate size. These phenomena may be divided into three stages: the first is one of hyperpnoea; the second, of developing dyspnoea, and finally of convulsions; and the third, of collapse. During the first stage the inspiratory portion of the respiratory centre especially is excited, the respirations being increased in frequency and depth. During the second stage the excitation of the expiratory portion of the respiratory centre is more intense than that of the inspiratory portion, so that the respira- tions become slow and deep, prolonged and convulsive, and the movements of inspiration are feeble and in striking contrast to the violent spasmodic expira- tory efforts. During the third stage the dyspnoea is followed by general exhaustion ; the respirations are shallow and occur at longer and longer inter- vals, the pupils become dilated, the motor reflexes disappear, consciousness is lost, the inspiratory muscles contract spasmodically with each inspiratory act, convulsive twitches are observed in the muscles of the extremities and else- where, gasping and snapping respiratory movements may be present, the legs are rigidly outstretched and the head and body are arched backward, feces and urine are usually voided, respiratory movements cease, and finally the heart stops beating. During these stages the circulation has undergone considerable disturbances. During the first and second stages the blood has been robbed of nearly all its O, the gums, lips, aud skin become cyanosed, and, owing to the venous condition of the blood, the cardio-inhibitory centre has been decidedly excited, so that the heart's contractions are rendered less frequent; the vaso- constrictor centre for the same reason has also been excited, causing a con- striction of the capillaries and an increase of blood-pressure. During the third stage these centres are depressed and finally are paralyzed. If asphyxia be caused by ligating the trachea, the whole series of events covers a period of four to five minutes, the first stage lasting for about one minute, the second a little longer, and the third from two to three minutes. If asphyxia be produced gradually, as by placing an animal within a relatively large confined air-space, death may occur without the appearance of any motor disturbances (p. 4.">i>). The heart usually continues beating feebly for several minutes after the cessation of respiration, so that by means of artificial respiration it is possible to restore the respiratory movements and other suspended functions. After death the blood is very dark, almost black. The arteries are almost if not entirely empty, while the veins and lungs are engorged. Death from drowning occurs generally from the failure of respiration, occasionally from a cessation of the heart's contractions. It is more difficult to revive an animal asphyxiated in this way than one which, out of water, has simply been deprived of air for the same length of time. Dogs submerged for one and a half minutes can rarely- be revived, but recovery can usually be 446 AN AMERICAN TEXT- BOOK OF PHYSIOLOGY. accomplished after deprivation of air, out of water, for a period four to five times longer. After ;i person has been submerged for five minutes it is extremely difficult to effect resuscitation. H. Artificial Respiration. Effective methods for maintaining ventilation of the lungs are important alike to the experimenter and to the clinician. In the laboratory the usual method is to expose the trachea, insert a cannula (Fig. 77), and then period- ically force air into the lungs by means of a pair of bellows or a pump. Some of the forms of apparatus are very simple, while others are complicated. An ordinary pair of bellows docs very well for short experiments, but for longer study, especially when it is necessary that the supply of air should be uniform, the bellows are operated by power. Some of these instruments are so con- structed that air is alternately forced into and withdrawn from the lungs. Periodical inflation of the lungs is termed positive ventilation ; the period- 1 ■'!.;. 77.— Cannulas for dogs (a) and for cats ical withdrawal of air from the lungs andrabbits < & >' by suction is negative ventilation; and alternate inflation and suction is compound ventilation. In practising artificial respiration we should imitate the normal rate and depth of the respiratory movements. Long-continued positive ventilation causes cerebral anaemia, a fall of blood-pressure, and decrease of bodily tem- perature. In human beings it is not practicable, except under extraordinary circum- stances, to inflate the lungs by the above methods, so that we are dependent upon such means as will enable us to expand and contract the thoracic cavity without resorting to the knife. One method is to place the individual on his back, the operator taking a position on his knees at the head, facing the feet. The lower ribs are grasped by both hands and the lower antero-lateral portions of the thorax are elevated, thus increasing the thoracic capacity, with a conse- quent drawing of air into the lungs; the ribs and the abdominal muscles are then pressed upon in imitation of expiration. These alternate movements are kept up as long as necessary. The following is Sylvester's method : " Place the patient on the back, on a flat surface inclined a little upward from the feet; raise and support the head and shoulders on a small firm cushion or folded article of dress placed under the shoulder-blades. Draw forward the patient's tongue, and keep it project- ing beyond the lips; an elastic band over the tongue and under the chin will answer this purpose, or a piece of string or tape may be tied around them, or by raising the lower jaw the teeth may be made to retain the tongue in that position. Remove all tight clothing from about the neck and chest, especially the braces" .... " To imitate the movements of breathing : Standing at the RESPIRA TION. 447 patient's head, grasp the arms just above the elbows, and draw the arms gently and steadily upward above the head, and keep them stretched upward for two seconds. By this means air is drawn into the lungs. Then turn down the patient's arms, and press them gently and firmly for two seconds against the sides of the chest. By this means air is pressed out of the lungs. Repeat these measures alternately, deliberately, and perseveringly about fifteen times in a minute, until a spontaneous effort to respire is perceived, immediately upon which cease to imitate the movements of breathing, and proceed to induce circulation and warmth." A new and effective method has been reported by Galliano : The patient is placed in Sylvester's position; the arms are drawn up above and behind the head, and the wrists tied. This causes the thorax to be expanded. Respiration is accomplished by pressing concentrically with the open hands upon the sides of the thorax and the epigastric region about twenty times a minute. This method is even more effective if in addition the jaw be wedged open, and short, sharp tractions of the tongue be practised immedi- ately preceding each pressure upon the thorax. These operations should be continued for at least one and a half hours, if necessary, and aided by fric- tion, external heat, etc. The periodical traction of the tongue acts as a strong excitant to the respiratory centre. I. The Effects of the Respiratory Movements on the Circulation. The respiratory movements are accompanied by marked changes in the cir- culation. If a tracing be made of the blood-pressure and the pulse (Fig. 78), and at the same time the inspiratory and expiratory movements be noted, it Fig. 78.— Blood-pressure and pulse tracing showing the changes during Inspiration (in. > and expi- ration (ex.). will be seen that the blood-pressure begins to rise shortly after the onsel of nspiration, commonly after a period occupied by one to three heart-beats, ami leaches a maximum after the lapse of a similar brief interval after the begin- ning of expiration, when it begins to fall, reaching a minimum after the beginning of the next inspiration. During inspiration the pulse-rate ifi more frequent than during expiration and the character <>f the pulse-curve is some- what different. The Effects on Blood-pressure. — The changes in blood-pressure are mechanical effects due to the actions of the respiratory movements. When it lis AN AMERICAN TEXT- HOOK OF PHYSIOLOGY. is remembered thai the lungs and the heart with their great blood-vessels are placed within an air-tight cavity, that the lungs become inflated through the aspiratory action of the muscles of inspiration, and that during inspiration intrathoracic negative pressure is increased, it is easy to understand how the action which causes inflation of the lung- must affect in like manner such hollow elastic structures as the heart and the great blood-vessels, and thus influence the circulation. It is obvious, however, that this influence must make itself felt to a more marked degree upon the vessels than upon the heart, and upon the flaccid walls of the vein- than upon the comparatively rigid walls of the arteries. Moreover, the effects upon the flow of blood through the vessels entering and leaving the thoracic cavity must be different : the inflow through the veins must he favored, and the outflow through the arteries hindered; but it i- upon the flaccid veins chiefly that the mechanical influences of inspiration are exerted. If the thoracic cavity be freely opened, movements of inspiration no longer cause an expansion of the lungs, nor is there a tendency to distend the heart and the large blood- vessels; if, however, in an intact animal the out- let of the thorax be restricted, as by pressure upon the trachea, the force of the inspiratory movement would make itself felt chiefly upon the heart and the vessels, and it is under such circumstances that the maximal influences of in- spiration upon the circulation are observed. The lungs on the one hand and the heart and its large vessels on the other may be regarded as two sacs placed within a closed expansible cavity, the former having an outlet communicating with the external air, and the latter having inlets and outlets communicating with the extrathoracic blood-vessels, both being dilated when the thorax ex- pands and constricted when it contracts. Moreover, the blood-vessels in the lungs may be compared to a system of delicate tubes placed within a closed distensible bag and communicating with tubes outside of the bag, simulating the communication of the venae cavae and the aorta with the extrathoracic vessels. When such a bag is distended the tubes undergo elongation and narrowing, and their capacity is increased. The narrowed vessels also tend to be expanded, owing to the negative pressure present ; and thus have their capacity further increased. The lungs in the same way, when expanded by the act of inspiration, exhibit a simultaneous elongation and narrowing of the intrapulnionary vessels, which results, however, in an increase in their total capacity. I)urin<_ r expiration negative intrathoracic pressure becomes less, so that there is a gradual return of the elongated and narrowed intrathoracic vessels to that condition which existed at the beginning of inspiration ; at the same time the intrapulnionary vessels are not only subjected to the passive influ- ence of the declining intrathoracic pressure, but are actively squeezed, as it were, between the air in the lungs on one side and the expiratory forces expelling the air on the other. Thus we have during expiration passive and active agents combining to bring about changes in the capacity of the intra- pulnionary vessels. The mechanical effects of the movements of respiration upon blood-press- RESPIRATION. 449 lire may be crudely demonstrated by Hering's device ( Fig. 79). The chamber a represents the thorax ) the rubber bottom B the diaphragm ; c, the opening of the trachea; e d, a tube leading from the thoracic cavity to the manometer I, by means of which intrathoracic pressure is measured ; <; is a vessel contain- ing water, colored blue in imitation of venous blood, communicating bv means of a tube with an oblong flaccid bag F, in imitation of the heart and the intra- thoracic vessels, and finally with the vessel h ; v' and v are valves in imitation of valves in the heart and pulmonary vein and aorta. If now the knob K which is fastened to the centre of the diaphragm be pulled down, rarefaction of the air within the chamber occurs, so that the greater external pressure forces air through the tube c into the two rubber bags (lungs) ; at the same time and for the same reason water is forced from the vessel g into f, which is distended. The diaphragm upon being released is drawn up in part by virtue of its own elasticity and in part by the negative pressure within the chamber. The rubber bags are emptied by their own natural elastic reaction. At the Fig. 79.— Hering's device to illustrate the Influence of respiratory movements upon the circulation. same time the distended bag F contracts on its contained fluid, forcing it into the vessel n, the valve v preventing a back-flow into G. The degri I" force exerted by the traction on the diaphragm is read from the scale ir- ondary waves are smaller and the dicrotic notch is more pronounced, SO that the dicrotic character of the curves is better marked. The Effects of Obstruction of the Air-passages and of the Respira- tion of Rarefied and Compressed Air on the Circulation. — The blood- pressure undulations produced during quiet breathing become marked in pro- portion to the depth of the respiratory movements. Inspiration or expiration against extraordinary resistance — as after closing the mouth and nostrils, or respiring rarefied or compressed air — may materially modify the circulatory phe- nomena. When we make the most forcible inspiratory effort, the air passages being fully open, not only is there a full expansion of the lungs, but great 452 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. diastolic distention of the heart and dilatation of the intrathoracic vessels ; yet, notwithstanding that this powerful aspiratory action encourages the flow of an extraordinarily large amount of blood into the thoracic- vessels, the heart-beats may be very small, because intrathoracic negative pressure is so great that the thin-walled auricles meet with great resistance while contracting; in conse- quence, then, of this forced inspiratory effort little blood is driven through the lungs to the left auricle and by the left ventricle into the general circulation, ff we make the greatest possible expiratory effort, and maintain the expira- tory phase with air-passages open, the heart-beats arc small, owing to the small amount of blood which How- through the venae cavse to the right auri- cle, and to the resistance offered by the compressed intrapulmonary vessels. If, after a most powerful expiration, we close the mouth and nostrils and make a powerful inspiratory effort, the aspiratory effect of inspiration on the heart and the blood-vessels is manifest to its utmost degree: the heart and the vessels tend to undergo great dilatation, the blood-flow to the right auricle and ventricle is increased, the intrapulmonary vessels and the heart become en- gorged, and, owing to the powerful traction of the negative pressure upon the heart, especially upon the right auricle, very little blood is forced through the lungs to the left auricle and ventricle and subsequently into the general circu- lation, thus causing a fall of blood-pressure; indeed, the heart-sounds and the pulse may disappear. If now we make the most forcible inspiratory effort, close the glottis, and make a powerful expiratory effort, not only is the air in the lungs subjected to high positive pressure, but the heart and the great vessels partake in the pressure-effects, the blood being forced from the pul- monic circulation into the left auricle, thence by the ventricle into the aorta, with the result of a temporary rise of blood-pressure. The pressure upon the intrathoracic veins is so great that the flow of blood into the chest is almost shut off, hence the veins outside the thorax become very much distended, as seen in the superficial veins of the neck, and the heart is pressed upon to such an extent that, together with the lessened supply of blood, the heart-sounds and the radial pulse may disappear and the blood-pressure falls. The respiration into or from a spirometer (p. 427) containing rarefied or compressed air modifies the blood-pressure curves. Inspiration of rarefied air causes a greater rise of blood-pressure than when respiration occurs at normal pressure, while during expiration, although the blood-pressure falls, it may remain somewhat above the normal. The increase of pressure is due to the aspiratory effort required to draw the air into the lungs, which effort also makes itself felt to a more marked degree upon the heart and the intrathoracic and intrapulmonary vessels, thus increasing the blood-flow through the pulmonary circulation. During expiration air is aspirated from the lungs into the spi- rometer, tending to dilate the intrathoracic and intrapulmonary vessels and the heart and thus to aid the pulmonary circulation. After a time, however, there is a fall of blood-pressure on account both of the engorgement of the thoracic vessels and the accompanying depletion of the general circulation, and of the distention of the heart and interference with its contractions. In.-piration of compressed air lessens the extent of, and may prevent, the RESPIRATION. 453 inspiratory rise, or it may cause a fall. If, upon the respiration of compressed air, the pressure of the air be above that exerted by the elastic tension of the lungs, no effort of the inspiratory muscles is required, the chest being expanded by the pressure of the air. Therefore, instead of an increase of negative intra- thoracic pressure, as in normal inspiration, there is a decrease, and negative intrathoracic pressure is replaced by positive pressure. As a result, the blood- vessels and the heart, instead of being dilated by an aspiratory action, are pressed upon, forcing the blood into the general circulation, and thus causing a transient rise of pressure, which is, however, succeeded by a fall due to obstruc- tion to the flow of blood through the heart and the pulmonary vessels. Ex- piration into compressed air causes at first a transient increase of blood-pressure followed by a fall, the former being due to the forcing of some of the blood from the intrathoracic and intrapulmonary vessels into the general circulation, and the latter to obstruction to the blood-flow through the heart and the pul- monary circulation. When individuals are exposed to compressed- air, as in a pneumatic cabinet, or to rarefied air, as in ballooning, the effects on the circulation become of a very complex character, owing chiefly to the additional influences of the abnormal pressure upon the peripheral circulation ; moreover, the effects of breathing against obstructions or of respiring rarefied or compressed air may be materially influenced by secondary effects resulting from excitation of the cardiac and vaso-motor mechanisms. In artificial respiration, as ordinarily performed in the laboratory, air is periodically forced into the lungs by a pair of bellows or a pump, and is ex- pelled from the lungs by the normal elastic and mechanical factors of expira- tion. When the lungs are inflated the pulmonary capillaries are subjected to opposing forces — the positive pressure of the air within the lungs on one hand, and the resistance of the thoracic -walls on the other — so that the blood is squeezed out, thus momentarily increasing the blood-pressure, but subsequently retarding the current and consequently lowering the pressure. During expira- tion the pressure is removed and the blood-flow is encouraged : there is, there- fore, a temporary fall during the filling of the pulmonary vessels, followed by a rise due to the removal of the obstruction. If the air is aspirated from the lungs, the rise of the pressure is augmented, owing to the further dilatation of the intrapulmonary capillaries ; hence, in artificial respiration, during the in- spiratory phase the blood-pressure curves arc reversed, there being a primary transient rise followed by a fall, and during the expiratory phase a transienl fall followed by a rise. In normal respiration the oscillations are due essen- tially to the changes in capacity of the intrapulmonary vessels caused essen- tially by the alterations in their length, while in artificial respiration the effects of these alterations are opposed and superseded by those due directly to positive intrapulmonary pressure. J. Special Respiratory Movements. The rhythmical expansion- and contractions of the thorax which we under- stand as respiratory movements have for their object the ventilation of the \'<\ AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. ] u iiLf-. There are, however, other movements which possess certain respiratory characters, but which are for entirely different purposes, hence they are spoken of as special or modified respiratory movements. Some of these movements are purposeful in character, others are spasmodic; some are voluntary or in- voluntary, "i- pi )>>(■-»> liiith volitional ami in volitional characteristics; some are peculiar to certain species, etc. Among such movements are coughing, hawking, sneezing, laughing, crying, sobbing, sighing, yawning, snoring, gargling, hic- cough, neighing, braying, growling, etc. In coughing a preliminary inspiration is followed by an expiration which is frequently interrupted, the glottis being partially closed at the time of the occurrence of each interruption, so that a series of characteristic sounds is caused. The air is forcibly ejected through the mouth, and thus foreign parti- cles, such as mucus in the respiratory passages, may be expelled. Coughing may be either voluntary or reflex. Hawking is somewhat similar to coughing. The glottis is, however, open during the expiratory act, and the expiration is continuous. The current of air is forced through the contracted passage between the root of the tongue and the soft palate. Hawking is a voluntary act. In sneezing a deep inspiration is followed by a forcible expiratory blast directed through the uose; the glottis is open, and should the oral passage be open, which is not usually the case, a portion of the blast is forced through the mouth. Sneezing is usually a reflex act commonly excited by irritation of the fibres of the nasal branches of the fifth pair of cranial nerves. Peculiar sen- sations in the nose give us a premonition of sneezing; at such a time the act may be prevented by firmly pressing the finger upon the upper lip. In laughing there is an inspiration followed, as in coughing, by a repeatedly- interrupted expiration during which the glottis is open and the vocal cords are thrown into vibration with each expiratory movement. The expirations are not as forcible as in coughing, the mouth is wide open, and the face has a characteristic expression due to the contraction of the muscles of expression. Crying bears a close relationship to laughing — so much so that at times it is impossible to distinguish between the two; hence one may readily pass into the other, as frequently occurs in cases of hysteria and in young children. The chief differences between the two are in the rhythm and the facial expres- sion. A secretion of tears is an accompaniment of crying, but not so of laughing, except during very hearty laughter. Crying normally is involun- tary ; laughing may be either voluntary or involuntary. Sobbing, which is apt to follow a long period of crying, is characterized as being a series of spasmodic inspirations during each of which the glottis is partially closed, and the series is loll,, wed by a long, quiet expiration. This is usually involuntary, but may sometimes be arrested volitionally. In sighing there is a long inspiration attended by a peculiar plaintive sound. The mouth may be either closed or partially open. Sighing i- usually voluntary. Yawning has certain feature- like the preceding. There occurs a long, deep inspiration during which the mouth is stretched wide open, and there is usually a simultaneous strong contraction of certain of the muscles of the BESPIRA TION. 455 shoulders and the back ; the glottis is wide open, and inspiration is accompa- nied by a peculiar sound ; expiration is short. Yawning may be either volun- tary or involuntary. In snoring the mouth is open, and the inflow and outflow of air throws the uvula and the soft palate into vibration. The sound produced is more marked during inspiration, and may even be absent during expiration. It is more apt to occur when the individual is lying on his back than when in any other posture. Snoring is usually involuntary, but it may be volitional. In gargling the fluid is held between the tongue and the soft palate and air is expired through it in the form of bubbles. In hiccough there is a sudden inspiratory effort caused by a spasmodic twitch of the diaphragm and attended by a sudden closure of the glottis, so that the inspiratory movement is suddenly arrested, thus causing a characteris- tic sound. Hiccough is sometimes not only distressing, but may be even seri- ous or fatal in its consequences. It is especially apt to occur in cases of gastric irritation, in certain forms of hysteria, in alcoholism, in uraemia, etc. Besides the above special respiratory movements, others are observed in certain species of animals, such as whining, neighing, braying, roaring, bellow- ing, bawling, barking, purring, growling, etc. Of all these modified respiratory movements, coughing possesses to the clinician the most interest, because it not only may express an abnormal condi- tion of some portion of the lungs, trachea, or larynx, but may indicate irrita- tion in even remote and entirely unassociated parts. Thus, coughing may be the result of irritation in the nose, ear, pharynx, stomach, liver, spleen, intes- tines, ovaries, testicle, uterus, or mamma. Coughs which are not dependent upon irritation of the larynx, trachea, or luugs are distinguished as sympa- thetic or reflex coughs. The term "reflex" is a bad one, however, inasmuch as all coughs are essentially or solely reflex. K. The Nervous Mechanism of the Respiratory Movements. The movements of respiration are carried on involuntarily and automati- cally — that is, they recur by virtue of the activity of a self-governing mech- anism. Each respiratory act necessitates a finely co-ordinated adjustment of the contractions of a number of muscles, which adjustment is dependent upon the operations of a dominating or controlling nerve-centre located in the medulla oblongata, and known as the respiratory centre. Besides this centre, others of minor importance have been asserted to exist in certain parts of the cerebro-spinal axis; these centres are distinguished as subsidiary or subordinate respiratory centres. Connected with the respiratory centre are afferent and efferent respiratory nerves. The Respiratory Centres. — After removal of all parts of the brain except the spinal bulb, rhythmical respiratory movements may still continue, but aftei destruction of the lower part of the bulb they at once cease. These facts indi- cate that the centre for these movements is in the medulla oblongata, and this conclusion is substantiated by the results of other experiments upon this region. According to the observations of Flourcns, the respiratory centre is 456 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. located in an area about •"> millimeters wide between the nuclei of the pneumo- gastric and spinal accessory nerves in the lower end of the calamus scriptorius. When this region was destroyed he found that respiratory movements ceased and death ensued, consequently he tinned it the noeud vital, or vital knot. The results of various investigations show, however, that Flourens' area, as well as certain other parts of the medulla oblongata that have been looked upon by others as being respiratory centres, are not such, but are largely or wholly collections of nerve-fibres which arise chiefly in the roots of the vagal, spinal accessory, glosso-pharyngeal, and trigeminal nerves, and which there- fore are probably nerve-paths to and from the respiratory centre. Moreover, excitation of the rweud vital does not excite respiratory movements, but simply increases the tonicity of the diaphragm ; nor is the destruction of the area always followed by a cessation of respiration. While the precise location of the centre is still in doubt, there is abundant evidence to justify the belief in its existence in the lower portion of the spinal bulb. The centre is bilateral, one half being situated on each side of the median line, the two parts being intimately connected by commissural fibres, thus con- stituting physiologically a single centre. This union may be destroyed by section along the median line. Each half acts more or less independently of, although synchronously with, the other, and each is connected with the lungs and the muscles of respiration of the corresponding side. These facts are rendered manifest in the following observations: If a section be made in the median line so as to cut the commissural fibres, the respiratory movements on the two sides continue synchronously ; if now the portion of the centre on the one side be destroyed, the respiratory movements on the corresponding side tem- porarily or permanently cease. If after section in the median line one pneumo- gastric nerve be divided, the sensory impulses conveyed from the lungs on the side of section to the corresponding half of the respiratory centre are prevented from reaching the centre, causing the movements of the respiratory muscles on the same side to be slower and the inspirations stronger as compared with those on the opposite side ; if both pneumogastrics be divided, and the central end of one of the cut nerves be excited high in the neck by a strong current, the respi- ratory movements on the same side may be arrested, yet they may continue on the opposite side. These facts indicate that each half is in a measure inde- pendent of the other. The operations in the two parts are, however, inti- mately related, a- shown by the fact that if the commissural fibres between the halves are intact, excitation or depression of one half is to a certain degree shared by the other. Thus, after section of one vagus not only are the respi- ratory movements less frequeni and the inspirations stronger on the side of the section, but there i- a corresponding condition on the opposite side; simi- larly, excitation of the central end of the cul nerve increases the respiratory rate both on the same and on the opposite side. Consequently, while there is more or less independence of the halves, the two are physiologically so intimately associated as to constitute a common or single centre. Moreover, each of the halve- may be supposed to consist of two distinct portions, one of which, upon excitation, gives rise to contraction of inspiratory RESPIBA TION. 457 muscles, the other to contraction of expiratory muscles; hence they are spoken of as inspiratory and expiratory parts of the respiratory centre, or as inspi- ratory and expiratory centres. Moderate excitation of the inspiratory centre causes not only contraction of inspiratory muscles, hut au increase in the respiratory rate; and if the irritation be sufficiently strong, there occur- a spasmodic arrest of the respiratory movements in the inspiratory phase. On the contrary, excitation of the expiratory centre causes contraction of expi- ratory muscles and diminishes the respiratory rate; powerful excitation of the same centre is followed by arrest of movements in the expiratory phase. The inspiratory portion may therefore be regarded not only as being spe- cifically connected with inspiratory muscles, but in the sense of an accelerator centre; and the expiratory portion maybe regarded as being similarly con- nected with expiratory muscles, and as being an inhibitor)/ centre. When the two are conjointly excited the accelerator effect prevails, because under ordinary circumstances the accelerator element of the centre seems more excitable and potent than the inhibitory ; therefore, when the centre as a whole is irritated, it manifests an accelerator character. In addition to this centre, the existence of subsidiary centres is claimed, situated both in the brain and in the spinal cord. One centre has been located in the rabbit in the tuber cinereum, which has been named a polypnceic centre, because when excited the respirations are rendered extremely frequent. The sensitiveness of this centre is readily demonstrated by subjecting an animal to a high external temperature, when a marked increase of the respiratory rate follows; if now the tuber cinereum be destroyed, there occurs an immediate cesssation of the accelerated movements. Another area has been located in the optic thalamus in the floor of the third ventricle ; this centre is believed to be excited by impulses carried by the nerves of sight and hearing, and when irritated causes an acceleration of the respiratory rate, and when strongly excited arrests respiration during the inspiratory phase ; hence it is regarded as an inspiratory or accelerator centre. Another centre has been Located in the anterior pair of the corpora quadrigeniina : it causes expiratory and inhibi- tory effects, and may therefore be placed among the expiratory or inhibitory centres. An inspiratory or accelerator centre has been recorded as existing in the posterior pair of the corpora quadrigemina and the pons Varolii. The nuclei of the triyemini are also said to act as inspiratory or accelerator centres. Respiratory centres are likewise claimed to exist in the brain-cortex, h is very doubtful, however, whether or not these so-called subsidiary respiratory centres should be regarded as being of a specific character. In any event, we cannot suppose that these centres are capable of evoking directly respiratory movements, [f they exist, they are probably connected with the medullary centre, through which (hey exert their influence on the respiratory movements. The existence of a respiratory centre in the spinal cord is also doubtful. The chief reason for the claim of its existence i< that respiratory movements may for a time be observed after section of the cerebro-spinal ;i\i- at the junc- tion of the spinal cord and bulb. In new-born animal- after such section respiratory movements may continue for some time, strychnine rendering them 458 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. more pronounced. Again, animals in which respiration has been artificially maintained for a long time may, alter section of the cord at the junction with the bulb, exhibit respiratory movements after artificial respiration has been suspended. The respiratory movements under these circumstances are, how- ever, of a spasmodic character, and distinctly unlike the co-ordinated rhythmi- cal movements observed in normal animals; the movements are rather of the nature of spasms simulating normal respirations. The Rhythmic Activity of tin Respiratory Centre. — The rhythmic sequence of the respiratory movements is due to periodic discharges from the respiratory centre. The cause of this periodicity is still obscure, but the fact that the rhythm continues after the combined section of the vagi and the glosso-pharyn- geal nerves, of the spinal cord in the lower cervical region, of the posterior roots of the cervical spinal nerves, and of the spinal bulb from the parts above, indicates that the rhythm is inherent in the nerve-cells, and is not caused by external stimuli carried to the centre through afferent nerve-fibres. Loewy 1 has shown that under the above circumstances, when the centre is iso- lated from afferent nerve-impulses, the rhythmical activity of the centre is due to the blood, which, while acting as a continuous excitant, causes discontinuous or periodic discharges, so that, although we usually speak of the activity of the respiratory centre as being automatic — that is, not immediately dependent upon external stimuli — yet as a matter of fact the apparently automatic discharges are in realitv due to the stimulation by the blood; the centre is therefore auto- matic only with reference to external nerve-stimulation. The rhythm as well as the rate, force, and other characters of the discharges may be affected materially by the will and emotions: by the composition, Bupply, and temperature of the blood; and especially by certain afferent im- pulses, pre-eminently those originating in the pneumogastric nerves. As to the influence of the will and emotions, we are able, as is well known, to modify voluntarily to a certain extent the rhythm and other characters of the respira- tions, while the striking effect of emotions upon respiratory movements is a matter of almost daily observation. The importance of the composition of the blood is manifested by the marked effect upon the respirations when the blood is deficient iii ( ), when it contains an excess of CO,, and during muscu- lar activity, when in the blood there is a relative abundance of certain products resulting from muscular metabolism. If the blood-supply to the centre is diminished, as after severe hemorrhage or after clamping the aorta so as to interfere with the cerebral circulation, the respirations are less frequent and the rhythm is affected, the form of breathing having a Cheyne-Stokes char- acter (p. 424) ; conversely, an increase in the blood-supply causes an increase in the rate. An increase or decrease in the temperature of the blood induces corresponding changes in the rate; thus, in fever the frequency of the move- ment- increases almost pari passuvnth the augmentation of temperature, while if the temperature of the blood be reduced by applying ice to the carotids, the rate is lessened. 1 Pfluger'a Archivf. Physiologic., 1889, Bd. xlii. S. 245-281. RESPIRA TION. 459 Afferent impulses exercise an important, and practically a continuous, influ- ence. After section of one pneumogastric nerve the respirations are somewhat less frequent; after section of both nerves the respirations become considerably less frequent and deeper and otherwise changed. If we stimulate the central end of one of these cut nerves below the origin of the laryngeal branches by a current of electricity of moderate intensity, the respiratory rate may be in- creased, and we may be able to restore, or even exceed, the normal frequency. The fact that section of these nerves is followed by a diminution of the rate and that excitation of the central end of the cut nerve causes an increase leads us to believe that the pneumogastric nerves are continually conveying impulses from the lungs to the respiratory centre, which impulses in some way increase the number of discharges, and thus the respiratory rate. The centre may be excited or depressed by excitation of the cutaneous nerves and the sensory nerves in general ; thus, external heat accelerates, while a dash of cold water may either accelerate or inhibit, respiratory movements. Excitation of the glosso-pharyngeal nerves inhibits the respirations. Such inhibition occurs during deglutition to avoid the risk of introducing foreign bodies into the larynx. Similar respiratory inhibition may be induced by excitation of the superior laryngeal nerves, when, if the degree of irritation be sufficiently strong, complete arrest of the respiratory movements may occur. Strong irri- tation of the olfactory nerves and of the fibres of the trigemini distributed to the nasal chambers excites expiration and may be followed by complete inhibi- tion of the respiratory movements; strong irritation of the optic and auditory nerves excites inspiratory activity ; and irritation of the sciatic nerve causes an increase of the rate, and may or may not affect the depth of breathing. The study of the rhythmic activity of the respiratory centre is further complicated by the fact that there is not only a rhythmic sequence of the res- pirations, but a rhythmic alternation of inspiratory and expiratory move- ments. While it is true that in ordinary quiet expiration but little of the muscular element is present, yet forced expiration is a well-defined co-ordinated muscular act. The mechanism whereby this alternation is broughl about is not understood. Some believe that the pneumogastric nerves contain both inspiratory and expiratory fibres which are connected with corresponding pails of the respiratory centre and alternately convey their respective impulses to the centre, inspiratory impulses being excited during expiration and expiratory impulses during inspiration (p. 397). These impulses are, however, not indis- pensable to the alternation of inspiration and expiration, because these acts follow each other regularly, even after the isolation of the respiratory centre from the lungs by section of the pneumogastric nerves. Thus we may conclude that the rhythmical discharges from the centre are due primarily to an inherent properly of periodic activity of the nerve-cells constituting the respiratory centre and maintained by the blood, and that the rhythm, rate, and other characters of these discharges may be affected by the will and the emotions, by the composition, supply, and temperature of the blood, and by various afferent impulses. The chief factors are, under ordi- 460 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. nary circumstances, the quantities of O and C0 2 in the blood, and the impulses conveyed from the lungs by the fibres of the pneumogastric nerves. The Afferent Respiratory Nerves. — The chief of these nerves are the pneumogastric, glossopharyngeal, trigeminal, and cutaneous nerves. The im- portant part taken by them in the regulation of the respiratory movements has frequently been alluded to in connection with the respiratory centres. Their functions, however, are of sufficient importance to demand special and detailed consideration. The pneumogastric nerves are pre-eminently the most important. Their functions may be studied by comparing the phenomena before and after section of one or of both nerves, and from the results following excitation by stimuli of varying quality and strength under normal and abnormal conditions. Section of one pneumogastric may be without effect or be followed by a transitory, slight diminution of the respiratory rate; by slower and deeper movements; by stronger, deeper, and longer inspirations; by unaltered or longer or shorter expirations; and probably by active expirations. These effects are transient, and the normal respiratory movements are usually restored within a half hour. Section of both nerves is sooner or later followed by a diminution of the respiratory rate; by slow, deep, powerful inspirations; by active expiration ; and by a pause between expiration and inspiration. The immediate results are variable unless certain precautions are taken to prevent irritation of the central ends of the cut nerves. If the ends are allowed to fall back into the wound, the respirations may become irregular; or they may be less frequent, with weakened inspirations, spasmodic expirations, and pro- longed expiratory pauses. The explanation of these variable results is found in the fad that the expiratory fibres are more sensitive to very weak stimulus than the inspiratory fibres, and that the mechanical irritation caused by the section, and the excitation due to the electric current in the cut ends of the nerves that is established when the central end of the nerve is replaced in the wound, excite expiratory impulses and cause expiratory phenomena; if the irritation be stronger, both inspiratory and expiratory impulses are excited, thus causing uncertain results, varying as one or the other is the stronger. If irritation be prevented, section is at once followed by typical slow, deep respirations. Stimulation of the central end of the cut vagus, the other nerve being intact, is followed by variable results dependent upon the character of the stimulus. Chemical stimuli, such as a solution of sodium carbonate, excite the expiratory fibres; mechanical stimuli, the inspiratory fibres; electrical stimuli, expiratory or inspiratory fibres or both, according to the strength of the current. Single induction shocks are without effect, but a tetanizing current is very effective. Should that current which will elicit the least response be used, the breathing is rendered less frequent, the inspirations are weakened, and the expirations may be active and lengthened; in other words, there are present the same phenomena which often immediately follow section of both nerve- when the cul end- are allowed to fall back into the wound and RESPIRA TION. 461 thus establish an exciting electric current which affects expiratory fibres. If the strength of the current be increased, these effects give place to those of an opposite character, the respirations becoming more frequent and the inspi- rations more marked in depth and force, the explanation of this difference being that the stronger current has also excited inspiratory fibres, so that now both expiratory and inspiratory impulses are generated, but the latter, being more potent in their influences, cause acceleration of the rate and accentuated inspirations. The effects following stimulation of the central end of the cut vagus by a current of moderate strength are best observed after both nerves have been divided and when there exist slow, deep, powerful respirations. Under such circumstances stimulation of the central end of one of the vagi is followed at once by an increase in the respiratory rate and a return of the general char- acters of the inspiratory and expiratory phases toward the normal ; and if the degree of excitation be properly adjusted, the normal rate and normal charac- ter of breathing may be restored. Still stronger excitation further accelerates the rate, causing the respiratory acts to follow each other with such frequency that inspiration begins before the expiratory act (relaxation of the inspiratory muscles) has been completed. The inspiratory muscles are therefore never completely relaxed. With a further increase of stimulus the expiratory relaxation becomes less and less, until finally the respirations are brought to a standstill in the inspiratory phase, the inspiratory muscles being in tetanus. If the nerves be fatigued from over-excitation or if the animal be thoroughly chloralized, stimulation of the central end of the cut nerve by a strong current is no longer followed by inspiratory stimulation, but is followed by expiratory stimulation (the inspirations being shortened and weakened, the expirations prolonged and spasmodic) and by long pauses between expiration and inspiration. If the excitation be sufficiently strong, arrest of respiration occurs in the expiratory phase. It will be observed from the above results that electrical irritation of the central end of the cut pneumogastric may be followed by effects of an oppo- site character, extremely weak irritation causing expiratory stimulation (weaker and shorter inspirations, prolonged and active expirations, expiratory pan--. and diminished respiratory rate) ; whereas moderate irritation causes inspiratory stimulation (stronger and deeper inspirations and increased respiratory rate). These diverse results are explained by the fact that these nerves contain two kinds of fibres having opposite functions: fibres of one kind convey impulses which affect the expiratory centre ; those of the other kind convey impulses which affect the inspiratory centre. The former are more susceptible to weak electrical stimulation, and thus their presence may be elicited by the weakest stimulus capable of causing any response. At the same time they arc less readily exhausted, so that if the vagi be subjected to prolonged stimulation by a strong current, the inspiratory fibres are exhausted before the expiratory fibres. For moderate and strong currents the inspiratory fibres are affected to a greater degree than the expiratory fibres, therefore inspiratory stimula- tion predominates. 462 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Both Bets of fibres convey impulses which have their origin essentially in the peripheries of the pneumogastric nerves in the lungs; but expiratory impulses may arise in the fibres of the superior and inferior laryngeal nerves, especially in the former. The impulses which arise in the lungs are under ordinary circumstances produced mechanically by the movements of the lungs, although it is believed by some that the composition of the gases in the alveoli is an important factor. According to the latter view, when the lungs are in the expiratory phase the accummulation of CO a in the air-cells excites the peripheries of the inspiratory fibres, thus giving rise to impulses which are carried to the inspiratory portion of the respiratory centre and excite inspi- ration ; whereas the stretching of the lungs during inspiration is held to excite the peripheries of the expiratory fibres, generating impuses which are conveyed to the expiratory portion of the expiratory centre, causing expiration. There is, however, no sufficient evidence to lead us to believe that the presence of ( '( )., in normal percentages influences in any way either set of fibres. On the contrary, the mechanical effects of the movements of the lungs are of great importance, as is apparent from the fact that inflation excites active expi- ration, whereas aspiration or collapse excites inspiration; moreover, if the movements of one lung be prevented by occlusion of the bronchi or by free opening of the pleural sac, the effects are the same as though the vagus of the same side were cut ; if now the other nerve be severed, the results are the same as when both nerves are cut. The movements of the lungs therefore generate alternate inspiratory and expiratory impulses, collapse causing inspiratory impulses, and expansion causing expiratory impulses. The inspiratory impulses, however, not only excite inspiration, but concurrently limit the duration of expiration ; while the expiratory impulses excite expiration and concurrently limit inspiration. Excitation of the swperwr laryngeal nervt causes expiratory stimulation, and there may occur respiratory arrest in the expiratory phase. These fibres are extremely sensitive; and they are of considerable physiological import- ance, as is illustrated by the fact that the entrance of foreign bodies into the larynx during deglutition causes an immediate arrest of inspiration, and even a forced, spasmodic expiration. The foreign particles, coming in contact with tin; keenly sensitive fibre- of these nerves, generate impulses which arrest inspiration, thus being prevented from being carried to the lungs. 'flic fibres of the glosso-pharyngeal nerves act similarly. Their excitation is followed by an arrest of respiration which last- for a period equal to that occupied by about three of the preceding respiratory acts. The value of such an inhibitory influence is obvious: During swallowing breathing is arrested, evidently for the purpose of preventing the aspiration of food and drink into the larynx. This act is purely reflex, and is due to the excitation of fibres of these nerves by the fluid or the bolus of food after the act of deglutition has begun. Such impulses flow to the respiratory centre, immediately arresting the inspiratory discharge' in whatever phase the inspiratory movement may BESPIRA TION. 463 happen to be. When swallowing has been accomplished the inhibitory influ- ence is removed and respiration is resumed. The inhalation of irritating gases may cause respiratory arrest by exciting either the sensory fibres of the trigeminal nerves in the nose or the pneumo- gastric fibres in the larynx and lungs. Some gases affect the former, some the latter, others both. In the rabbit, for example, the introduction of tobacco- smoke into the lungs through a tracheal opening produces no effect upon the respirations, but if injected into the nose respiration is at once arrested. When ammonia is similarly introduced into the lungs the respirations may be either accelerated or diminished, and may be arrested in the inspiratory or the expi- ratory phase, but when drawn into the nose expiratory arrest follows. Some irritating gases arrest respiration in the inspiratory phase, others in the expi- ratory phase. Odorous gases which are powerful and disagreeable may simi- larly cause arrest by acting upon the olfactory nerves. Excitation of the splanchnic nerves causes expiratory arrest; stimulation of the sciatic and sen- sory nerves in general usually increases the number of respirations, yet under certain circumstances it may cause a decrease and final arrest during expi- ration. Stimulation of the cutaneous nerves, as by a cold douche, slapping, etc., causes primarily a tendency to an increase in the number and depth of the res- pirations, but finally causes cessation in the expiratory phase. It is stated that excitation of these nerves is more effective in causing respiratory movements than irritation of the vagi. The influence of external heat is very powerful, and is perhaps the most potent means, under ordinary circumstances, of exciting the respiratory centre. The respiratory movements caused by cutaneous irrita- tion, are, however, of the character of reflex spasms rather than of normal movements, and when the excitation is sufficiently strong the movements may be distinctly convulsive. Finally, afferent (intercentral) fibres connect the brain-cortex, and probably the ganglia at the base of the brain, with the respiratory centres. The Efferent Respiratory Nerves. — During ordinary respiration the only efferent or motor nerves necessarily involved are the phrenics, and certain other of the spinal nerves, and the pneumogastrics. Section of one phrenic nerve causes paralysis of the corresponding side of the diaphragm; section of both phrenics is followed by paralysis of the entire diaphragm. So important are these nerves in respiration that in most cases after section death occurs from asphyxia within several hours. In such cases not only is the work <>f inspiration thrown upon the other inspiratory muscles, but the effectiveness of the latter is greatly compromised by the relaxed condition of the diaphragm, which permits of its being drawn into the thoracic cavity with each inspiration, thus hindering the expansion of the lungs. If section be made of the spinal < •« »r< 1 just below the exit of the fifth cervical nerve, costal movements cease, l>ut diaphragmatic con- tractions continue. The level of the section is just below the origin of the roots of the phrenics, so thai the motor fibres for the diaphragm arc left intact, but the motor impulses which would have gone out to other inspiratory muscles 464 AN AMERICAN TEXT-HOOK OF PHYSIOLOGY. through the spinal nerves below the point of section are cut off. If the cord be cul jusl below the medulla oblongata or above the origin of the phrenics, both costal and diaphragmatic movements immediately or very soon cease, but respiratory movements may continue in the larynx, and when dyspnoea occurs tiny may be observed in the muscles of the face, neck, and month. In rare cases, after section at the junction of the medulla oblongata and the spinal cord, respiratory movements may continue in the thorax and the abdomen, but these instances are exceptional and the movements are of the nature of reflex spasms. During each respiratory act there flow to the larynx impulses which open the glottis during inspiration. 'Fhe pathway of these impulses is through the laryngeal branches of the vagi, almost solely through the recurrent or inferior laryngeal nerves. (See section on the Physiology of the Voice.) If the pneu- mogastrics are cut above the origin of these branches, respiratory movements in the larynx cease, and, owing to the paralysis of the laryngeal muscles, the vocal cords are flaccid, the glottis is no longer widened, and thus great resist- ance is offered to the inflow of air, causing difficulty during inspiration. During forced breathing, besides the above nerves a number of others may be involved, especially the spinal nerves, which supply the extraordinary respi- ratory muscles of the chest, abdomen, pelvis, and vertebral column, and the facial, hypoglossal, and spinal accessory nerves. L. The Condition of the Respiratory Centre in the Fetus. During intra-nterine life the child receives O from and gives C0 2 to the blood of the mother. No attempt is made by the child to breathe, because the centre is in an apnoeic condition, due to a low condition of irritability and to the relatively large amount of () in the blood. The fetal blood contains a larger percentage of haemoglobin than the blood of the mother; Quinquaud has shown that the fetal blood has a larger respiratory capacity than adult's blood ; and Regnard and Dubois have proven the same to be true of the calf and the cow. Were it not for these two conditions, the child would continu- ally attempt to breathe. While such efforts do not occur under normal cir- cumstances, they may be present if we interfere in any way with the supply of oxygen, as by pressure upon the umbilical vessels. The child has been seen to make respiratory efforts while within the intact fetal membranes. It seems evident, therefore, that all that is necessary to excite the respiratory centre to •activity is a venous condition of the blood. /;/ utero, and as long as the child is bathed in the amniotic fluid, respiratory movements cannot be carried on even though the respiratory centre be excited to activity, the reason being that with the first movement of inspiration amniotic fluid is drawn into the nasal chamber; the fluid acts as a powerful excitant to the sensory fibres of the mucous membrane, thus causing inhibitory respiratory impulses. From this tact we learn the practical application that it is desirable immediately after birth of a child, if spontaneous respirations do not immediately and effectively occur, t<> carefully remove mucus or other matter from the nose, so that the inhibitory influences generated by nasal irritation shall be discontinued. RESPIRATION. 465 When the exchange of O and C0 2 is interfered with for a long period, as in cases of prolonged labor, the respiratory centre may become so depressed that spontaneous respirations do not occur upon the birth of the child. In such a case respirations may usually be initiated by irritation of the skin, as by slapping, sprinkling with iced water, etc. Respirations may also be carried on successfully by artificial means (see p. 446). In utero the lungs are devoid of air; the sides of the alveoli and of the small air-passages are in apposition, although the lungs completely fill the compressed thoracic cavity. During the first inspiration comparatively little air is taken into the lungs, because of the force necessary to overcome the adhesion of the sides of the alveoli and of the smaller air-tubes, but as one inspiration follows another inflation increases more and more until full disten- tion is accomplished. The vigorous crying which so generally occurs immedi- ately after birth doubtless is of value in facilitating this expansion. If once the lungs have been filled with air, they are never completely emptied of it, either by volitional effort or by collapse after excision. M. The Innervation of the Lungs. The nerves of the lungs are derived from the pnewmogastrics, the sympa- thetica, and the upper dorsal nerves. Scattered along the paths of distribution of these fibres are many small ganglia. The Pneumogastric Nerves. — The pulmonary branches of the pneumogas- tric nerves contain not only fibres which convey impulses that affect the gen- eral characters of the respiratory movements, but other fibres that are of great importance to the respiratory mechanism. Setting aside the effects on the respiratory movements following section and stimulation of one or of both vagi, there are observed phenomena which are of an entirely different character, and which are due to excitation or paralysis of certain other specific nerve- fibres. Among these fibres are efferent and afferent hroncho-conxtrictors and broncho-dilators. Roy and Brown 1 found in investigations upon dogs that stimulation of one vagus caused constriction of the bronchi in both Lungs; section of one vagus was followed by expansion of the bronchi in the corre- sponding lung, which expansion was sometimes preceded by a slight contraction owing to the temporary irritation caused by the section; stimulation of the peripheral end of the cut nerve caused a contraction of the bronchi in both lungs; stimulation of the central end of the cut nerve was followed by a con- traction of the bronchi in both lungs, lint not so marked as when the peripheral end was stimulated ; stimulation of sensory nerves other than the vagus rarely, and then only to a slight extent, caused contraction ; atropine paralyzed the constrictor fibres ; nicotine in small doses had a powerful expansive effeci on the bronchi; after etherization stimulation of either the central or the periph- eral end of the cut pneumogastric nerve was often followed by broncho-dilata- 1 Journal of Physiology, vol. 6, 1885 (Proceedings of the Physiological Society, iii. p. xxi.i; Einthoven, Pftiiger's Archiv fur Physiologie, 1892, Bd. 51, 8. 367 ; Sandeman, DuBois-ReymoncT s Archivfur Physiologie, 1890, S. 252. Vol. I 30 466 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. timi ; asphyxia causes broncho-constriction, but not alter section of the pneu- mogastric oerves; after section of both vagi it is impossible to cause reflex broncho-constriction or broncho-dilatation; the constriction of the bronchi may be so great as to reduce their calibres to one-half or one-third, or even more. Theabove results are very instructive, and show — (1) That broncho- constriction or broncho-dilatation can be obtained by stimulating the peripheral end of the vagus, and that these changes occur in the bronchi of both lungs when only one nerve is excited, tints proving that each nerve supplies both kinds of fibres to both Lungs; (2) that the same results can be obtained by ex- citation of the central end of the cut nerve, thus showing that the pneumogas- trics contain both afferent constrictor and afferent dilator fibres ; (3) that reflex broncho-constriction and broncho-dilatation cannot be produced after section of the vagi, thus proving that all of the efferenl fibres pass through the pneu- mogastrics; (4) that asphyxia and the inhalation of CO, cause broncho-con- striction, but not after section of the vagi, thus indicating that under these circumstances the effect- on the bronchi are reflex; (5) that certain poisons affect one or the other of these two sets of* fibre-. The presence of efimit r res pass from the spinal cord in the anterior root- of the second to tin- seventh dorsal nerve, inclusive, to join the sympathetics, thence through the first thoracic ganglia to the lung-. The Ganglia. — Nothing i- known of the functions of the ganglia. 1 .fniirnnl i,f I'hii.-iohnfii. I S'.t |, vol. ]f>, p. 70. VIII. ANIMAL HEAT. A. Bodily Temperature. Homothermous and Poikilothermous Animals. — Animal organisms are divided as regards bodily temperature into two classes, homothermous and poikilothermous. The temperature of homothermous (warm-blooded) animals is constant within narrow limits and is not materially affected by alterations of the temperature of the medium in which the organism lives. The tempera- ture of poikilothermous (cold-blooded) animals normally ranges from a frac- tion of a degree to several degrees above that of the surrounding medium, and under ordinary circumstances rises and falls with corresponding changes of sur- rounding temperature. The old terms warm-blooded and cold-blooded imply that the difference between the two classes is one of absolute temperature, the former having a temperature higher than the latter, and although this is gener- ally the case it is not necessarily so. For instance, Landois has recorded thai a frog (cold-blooded) in water at a temperature of 20.6° C. had a temperature of about 20.7° C, and that when the water was at 41° C. his temperature rose to about 38° C, which is higher than the mean temperature of man (warm- blooded). The temperature of cold-blooded animals may, therefore, be higher than that of warm-blooded animals. The difference therefore is relative and not absolute, the chief distinguishing feature being that the temperature of homothermous animals is practically constant, while that of poikilothermous animals fluctuates with the temperature of the medium in which (lie organism exists. The class of homothermous animals includes mammals and birds ; and that of poikilothermous animals, fish, reptiles, amphibia, and invertebrates. Temperatures of Different Species of Animals. — The temperature of every animal varies in different parts of the organism, so that in making com- parisons it is necessary that the observations be made in the same region of the body of the different individuals, and as far as possible under the same internal and external conditions. As a rule, rectal temperatures are preferable, and in making them it is especially desirable, in order to ensure practical accuracy, that the bulb of the thermometer be inserted well into the pelvis, and that it does not rest within a mass of Cecal matter. The depth to which the bull) is inserted is also of importance, as shown by Kinkier, who (bund in experiments on a guinea-pig that the temperature was 36.1° C. :it a depth of 2.5 centimeters, 38.7° C. at 6 centimeters, and 38.9° C. at 9 centimeters. The following records of mean bodily temperature of various species have been derived from various sources, chiefly from the compilations of (iavarret : 407 168 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Mammals. Birds. Reptiles and Fish. 1 Centigrade. Centigrade. | Centigrade. Mouse 41.1° Minis .... 11.03° Frog 0.32-2.44° Sheep 37.3-40.5° Duck 42.50-43.90° Snakes 2.5-12.0° \pe 35.5-39.7° Goose 41.7° Rabbit 39.6-40.0° Gull 37.8° Guinea-pig. . . .38.4-39.0° Guinea 43.90° Dog 37.4-39.6° \ Turkey 42.70° Cat 38.3-38.9° Sparrow .... 39.08-42.10° Chicken .... 43.0° Crow 41.17° Horse 36.8-37.5° Rat 38.8° Ox 37.5° Ass 36.95 c Fish 0.5-3.0° Invertebrates. 1 Crustacea 0.6° (Vphalopods - . .0.57° Medusae 0.27° Polyps 0.21° Molluscs 0.46° The Temperature of the Different Regions of the Body. — The quanti- ties of heat produced and dissipated by different parts of the economy vary, consequently there must continually be a transmission of heat from the warmer to the cooler parts to establish throughout the organism an equilibrium of tem- perature. Heat is distributed by direct conduction from part to part, but prob- ably chiefly by the circulating blood and lymph. These means of distribution are, however, not sufficiently active to establish a uniform temperature. Thus we fiud that the internal parts of the body have a higher temperature than the external parts ; that some internal organs are considerably warmer than others ; that every organ is warmer when active than when at rest ; that the tempera- ture varies in different regions of the surface of the body, etc. The following figures by Kunkel 2 instance some of these differences, the temperature of the room being 20° C. : Centigrade. I Centigrade. Forehead 34.1 c -34.4° Sternum 34.4° Cheek under the zygoma .... 34.4° lVetorales 34.7° Tip of ear 28.8° Right iliac fossa 34.4° Back of hand 32.5°-33.2° Left iliac fossa 34.6° Hollow of the hand (closed) . . . 34.8°-35.1° Os sacrum 34.2° Hollow of the hand (open) .... 31.4°-34.8° Forearm 33.7° Forearm (higher) 34.3° Eleventh rib (back) 34.5° Tuberosity of ischium 32.0° Upper part of thigh 34.2° ( all 33.6° The temperature of the skin is higher over an artery than at some distance from it ; it is higher over muscle than over sinew ; it is higher over an organ in activity than when at resl ; it i- higher in the frontal than in the parietal region of the head, and on the left side of the head than on the right, etc. Temperature observations arc usually made in the rectum, in the mouth under the tongue, in the axilla, and in the vagina, the rectum being preferable, although in the human being the temperature is usually obtained in the mouth and axilla. In the same individual when records are taken simultaneously in all four regions appreciable differences will be noted. The temperature in the axilla is, according to Hunter 37.2° C, to Davy 37.3° C.,to Wunderlich 36.5° to 37.25° C. (mean 37.1° ('.). to Liebermeister 36.89° C, to Jurgensen 37.2° C, 1 Temperatures above that of the surrounding medium. 2 Zeitsi-hrift fur Biologic, L889, Bd. 25, S. o9-73. ANIMAL HEAT. 469 and to Jaeger 37.3° C. The mean axillary temperature may be put down as being about 37.1° C. (98.8° F.), the normal limits being 36.25° to 37.5° C. (97.2° to 99.5° F.) The temperature in the mouth is about 0.2° to 0.5° C. higher than in the axilla, in the rectum from 0.3° to 1.5° C. higher, and in the vagina from 0.5° to 1.8° C. higher. 1 The temperature of different tissues varies. Davy, as results of observa- tions on a fresh-killed sheep, gives the temperature of the brain as about 40° C.j of the left ventricle 41.67° C. ; of the right ventricle 41.11° C.; of the liver 41.39° C. ; of the rectum 40.56° C. According to Bernard, the liver is the warmest organ in the body, and then the following in the order named — brain, glands, muscles, and lungs. The temperature of the blood varies considerably in different vessels. In the carotid it is from 0.5° to 2° C. higher than in the jugular vein; in the crural artery, from 0.75° to 1° C. higher than in the corresponding vein ; in the right side of the heart about 0.2° C. higher than in the left; in the hepatic vein 0.6° C. higher than in the portal vein during the intervals of digestion, and as much as 1.5° to 2° C. or more during periods of digestion ; the venous blood coming from internal organs is warmer than the arterial blood going to them, but the blood coming from the skin is cooler than that going to it ; the blood coming from a muscle in a state of rest is about 0.2° C, and during activity as much as 0.6° to 0.7° C, warmer than that supplied to the muscle. The mean temperature of the blood as a whole is about 39° C. (102° F.); of venous blood about 1° C. (1.8° F.) lower than of arterial blood. The warm- est blood in the body is that coming from the liver during the period of diges- tion; the coolest blood is that coming from the tips of the ears and nose and similarly exposed parts. Conditions affecting- Bodily Temperature. — The mean temperature of the body is subjected to variations which depend chiefly upon age, sex, consti- tution, the time of day, diet, activity, season and climate (surrounding tem- perature), the blood-supply, disease, drugs, the nervous system, etc. The temperature of a new-born child (37.86° C.) is from 0.1° to 0.3° C. higher than that of the vagina of the mother; it falls about 1° < '. during the first few hours after birth, and then ii>cs within the next twenty-four hours to about 37.4° to 37.5° C The mean temperature of an infant a day or two old is about 37.4° C. It very slowly sinks until full growth is attained, when the normal mean temperature of adult life is reached (37.1° C), a standard which is maintained until about the age of forty-five or fifty, when it declines until about the age of seventy (36.8° C), and then slowly rises and approaches in very old people (eighty to ninety years) the temperature of very young infants (37.4° C). It is important to observe that during the early weeks "I life the temperature may undergo considerable variation-, and thai it is readily affected by bathing, exposure, crying, pain, sleep, etc, and by many circum- 1 The average figures of the mean daily temperatures obtained from tin- records of ;i num ber of investigators are, mouth, o<5.S7° ; axilla, 3d. 94° ; ami rectum, 37.02°. The mean figures for the twenty-four hours are in each rase about 0.2° less. 470 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. stances which have little or absolutely no influence upon the temperature of the adult. The mean temperature of the female is said to be slightly lower than that of the male In observations on children Sommer noted a difference of 0.05° ('.. and Fehlinga difference of 0.33° C. Individuals with vigorous constitutions have a somewhat higher temper- ature than those who are weak. Records obtained by various European investigators indicate that the bodily temperature is subjected to regular diurnal variations. The limits of variation in health are from 1° to 2° C. The maximum temperature observed is usu- ally from 5 to 8 p. If. (mean, about 7 p. m.) ; the minimum, from 2 to 6 a. m. (mean, about 4 a. M.J. Carter's 1 experiments on rabbits, cats, and dogs show that rhythmical temperature-changes occur in these animals which agree with those noted by Jurgensen in man. This same rhythm is stated to occur during fasting, so that the ingestion and the digestion of food cannot he claimed to account for it; moreover, it is present in fever and not disturbed by muscular activity and by cold baths. If an individual works at night and sleeps during the day, thus reversing the prevailing custom, the temperature curve is more or less modified, but, according to Mosso, 2 not reversed as stated by Krieger. 3 Chclmonski found, however, in old persons that the temperature variations are not uncommonly inverted, being higher in the morning and lower in the evening. Insufficient diet causes a lowering of the temperature; a liberal diet tends to cause a rise slightly above the normal mean, especially during forced feeding or when the food is particularly rich in fats and carbohydrates. There is a rise during digestion which is usually slight, but it may reach 0.2° or 0.3°, the increase being due chiefly to the activity of the intestinal muscles (see p. 431). Although considerably more heat is produced during the periods of digestion than during the intervals, the excess is dissipated almost as rapidly as it is formed, so that but little heat is permitted to accumulate and thus cause a rise of temperature. Hot drinks and solids tend to augment, and cold drinks and solids to lower bodily temperature. In the nursing child I temme found that the n.tal temperature sinks during the first half-hour after taking food, then rises during the next Bixty to ninety minutes to a point from 0.2° to 0.8° C. higher than the temperature before feeding, and falls again during the next thirty to sixty minute-. All condition- which increase metabolic activity are favorable to an increase of temperature. Thus, during the activity of the brain, glands, muscles, etc., more heat is produced than when the tissues are at rest; indeed, so abundant is heat-production during severe muscular exercise that the temperature of the body may rise a- much as <>..~,° to 1.5° C. (l°to 2.7° F.). During sleep the temperature falls from <)..'5° to 0.9° C. or more in young children. : Journal of Nervous and Mental Diseases, 1890, vol. xvii. p. 782. - Archives it„ m < ,U biologic, L887, t. viii. p. 177. 3 Zeilsckriftfilr Biologic, 1869, Bd. \. S. 479. 'ANIMAL HEAT. 471 During the summer the mean bodily temperature is from 0.1° to 0.3° C. higher than during the winter. In warm climates it is about 0.5° C. higher than in eold climates, but the difference is not due to race, since it is observed in individuals who have changed their habitations from one climate to another. Continued exposure to excessively high or low temperatures is inimical to Jife. Exposure in dry air at a temperature of 100° to 130° C. may cause the bodily temperature to increase as much as 1° to 2° C. within a few minutes, and the temperature may rise so rapidly as to cause fatal symptoms within ten or fifteen minutes. A hot moist air is far more oppressive and dangerous than hot dry air. Baths exercise a potent influence on bodily temperature, hot baths increasing and cold baths decreasing it. The effect of a cold bath is less if it follows a hot bath. Thus Dill ' found that his morning temperature varied from 33.7° to 36.6° C, after a hot bath (40°-41° C.) it rose, in one instance, as high as 39.5° C, and after a cold bath it remained at 37° C. When, however, the hot bath was omitted the cold bath reduced the temperature to 35.4° C. Bal- jakowski 2 has recorded some very interesting results which show that the local application of heat causes the bodily temperature to sink and the cutaneous temperature of the part experimented upon to rise. The experiments were conducted on young men, whose arms and legs were encased in hot sand at a temperature of 55° C. When the arm was used the axillary temperature sunk an average of 0.13° C. during the bath and subsequently 0.24° C, the corre- sponding records of average rectal temperature being 0.23° and 0.31° C. In case of the leg bath the corresponding records were axillary 0.06° and 0.32° C. ; and rectal 0.21° and 0.25° C. The cutaneous temperature of the limb experimented upon increased materially, the average rise varying from 0.73° to 1.20° C, according to the part of the limb. Long-continued severe exter- nal cold may prove fatal, but this is not necessarily due to the effect on bodily temperature, for Milne- Edwards 3 has shown that rabbits die within five or >ix days when exposed to a temperature of —10° to -15° C, without the bodily temperature falling more than 1° C. There is a general relationship between the frequency of the heart's beat and the bodily temperature, especially in fever. Barensprung noted such a coinci- dence between the diurnal variations of the pulse and bodily temperature; and, in fever, Aiken found that for each increase of 0.55° C. (1° F.) above the mean normal temperature the pulse-rate was increased about ten beats per minute. But the variations in the two do not always correspond either quantitively or qualitatively. Liebermeister found in man that for a rise of each degree from 37° to 42° C. the increase in the pulse-rate was 12.6, 8.6, 8.7, 11.5, and 27.5 beats per minute respectively. Beljakowski's 4 experiments show that the bodily temperature may fall and the pulse-rate rise — in one set of experiments the rectal temperature falling on an average 0.23° C. and the pulse increasing 1 British Mrihral J.nrnal, lN'.HI, vol. i. ]). 1136. 2 Vratch, 1889, p. 436; PtovmcM Medical Journal, 1890, i>. 113. 3 Comptes rendus de la Soc. dc Bioloi/ie, 1891, t. 1 12, pp. 201- 205. * Lor. rit. 472 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. on an average 6.85 beats per minute. After the local hot bath the temperature remained subnormal, and the heart-beats became less frequent, and finally were mi an average from 2.7 to 3.1 beats per minute less than the normal rate. More important, however, than the pulse-rate is the effect of the amount of blood supplied to any given part of the body. The mere lowering or rais- ing of the arm is sufficient to alter the blood-supply to the part; thus Romer found that keeping the arm elevated for five minutes was sufficient to reduce the temperature of the hand 0.19° C, and that if the period was doubled the fall amounted to 0.38° C. Compression of the veins of the arm may diminish the temperature of the hand as much as 0.25° to 2.45° C, while compression of the brachial artery may cause a fall of 2.4° within fifteen minutes. A larger supply of blood to the cutaneous surface increases cutaneous temperature and tends to decrease internal temperature, while a lessened supply causes the opposite effect-. In abnormal conditions the temperature may be increased or decreased : in cholera, diabetes, and in the last stages of insanity, it may be lowered 6° or 8° C. or even more. In fever it is increased, usually ranging between 37.5° and 41.5° C. (99.4° and 106.7° F.), but in very rare cases it may reach 44° to 45° C. (111° to 113° F.) just before death. A temperature of 42.5° C. (108.5° F.) maintained for several hours is almost inevitably fatal. In frogs, the highest temperature consistent with life for any length of time is below 40° C. ; in birds, from 48° to 50° C, and in dogs, from 43° to 45° C. Ex- ceptional cases are on record of people having survived extraordinarily high or low bodily temperature, Richet having reported one in which the tempera- ture several times was 46° C. (114.8° F.), while Teale records an axillary tem- perature of 50° C. (122° F.) in an hysterical (?) woman. Frantzel noted a temperature of 24.6° C. (76.2° F.) in a drunken man, and Kosiirew a temper- ture of 26.5° C. (79.7° F.) in a man having a fractured skull. Bodily temperature may be variously influenced by drugs and other sub- stances, micro-organisms, etc. Some increase it, others decrease it, others are without any marked influence, while others exert primary and secondary actions. Among those which increase bodily temperature are cocain, atropin, strychnin, brucin, caffein, veratrin, etc., and, as shown by Krehl 1 and others, a large number of other organic substances and micro-organisms. Temperature is decreased by anaesthetics, morphin and other hypnotics, quinin, various antipyretics, large doses of alcohol, etc. A.mong the most important of the conditions which affect bodily tempera- ture are disturbances of the nervous system. Injury or irritation of almost any part of the nerve-centres and of certain nerves may give rise directly or indirectly to alterations of temperature, and there are some parts which are very sensitive in this respeet, especially certain areas of the brain cortex, the striated bodies, the pons Varolii, the spinal bulb, and the cutaneous nerves. The results of injury or stimulation of these as well as of other parts will be considered later on (p. 193). 1 Archir fur experimentelle Pathologie und Pharmakologi&, 1895, Bd. 35, S. 222-268. ANIMAL HEAT. 473 Temperature-regulation. — The fact that during life the organism is con- tinually producing and losing heat, and that the bodily temperature of homo- thermous animal is maintained at an almost uniform standard, notwithstanding considerable mutations of surrounding temperature, renders it evident that there exists an important mechanism whereby the regulation of the relations between heat-production and heat-dissipation is effected. It must be evident that when the variations in heat-production and heat-dissipation balance, bodily temperature must remain unaltered, and that if the changes in one exceed those in the other the temperature rises or falls, depending upon whether more or less heat is produced than is dissipated. It does not follow that because heat-production is increased the bodily temperature must similarly be affected, since heat-dissipation may be increased to the same extent and thus effect a compensation. Therefore an alteration in heat-production or in heat-dissipation by no means implies that the temperature must be affected. Moreover, when the temperature is increased or diminished the change may be caused by various alterations in the quantities of heat produced or lost, singly or com- bined, and the temperature may remain constant even when both processes are materially affected. Thus, the temperature remains constant when both heat- production and heat-dissipation are normal, and when both are increased or decreased to the same extent. The temperature is increased when heat-pro- duction is normal and heat-dissipation diminished ; when both heat-production and heat-dissipation are diminished, but when heat-production is diminished to a less extent than heat-dissipation ; when heat-production is increased and heat-dissipation remains normal; when both heat-production and heat-dissipa- tion are increased, but when heat-production is increased to a greater extent than heat-dissipation ; and when heat-production is increased and heat-dissipa- tion is diminished. The temperature is diminished when heat-production is normal and heat-dissipation is increased ; when heat-production is diminished and heat-dissipation remains normal; when heat-production and heat-dissipa- tion are diminished, but when heat-production is diminished to a greater extent than heat-dissipation ; when heat-production is diminished and heat-dissipa- tion is increased ; and when both heat-dissipation and heat-production are increased, but when heat-production is increased to a less extent than heat- dissipation. It is generally regarded by clinicians that bodily temperature varies directly with heat-production — that is, that a rise means increased production, and a fall diminished production ; but the fallaciousness of such a conclusion must be apparent. It may, however, be accepted as a fact that in fever, as a rule, an increase of bodily temperature is a concomitant of increased heat-produc- tion, and diminished temperature of diminished heat-production; bftl it must also be observed that pyrexia, although generally due to increased heat- production, may also be due partly or wholly to diminished heat-dissipation. It is obvious, therefore, that temperature variations simply show that the balance between heat-production and heat-dissipation is disturbed, without positively indicating how the processes of heat-production and heat-dissipation are affected. 474 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. The mechanism concerned in the adjustment of the relations between heat- production and heat-dissipation will be considered under another heading (p. 495). B. Income and Expenditure of Heat. Broadly speaking, the source of animal heat is in the potential energy of organic food-stuffs — so little relatively being obtained from the heat of warm food and drink and directly from external sources, such as the sun's rays, that these sources may be disregarded. The researches of Rubner 1 have clearly shown that chemical changes in the body constitute the source of animal heat. He made estimations of the amount of heat that should be formed in the body as indicated by the ex- change of ingesta and egesta, and also determined by direct calorimetry (see below) the heat production in dogs under conditions of fasting and varying diet. The results in the two cases are strikingly close, as will be observed from the following table: ,- re r, Quantity of heat ^ Vhv^ Per cent, dlf- Condition of dog. ^ calculated. Staeter. ference. Fasting 1193.7 calories 1180.1 calories —1.42 Diet of Fat 1510.1 " 1495.3 " -0.97 " Meat and Fat 3238.9 " 3223.2 " - 0.42 « Meat 3515.3 " 3523.1 " +0.43 These figures, which are in so close accord, are substantiated in their correct- aess and import by the results obtained by Laulanie 2 in studies on guinea- pigs, rabbits, ducks, and dogs. This potential energy of food may be converted into heat directly or indi- rectly: directly, as an immediate result of chemical decomposition; and in- directly, by mechanical movements, such as muscular contraction, the flow of the blood, the friction of the joints, etc. About 90 percent, of the heat of the organism results directly from chemical decompositions, and about 10 per cent, results indirectly from mechanical movements. The potential energy of the food is transformed into kinetic energy (heat and work) essen- tially by processes of oxidation. The energy-yielding food-stuffs enter the body in the form of proteids, fats, and carbohydrates, due proteid is broken up into urea, C0 2J I L<>, and various extractives; and the fats and carbo- hydrates into C0 2 and IIJ). During these oxidative processes, by which the potential energy of the molecules is transformed into kinetic energy, the total amount of energy evolved by the complete oxidation of a given amount of any substance is the same whether the processes are carried at once to the final stages, that is, to the final disintegration products, or whether they pass through an Indefinite number of intermediate stages, provided that the final product or products are the same. In other words, the amount of heat evolved by the oxidation of 1 gram of proteid into urea, C0 2 , and II.O is the same when the molecule is oxidized immediately into these substances as when tin' decomposition is carried through a number of intermediate stages. 1 Zeilschrift J. Biologic, 1893, Bd. xxx. S. 73. * Archives 77s 693,3ti0 Fats 90 x 9312 837,080 Carbohydrates 330 x 411G 1, 358,28 2,888,720 Dedmt the proteid energy in 40 grams of urea, 40x2523= 100,92 Total daily heat-production 2,787,800 This is assuming that the entire quantity of proteids, fats, and carbohydrates is digested, absorbed and ultimately broken down into 0O 2 , H 2 0, and urea. This assumption, however, is not justified by facts, since we know, for instance, that more or less food escapes digestion. Moreover, the calorimetrical values, at hast for proteids, are probably too high. In practice, therefore, it is nec- essary to ascertain from the excreta of the animal (see section on Nutrition) just how much of the ingested food has been absorbed and completely or partially destroyed in the body. Calorimetric investigations also afford us indirect information as to the income of heat by showing the quantities of heat produced and dissipated. Such data are of much value, since it is evident that should the energy of the body be maintained in a condition of equilibrium from day to day, and should the energy resulting from the transformation of potential energy be manifested solely in the form of heat, it follows that the mean daily heat-production and income of available energy must balance. But it cannot be considered that this balance is maintained at a constant standard from hour to hour, nor from day to day; on the contrary, the fluctuations are undoubtedly considerable, as is obvious by the fact that we are continually expending energy and only periodi- cally (at meal-time-) acquiring energy. During fasting there is absolutely no income of energy, yet the output of heat may be subnormal, normal, or hyper- normal ; on the other hand, if an exec— of energy be ingested, as in excessive eating, it is not by any means implied that there is a similar excess in heat-pro- duetion, because >oine of the food ingested may be lost as undigested food or as partially oxidized excrementitious matters, or may be stored in the body in the form of carbohydrate, fat, or proteid; nor does an excess of heat-production imply an excess of income of energy, because the stored-up energy may be drawn upon. ( For results of the calorimetric method see p. 482.) The results of the various methods are in close accord, and indicate that in the adult the total income of available energy i> about 2,500,000 calories. Expenditure of Heat. — Assuming that the energy of the organism is expended in the form of heat, and that the total income of available energy is 2,500,000 calories, it has been estimated by Yierordt that about — A NI3IA L HE. IT. 177 1.8 per cent, is lost in the urine and feces 47,500 calories. 3.5 " " " expired air 84,500 7.2 " ■" " -evaporation of water from the lungs 182,120 " 14.5 " " " " " " skin. 364,120 73.0 " " " radiation and conduction from skiu 1, Till, 820 " 2,500,000 calories. Therefore, about 87.5 per cent, is lost by the skin, 10.7 per cent, by the lungs, and 1.8 per cent, in the urine and feces. O. Heat-production and Heat-dissipation. Calorimetry. — The intensity of heat of any substance is measured by means of a thermometer or thermopile ; the quantity of heat present is estimated by the weight, the specific heat, and the mean temperature of the body ; the quan- tity of heat dissipated is measured by the calorimeter ; and the quantity of heat produced is determined by the quantity dissipated plus any addition of heat to that of the body or minus any that is lost (p. 481). The calorie, or heat unit, is the quantity of heat that is necessary to raise the temperature of one gram of water 1° C. ; the mechanical unit, or grammeter, is the quantity of energy required to raise one gram a height of one meter, 424.5 grammeters being equal to 1 calorie; a kilocalorie or kilogramdegree is equal to 1000 calories, and a kilogram meter to 1000 grammeters. By specific heat is meant the quantity of heat required to raise the temperature of any substance 1° C, this quantity varying considerably for different substances. It" water be taken as 1, as a standard of comparison, the specific heat of the animal body may be regarded as being about 0.8 ; in other words, 0.8 of the quantity of heat will be required to heat the animal body as to heat the same weight of water. Knowing the weight, specific heat, and temperature of any substance the total quantity of heat stored in it at a given temperature, compared with the same body at 0° C. may be readily calculated. Thus, if the animal experimented upon weigh 20 kilos, its specific heat be 0.8, and its temperature be 39°, the total quantity of heat stored would be 20 X 0.8 X 39° = 62.4 kilo- gramdegrees. In calorimetric work the total heat in the organism is seldom considered, but the specific heat of the organism is of importance in determin- ing the quantity of heat involved in a change of the animal's temperature. For instance, should the animal weigh 20 kilograms and its temperature be increased or decreased 0.2°, the quantity of heat added to or taken from the heat of the body, as the case may be, would be 20X0.8X0.2=3.20 kilograradegrees. These calculations are of fundamental importance in studying heat-production and heat-dissipation. In making estimates of the dissipation of heat no regard is paid usually to the quantity lost in the urine and feces, because the error involved is so slight, but the quantities imparted to the air, both in wanning the inspired air and in evaporating water from the lungs and skin, represent important percentages. Calorimetry is spoken of as direct and indirect. The former method is the direct determination of the amount of heat produced and dissipated ; the 178 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. latter is the indirect determination based upon estimates of the quantities of O absorbed and CO a eliminated, or upon the amount of potential energy ingested in the food and probably transformed into kinetie energy within the body (p. 474). Calorimeters of various forms have been employed, some of which have been devised to study the body as a whole, while others are adapted only for studying parts, such as a leu or arm. They may be classified as ice, air, and wafer calorimeters in accordance with the chief medium employed to absorb the heat. They consisl essentially of an insulated jacket of ice, air, or water, which encloses the animal and serves to absorb the heat. The ice calorimeter is impracticable for physiological uses ; the air calorimeter until very recent years lias found but little acceptance, hut is deservedly fast gaining in popular- ity; the water calorimeter is the form of apparatus usually employed, having been first used by Crawford in 1788; it has been materially modified by Despretz and Dulong and subsequent investigators. The now classical instrument of Dulong consists of two concentric cases. The animal is placed within the smaller case, which is submerged in the water contained in the larger ease, this in turn being placed within a large box, between which and the calorime- ter some non-conducting material such as feathers or w r ool is packed. Suit- able openings are made for the proper supply of fresh air and for the agitation of the water in the calorimeter so that an equalization of the temperature of the instrument can be obtained. This apparatus has certain serious defects, however, which render it troublesome for expeditious and accurate work. An improved form devised by the author 1 which is now in general use meets every essential re(|nircment for a satisfactory instrument. The apparatus con- sists of two concentric boxes of sheet metal which are fastened together so that there is space of about oue and a half inches between them filled with water ( Fig. 80). The outer box is fifteen inches in height and width, and eighteen inches in length. An opening (A) nine inches in diameter is made in one end for the entrance and exit of the animal. It is also perforated with three small holes in the top corners, and a slit-like opening in the top on one side. Two of the holes are for the tube- for the entrance and exit of air (AW, EX), the entrance tube being carried close to the bottom, while the exit tube extends only to the top of the box, and is placed in the opposite diagonal corner, thus ensuring adequate ventilation. In the third hole a thermometer (C T) is inserted, by means of which the temperature of the calorimeter (jacket of metal and water) is obtained. The opening in the side is for the insertion of a stirrer (S), which is for the purpose of thoroughly mixing the water and thus equalizing tin' temperature of both water and metal — in other words, of the calorimeter. Before using the apparatus the cahHmetric equivalent must be determined, that is, the amouutof heat required to raise the temperature of the instrument 1°. This may be obtained indirectly by knowing the- different substances used in the construction of the instrument, their weights, and their specific heats, and estimating from these data. It is better, however, to make the determination 1 Reichert: University Medical Magazine, L890, vol. 2, p. 173. ANIMAL 111-: A '/'. 479 by burning a definite amount of absolute alcohol or hydrogen within the instru- ment, or by using a sealed vessel of hot water of a known temperature and allowing it to cool to a definite extent. The process is simple; for instance, each gram of alcohol or each liter of hydrogen completely oxidized yields a definite number of calories ; similarly, a definite weight of water cooled a Fig. 80.— Reichert's water calorimeter. definite number of degrees gives oft' a definite quantity of heat. The heat thus generated by the oxidation of the alcohol or hydrogen or given off by the cool- ing of the water is imparted to the calorimeter and increases its temperature. Knowing the quantity of heat given to the calorimeter and the increase of temperature of the instrument, the determination of the calorimetrical equiva- lent may be easily made. Thus, 1 gram of alcohol yields in round numbers 7000 calories; if we burn 10 grams of absolute alcohol, 70,000 calorics will result; if the temperature of the calorimeter be increased 1°, the calorimetric equivalent will be 70,000 calories or 70 kilogramdegrees ; in other word-, for each degree of increase of the temperature of the calorimeter a quantity of heat equivalent to 70 kilogramdegrees is absorbed. The heat dissipated by an animal is only in part absorbed by the calori- meter, another portion being given to the air which passes from the instrument, and another portion to water which is evaporated from the lungs and skin. Three estimates, therefore, arc necessary — (1) of the heat given to the calori- meter, (2) of the heat given to the air, and (3) of the heat given off in the evaporation of water. The estimate of the heat given to the air necessitates the measurement of the quantity of air supplied to the calorimeter, and of the temperature of the 480 AN AMERICAN TEXT-HOOK OF PHYSIOLOGY. air on entering and leaving the calorimeter; while the estimate of the heat lost in evaporating water involves the measurement of samples of the air entering and leaving the instrument and of the quantities of water in both eases, the total quantity of water evaporated from the animal being estimated from these data. The conduct of such experiments is not attended with any material dif- ficulties. The water of the calorimeter is stirred for a suffieient length of time in order to obtain a uniform temperature. The temperature of the animal is taken and the animal then placed within the animal chamber. The temperatures of the calorimeter and of the air entering and leaving the instru- ment, and readings of the three gas-meters are recorded. During the progress of the experiment air temperatures are recorded at regular intervals of ten or fifteen minutes and the water stirred for a few seconds each time. At the conclusion of the experiment there are recorded — the temperature of the calori- meter, the temperatures of the air entering and leaving the calorimeter, the quantities of air passing through the three gas-meters, and the temperature of the animal. The quantity of heat given to the calorimeter \> now determined by multi- plying the increase of temperature of the instrument by the calorimetric equivalent. If the rise of temperature be 0.6° C. and the calorimetric equiva- lent be 90 kilogramdegrees, the quantity of heat imparted to the water jacket will be 90 X 0.6° = 54 kilogramdegrees. The quantity of heat imparted to the air is determined by finding first the corrected volume of the air, then reducing the corrected volume to weight, then multiplying the weight by the specific heat of air at 0° C, and finally multiplying by the increase of temperature. The corrected volume may be V P obtained by the following formula: V= — , where V is 760 (1 + 0.003665 t) the required volume at 0° C. and 760 mm. barometric pressure, V the ob- served volume, P the observed pressure, and t the observed mean temperature: 760 (1 + 0.00366-0 is conveniently obtained from standard tables. The errors incident to changes in barometric pressure and in aqueous tension are so slight that they are not usually taken into consideration. Assuming that the quan- tity of air supplied amounted to 6000 liters, and that the mean temperature of the air was 20°, the corrected volume would be, omitting barometric V 6000 pre— nre and aqueous tension, V = — — = 5590 liters (1 + 0.0036656 t) 1,0733 at 0° C. One liter of dry air at 0° C. weighs 0.001293 kilogram ; therefore, 559* I liters x 0.001293 = 7.22s kilograms. 1 1' we assume that the air during its passage through the calorimeter had its temperature increased 3°, and the specific heat of air is O.L > :',77. the quantity of heat imparted to the air must have been 7.228 x 3 x 0.2377 = 5.152 kilogramdegrees. The next estimate is of the quantity of heat lost in the evaporation of water. This is determined by finding the difference between the quantities ANIMAL HEAT. 481 of water in the samples of the air passiug into and from the calorimeter, and estimating from these results the amount of moisture imparted to the total air leaving the chamber. Assuming that 10 grams of water were thus evaporated, since each gram requires about 582 calories or 0.582 kilogramdegree, the quan- tity of heat evolved would be equal to 10 X 0.582 = 5.82 kilogramdegrees. The total quantity of heat dissipated would therefore be the sum of the quantities given to the calorimeter, to the air, and to the water evaporated : Given to the calorimeter 54,001) kilogramdegrees. Given to the air 5,152 " Lost in evaporating water 5,820 Total heat-dissipation ti4/J72 " The quantify of heat produced is determined by adding to or subtracting from the quantity dissipated the amount of heat that may have been gained or lust by the organism. It is obvious that any difference between the quantities of heat dissipated and produced must be represented by an increase or decrease of the mean temperature of the animal. If the animal's tempera- ture remains unchanged, the quantity of heat produced is the same as the quantity lost; if, however, the animal's temperature increases, less heat is dissipated than is produced ; if it falls, vice versa. The quantity of heat involved in a change of body-temperature is determined by the product of the change in temperature into the animal's weight and specific heat. Assum- ing that the animal's temperature at the beginning of the experiment was 38.95° C. and at the end 39.32° C, the temperature being increased 0.37° C, that the animal's weight was 25 kilograms, and that the animal's specific heat was 0.8, the quantity of heat would be 0.37 X 25 X 0.8 = 7.4 kilogramdegrees. The quantity of heat produced would, therefore, be the total quantity dissipated plus the quantity of heat added to the heat of the organism at the time the experiment begun ; therefore, the heat-production was 64.972 -\- 7.4 = 72.372 kilogramdegrees. If the animal's temperature had fallen, more heat would have been dissipated than produced, because the total quantity of heal in the organism was greater at the beginning than at the end of the experiment ; therefore, the quantity of heat represented in the change of temperature would have been deducted from the quantity of heat dissipated. While calorimetric experiments do not generally involve any special diffi- culties, accurate results can only be ensured by the strict observation of certain details: (1) The temperatures of the calorimeter and room should be as nearly as possible alike and kept as far as possible constant. (2) The thermometers employed should be SO sensitive that readings can be made in hundredths of a degree, and they should respond very quickly, SO that rectal temperatures can be obtained within three minutes. (3) Rectal temperatures are to be preferred, the thermometer always being inserted to the same extent and held in the same position, care being exercised to prevent the burying of I he bulb in fecal matter. (4) The animal during the taking of its temperature must on no account be tied down, but gently held, and all circumstances seduously avoided Vol. r.— 31 182 i.v AMERICAN TEXT-BOOK OF PlfYSIOLOd V. that tend to excite the animal. Tin- chief sources of error in the calorime- try are in failures to obtain accurate temperatures of the calorimeter and of the animal. In the latterea.se inaccuracy is to some extent absolutely una- voidable, chiefly because of normal fluctuations which occur frequently and are often very marked. Conditions affecting- Heat -production. — The quantity of heat produced must necessarily vary with many circumstances. Estimates of heat-production in the adult range in round numbers from 2000 to 3000 kilogramdegrees per diem according to the method and incidental circumstances. Thus, according to— vScliarling 3169 kilogramdegrees Vogel 2400 " Him 3725 " Leyden 2160 " Hemholtz 2732 " Rosenthal 2446 " Danilesky 3210 « Ludwig 3192 " Ranke 2272 kilogramdegrees Kiibner 2843 " Ott 103 '• per hour during the afternoon (weight of man 87.3 kilograms). Lichatschew .... 33.072 to 38.723 kilo- gramdegrees per kilogram of body-weigh! per diem. 1 The chief conditions which affect heat-production are age, sex, constitution, body-weight and body surface, species, respiratory activity, the condition of the circulation, internal and external temperature, food, digestion, time of day, muscular activity, the activity of heat-dissipation, nervous influences, drugs, abnormal and pathological conditions. Young animals produce more heat, weight for weight, than the mature. This is owing chiefly to the greater activity of the metabolic processes in the former, and in part to the relatively larger body surface, young animals generally being smaller than the matured and thus having, in proportion to body-weight, larger radiating surfaces. Heat-production is more active in the robust than in the weak, other con- ditions being the same. The weight of the body is obviously a most important factor in relation to the quantity of heat produced, especially as regards the weight of the active tissues in relation to inactive structures such as bone, sinew, and cartilage. Two animals of the same weight may produce very different quantities of heat per diem, other things being equal. Thus, a fleshy animal should naturally be expected to produce more heat than one with very little flesh and an abundance of fat, which is an inactive heat-producing structure. While, therefore, the relation of heat-production to body-weight does not seem to be definite, yet the experiments by Reichert 2 and by Carter 3 indicate that heat- production bears, broadly speaking, a direct relation to body-weight. Heat-production is greater relatively in homothermous than in poikibther- 1 The figures by ott {New York Medical Journal, 1889, vol. 16, p. 29) and Lichatschew inauguralis, St. Petersburg, 1893; quoted in Hermann's Jahresberichte der Physioloyie, 3. 99) were obtained by means of a water calorimeter. 2 University Medical Magazine, 1890, vol. '_', p. 225. 3 Journal of Nervous and Mental Diseases, 1890, v>>\. 17, p. 782. ANIMAL HEAT. 483 mous animals; it varies materially in intensity in different species, especially in warm-blooded animals; and it is closely related to the intensity of respiration. Moreover, it is probable that each species, and even each individual of the species, has its own specific thermogenic coefficient, that is, a mean standard of heat-production for each kilogram of body-weight or for each square centime- ter of body-surface. The following figures giving the heat-production per kilogram per hour, compiled by Munk, 1 are of interest both as regards species and size and weight of the animal in relation to heat-production : Horse 1.3 kilogramdegrees. Man 1.5 " Child (7 kilograms) . . 3.2 " Dog (30 " ) . . 1.7 " Dog (3 " ) . . 3.8 " Guinea-pig 7.5 " Duck 6.0 kilogramdegrees. Pigeon 10.1 " Rat 11.3 " Mouse 19.0 " Sparrow 35.5 " Greenfinch 35.7 " These figures have an additional interest when compared with the respira- tory activity of different species (p. 429). The intensity of respiration has a marked significance both in connection with the species and the individual. The larger the quantity of oxygen consumed the greater relatively is the activity of oxidation processes, and, consequently, the more active is heat-pro- duction (see p. 429). Therefore, all circumstances which affect respiratory activity tend to affect thermogenesis. The intensity of respiratory activity and the extent of body-surface in relation to body-weight are closelv related (p. 430). Increased activity of the circulation is favorable to increased heat-produc- tion, this being due to several factors: (1) A more abundant supply of blood may be accompanied by increased metabolic activity. (2) Increased circulatory activity is favorable to increased heat-dissipation by causing a larger supply of blood to the skin, thus facilitating loss by radiation and indirectly tending to increase thermogenesis. (3) Increased circulatory activity also excites the respi- ratory movements and the secretion of sweat, thus increasing heat-loss and in- directly favoring heat-production. (4) The more active the circulation the larger the amount of heat produced by the heart and the movement of the blood. The diurnal fluctuations of the pulse-rate are said to be more or less closely related to similar changes of body temperature. Arise of internal temperature (body temperature) is favorable to increased metabolic activity (p. 432) and, therefore, to an increase of heat-production ; conversely, a fall of body temperature tends to reduce heat-production. The influences of body temperature are, as a whole, less important than those of external temperature. The influences of external temperature axe in a measure differenl upon homo- thermous and poikilothermous animals. In the former, heat-production is in inverse relation to the temperature of the surrounding medium, so that the cooler the ambient temperature the greater the heat-production ; in the latter 1 Physiologie dea Menachen und der Sdugethiere, L892, 8. 302. 1M AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. heat-production increases with an increase of external temperature, because with the rise of the latter bodily temperature increases, which in turn increases metabolic activity (pp. 4:52, 433). ( lonsequently, in warm-blooded animals heat- production is greater in cold climates and seasons than in the opposite conditions, while in cold-blooded animals the opposite is the case. Cold applied to the skin increases heat-production by reflex ly exciting muscular activity (shivering, etc., p. 433) ; moderate heat exerts the opposite influence unless the bodily tem- perature is affected, as shown by the results of studies of respiration (p. 433). The character of the food is important. Danilewsky 1 has estimated that the following quantities of heat are produced under different diets, etc. : On a minimum diet 1800 kilogramdegrees. On a reduced diet (absolute rest) 1989 On a non-nitrogenous diet 2480 " On a mixed diet (moderate work) 3210 " On an abundant diet (hard work) 3646 " On an abundant diet (very laborious work) 3780 The influence of the quantity and quality of the diet must be potent when it is remembered that 1 gram of proteid yields about 4100 calories, 1 gram of fat about 9312 calories, and 1 gram of carbohydrate about 4116 calories. In cold climates fats enter very largely into the diet because of the greater loss of heat and the consequent increased demand for heat-producing substances. During the periods of digestion more heat is produced than during the in- tervals, this increase being due chiefly to the muscular activity of the intestinal walls (p. 431). Langlois' experiments indicate that during digestion heat- production may be increased 35 to 45 per cent. It is said that heat-production undergoes diurnal variations which corre- spond with the fluctuations of bodily temperature, but this is doubtful. All structures produce more heat during activity than during rest. Heat- production has been estimated to be from two and a half to three times greater when awake and resting than when asleep, and from one and a half to three times more when active than when at rest, in proportion to the degree of activity. During hybernation the absorption of O falls considerably (p. 434), consequently heat-production is believed to decline to a like degree. All conditions which affect heat-dissipation (p. 494) tend indirectly to influence heat-production. The most important of the factors influencing heat-production is the ner- vous mechanism which controls the heat-producing processes (p. 490). Various dnu/s exert more or less potent influences directly or indirectly upon heat-production. Cocain, strychnin, brucin, and other motor excitants increase heat-production; while chloroform, most antipyretics, narcotics generally, bro- mides, and motor depressants decrease heat-production. I bat-production is diminished in most forms of anaemia, after severe hem- orrhage, and in most non-febrile adynamic conditions. It is usually increased in fevers, especially so in infectious fevers. According to Liebermeister, the 1 Pflugei>s Arehivfur Physiologk, 1883, Bd. xxx. S. 190. ANIMAL HEAT. 485 increase in fever is probably about 6 per cent, for each increase of 1° C. of bodily temperature, so that were the increase of temperature 3° C. the increase of heat-production would be 18 per cent. Conditions affecting- Heat-dissipation. — The loss of heat from the body occurs through several channels — in the urine, feces, sweat, and expired air, and by radiation and conduction from the skin; hence, all conditions which affect the loss of heat in the above ways must influence heat-dissipation. The chief of these are : Age, sex, species, the quantity of subcutaneous fat, the nature of the surrounding medium, clothing, internal and external tempera- ture, activity of heat-production, body-surface, the condition of the circulation, respiration, sweat, activity, radiating coefficient, nervous influences, drugs, and abnormal conditions. The influence of age is shown by the fact that the young dissipate and produce more heat in proportion to body-weight than the adult, this being due chiefly to the relatively greater metabolic activity and the larger proportional body-surface (p. 430), and consequent greater radiation, in the young. Sex per se does not seem to exert any influence, although the adult human female, weight for weight and for an equivalent bodily surface, probably dissi- pates less heat than the male, because of her relative abundance of subcu- taneous fat, which hinders heat-dissipation. No difference so far as sex is concerned has been noted in the lower animals. Heat-dissipation varies greatly in different sjiecies, owing chiefly to relative size and respiratory activity, to the nature of the medium in which the animal lives, and to the character of the body-covering. Heat-dissipation is more active in homothermous animals than in poikilothermous animals, because of the greater activity in the former of heat-production. In amphibia heat-dissi- pation is greater when the animal is in the water than when exposed to the air if both water and air be of the same temperature, because water is a better conductor of heat and consequently withdraws heat from the body more rapidly. The higher the temperature of the surroundings the higher the bodily temperature of cold-blooded animals, consequently the greater are heat- production and heat-dissipation. In warm-blooded animals the effect on both heat-production and heat-dissipation is in inverse relation to the surrounding temperature (unless the bodily temperature is affected), external heat decreasing both heat-dissipation and heat-production, and internal heat increasing both. Subcutaneous fat is a poor conductor of heat, consequently the greater the abundance of it the greater the hindrance offered to the dissipation of heat. The value of fat in this respect is illustrated in water-fowls, which, as a rule, are far more abundantly supplied with fat than other species; and by the ex- ceptional abundance of subcutaneous fat in species of fowl which inhabit very cold waters. Bathing the skin with grease hinders radiation, and is adopted by swimmers both to conserve the bodily heat and to protect the skin. When air and water are of the same temperature, heat-dissipation is greater when the animal is exposed to the water, because the latter is abetter con- ductor. Heat-loss is greater in dry than in moist air, other things being 186 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. equal, because in the former the evaporation of sweat from the body and the loss of \\at> of heat by this channel. The heat-loss occurs both in warming the air and in the evaporation of water from the lungs, so that the cooler and drier the air inspired the larger relatively is the heat-loss. The importance of respiration as a heat-dissipating factor is illustrated by the fact that about 10.7 per cent, of the total heat-dissipation occurs in this way (see p. 477). Next in importance to radiation is the amount of water evaporated from the sldn. Each gram of water requires 582 calories to vaporize it, and it is estimated (p. 477) that 364,120 calories are dissipated in this way, or 14.5 percent, of the total heat-dissipation. An increase of external temperature increases the irritability of the sudoriparous glands, thus favoring secretion and heat-dissipation. The value of sweat, however, as a means of carrying off heat, is materially affected by the temperature of the air as well as by the amount of moisture present. The higher the temperature and the less the moisture the more rapidly evaporation occurs, and consequently the greater the loss of heat ; when air i> moist and of high temperature evaporation takes place relatively slowly, if at all. Therefore, individuals can withstand sub- jection to dry air of a higher temperature and for a longer period than when the atmosphere is moist. In the former case sweat is rapidly secreted and vaporized, and thus a marked rise of internal temperature may be prevented. James found that a vapor bath at 44.5° C. (112° F.) was insufferable, while dry air at 80° C. (176° F.) caused little inconvenience. When air is of high temperature and loaded with moisture we say that it is "sultry," but dry air of the same temperature is not unpleasant. Muscular activity increases heat-production, excites the circulation and respiration, and increases the secretion of sweat, all of which directly or indi- rect Iv increase heat-dissipation. The surface of //" body as a radiating surface cannot be regarded in the same light as an indifferent, inanimate surfape, such as metal or wood. The coefficient of rn (the quantity of heat emitted during a unit of time at a standard temperature from a given area) in an inanimate body remains fixed, because the surface itself is virtually unchangeable; but the coefficient for the living organism is subject to material alterations. These alterations depend chiefly (1) upon the actions of the pilo-motor mechanism whereby the relation of the natural covering (hair or feathers in the lower animals) of the body to the skin is effected ; (2) upon changes in the conductivity of the skin owing to variations of the blood-supply ; (3) upon the varying thickness of the skin in different species, in different individuals, and in different parts of the body; (4) upon the temperature of the surroundings; (5) upon the extent of the body-surface exposed; Hi) upon the character of the clothing. When the arrector pili muscles contract the skin is made tense and the cutaneous blood- vessels .ire pressed upon and rendered anaemic, thus lessening the quantity of fluid in the skin and as a consequence lowering the coefficient of dissipation; moreover, in animals whose natural covering is fur or leathers, these fibres cause an erection of one or the other, a- the case may be, and in this way affect the radiating coefficient. The coefficient is enormously increased by ANIMAL HEAT. 489 removing the natural covering, such as the fur of the rabbit, under which cir- cumstances, even though the animal be subjected to a relatively high external temperature, heat-dissipation is so enormously increased that death ensues within two or three days. When one side of the body of a horse was shaved and the animal subjected to an atmosphere having a temperature of 0° C, the tem- perature of the skin of the shaven side fell 8° in forty minutes, while the temperature of the unshaven side fell only 0.5°. The coefficient is diminished where there is excessive sebaceous secretion, and where grease is artificially applied, and by an accumulation of subcutaneous fat ; it is increased by wetting the skin, as by sweat or bathing ; and it is affected by many other circumstances. Through the operations of the nervous system heat-dissipation may be affected directly or indirectly by action upon the heat-dissipating and heat- producing processes — circulation, respiration, sudorific and sebaceous glands, and arrector pili muscles. There are many drugs which directly or indirectly affect heat-dissipation. Drugs which cause dilatation of the cutaneous vessels tend to increase heat- dissipation ; conversely, those which cause contraction of the blood-vessels hinder dissipation. Diaphoretics increase heat-loss essentially by increasing the amount of sweat. Respiratory excitants increase the loss of heat by means of the increased volume of air respired. Drugs which increase heat-production tend to indirectly increase heat-dissipation. All pathological states which affect heat-production tend to similarly disturb heat-dissipation. Conditions of malnutrition favor heat-dissipation by causing a loss of subcutaneous fat, but this is to a greater or less extent compensated for by the enfeeblement of the circulation, respiration, and metabolic processes in general. In fever, both heat-production and heat-dissipation are generally increased, the former being affected more than the latter, so that the bodily temperature rises. In some forms of fever the rise of temperature is essentially due to diminished heat-dissipation. D. The Heat-mechanism. The heat-mechanism consists of two fundamental parts, one being concerned in heat-production, and the other in heat-dissipation. Heat-production is briefly expressed as thermogenesis ; and heat-dissipation, as thermolysis. The operations of these mechanisms are so intimately related that fluctuations in the activity of one are rapidly compensated for by reciprocal changes in the other, so that under normal conditions heat-production and heat-dissipation so nearly balance that the mean bodily temperature is maintained within narrow limits. The regulation of the relations between heat-production and heat-dissipation is termed thermotaxis, which regulation may be effected by alterations in either thermogenesis or thermolysis. The Mechanism concerned in Thermogenesis. — The portion of the heat- mechanism concerned in heat-production consists of (1) thermogenic tissues, (2) thermogenic nerves, and (3) thermogenic centres. 490 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. The Thermogenic Tissues. — Almost if not every tissue of the body may be regarded as being a heat-producing structure. The very tact that oxidative processes lie at the bottom of all forms of vital activity, and that heat-produc- tion is a concomitant of oxidation, leads inevitably to the conclusion that as Ion- as cells possess life they must produce heat. There arc, however, certain of the bodily structures, especially the skeletal muscles and the gland-, which are exceptionally active as heat-producers. Indeed, in the case of the skeletal muscles the heat-producing processes are of such a character as to justify the belief' that with them therniogendsis is a specific function, because heat is pro- duced not merely as an incidental product of activity but as a specific product. When a muscle contracts, heat is evolved as an incident of the performance of work, and when it is at rest heat is produced not only as an incident of growth and repair but as the result of a specific act. This latter is proved by the fact that when the muscles have been in a state of prolonged rest, when the chemi- cal changes concerned in growth and in repair of waste are practically inactive, heat-production continues to a marked degree. Moreover, the quantity which is produced varies with the immediate needs of the economy and bears a reciprocal relationship to the quantity of heat formed in other structures, 1 and is regulated apparently by specific nerve-centres. When the muscles are contracting less than one-fifth of the energy appears as work, and more than four-fifths as heat. The contractions of the heart also furnish an appreciable percentage of heat as an accompaniment of contraction; and considerable heat is formed indirectly by the resistance offered by the the blood-vessel walls to the blood current. Indeed, the entire work of the heart becomes converted into heat, representing approximately 5 to 10 per cent, of the total heat-production. The quantity formed as by-products of tin- activity of various structures during a state of muscular quiet is doubtless small compared with the quantity produced by the muscles. The Thermogenic Nerves . 1 •">">. 3 Ibid., 1891, p. 151. 1 Schultze: Archiv fur experimentelle Pathologic und Pharmakologie, 1899, Bd. 43, S. 193. ANIMAL HEAT. 4Ul another in the form of contraction known as shivering ; and a third, giving rise to heat as the only important phenomenon. The heat produced by muscles in ordinary or general muscular acts and in repair and growth is a mere incident to activity; but the heat arising during shivering is undoubt- edly a specific product — i. e., the object of the shivering is a production of heat (see p. 433). If the nerve-fibres which convey the impulses tli.it cause shivering be ordinary motor fibres, then these fibres are not only motor film-, but specific thermogenic fibres in so far as they are connected with heat- production by this act. There are also, apparently, fibres which are entirely distinct from the motor fibres, and which convey impulses that give rise to heat-production as a specific product, and even in the entire absence of motor phenomena. Thus, in a curarized animal in which all motor activity of the skeletal muscles is abolished, an enormous increase of heat-production may occur (Reichert) which cannot satisfactorily be explained in any other way than by assuming the existence of such specific thermogenic fibres. Our information at present is, however, so limited that we can do scarcely more than speculate. Our knowledge of the character of the afferent fibres which carry impulses that reflexly affect thermogeuesis is very unsatisfactory. There can be no doubt that sensory impulses arise in various parts of the organism, especially in the skin, which exercise important influences upon the heat-producing pro- cesses. Thus, cooling the skin reflexly excites heat-production, which cannot be attributed to indirect influences upon other functions, but whether or not there exist specific afferent thermogenic fibres is not known. It is possible that the temperature nerves of the skin, the cold and the heat nerves, may be responsible for reflex excitation or depression of heat-production. The Thermogenic Centres. — The existence of specific thermogenic centre- has for many years been conceded, but it has only been recently that hypothesis has given place to fact. The most important results of recent research may be generalized as follows: (1) That the irritation of the skin by heat or cold is followed by marked changes in thermogeuesis, which effects are to a certain extent entirely independent of vasomotor and other incidental changes, and which, therefore, are due in part to an increase of heat-production dependent directly upon efferent thermogenic impulses. (2) That injury or excitation of certain parts of the brain is followed by an increase of heat-production. (3) That injury or excitation of certain other parts of the brain is followed by diminished heat-production. (4) That injury of the spinal cord may be fol- lowed by an increase or decrease of heat-production which cannot be entirely accounted for by vaso-motor and other attendant alterations. (5) That after operations upon certain parts of the cerebro-spinal axis their follows an increase or decrease in the quantity of 0O 2 formed, indicating a corresponding effed <>n the heat-producing processes. The results of recent calorimetric work show that there are definite regions of the cerebro-spinal axis which are apparently specifically concerned in ther- mogenesis; that the effects of excitation or destruction of each region are more 492 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. or less characteristic ; and that the different regions seem to be so intimately related to one another as to constitute a co-ordinate mechanism. Certain of these regions when irritated give rise, as a direct result, to increased thermogenesis, hence they are of the nature of thermo-accelerator centres; and others to diminished thermogenesis, hence are thermo-inhibitory centres. Both kinds of centres seem to be associated with and to govern a third kind which is dis- tinguished as the general or automatic thermogenic centres. The mechanism may be theoretically expressed in this form: The general thermogenic centres may be regarded as maintaining by virtue of independent activity a fairly con- stant standard of thermogenesis, and as being influenced to increased activity by the thermo-accelerator centres and to diminished activity by the thermo-inhib- itory centres. The finer or smaller variations iu thermogenesis are presumably effected by the general centres, whereas the grosser variations are probably ef- fected by the influences of the thermo-accelerator and thermo-inhibitory centres. Specific heat-centres (thermogenic and thermolytic) have by various ob- servers been held to exist in certain regions of the brain cortex, in the base of the brain just in front of and beneath the corpus striatum, in the corpus stri- atum, in the septum lucidum and the tuber cinereum, in the optic thalamus, in the corpora quadrigemina, in the pons and medulla oblongata, and in the spinal cord. Some of these centres have been regarded as being thermogenic and others as being thermolytic. Many errors in deduction have, however, been made because of the many inherent difficulties attending experimenta- tion upon the cerebro-spinal axis, and because almost all the methods used necessarily involve injury or excitation of contiguous parts. The methods adopted of studying these various regions have been chiefly destruction or injury by means of a probe, actual cautery, excision, and the injection of cauterants; by transverse incisions across the cerebro-spinal axis so as to sepa- rate higher from lower portions of the cerebro-spinal axis; and by excitation by small punctures, electricity, etc. In classifying these centres Ave are governed by the results which follow excitation and destruction. When irritation or destruction directly affects thermogenesis, the centre is regarded as being thermogenic, but if heat-dissi- pation is the process directly affected, the centre is regarded as being thermo- lytic. In classifying thermogenic centres we would regard the centre as being a general thermogenic centre if it is capable, after the destruction of other thermogenic centres, of causing the normal output of heat; a thermo-acceler- ator centre is distinguished by the lad that excitation increases thermogenesis, while destruction does not diminish thermogenesis, unless the centre happens to be active at the time, and further by the fact that after its destruction the normal output of heal may continue; a thermo-inhibitory centre is distinguished by a decrease of heat-production following stimulation and by the absence of any permanent effect on thermogenesis when the centre is destroyed. The general or reflex thermogenic centres are undoubtedly continuously active, the degree of activity varying according to the immediate demands of the organism for heat ; while the thermo-accelerator and thermo-inhibitory centres are prob- ANIMAL HEAT. 493 ably only intermittently active, coming into play when the general centres are of themselves unable to effect a sufficiently rapid compensation. While it must be admitted that our knowledge of the precise locations, physiological peculiarities, and correlations of the thermogenic centres is by no means complete, we have at our disposal some most important and significant data. The general thermogenic centres have been shown by Reichert 1 to be located in the spinal cord. The thermogenic centres in the brain are either thermo-accelerator or thermo-inhibitory. Thermo-accelerator centres probably exist in the caudate nuclei (possibly also in the tuber cinereum and optic thalami), pons, and medulla oblongata. 2 Excitation of any one of these regions is followed by a pronounced rise of heat-production ; destruction of any one region may or may not be followed by a decrease of heat-production, and if a decrease does occur it may in most cases be attributed to incidental causes, such as shock and other attendant conditions. The centre which is common to the pons and medulla is for the most part probably located in the latter, but it is not so powerful in its influ- ences on thermogenesis as the thermo-accelerator centres in the basal regions of the cerebrum. These cerebral centres are affected by agents which have little or no effect on the heat centres of the spinal cord. Thermo-inhibitory centres have been located in the dog in the region of the sulcus cruciatus and at the junction of the supra-sylvian and post-sylvian fissures. 3 Irritation of either of them is followed by a decrease of heat-production, while their destruction may be followed by a transient increase of heat-production. The cruciate centre is the more powerful. None of these cerebral centres exercises any influence on thermogenesis after section of the spinal cord at its junction with the medulla oblongata. Theoretically, these centres are associated in this way : The general thermo- genic centres are in the spinal cord, and while they are perhaps impressionable to impulses coming to them through various sensory nerves, they are not apparently in the least influenced by cutaneous impulses caused by change- in external temperature nor by changes of the temperature of the blood. It is not improbable that these centres are in the anterior cornua of the spinal cord. The thermo-accelerator and thermo-inhibitory centres are connected with the general centres by nerve-fibres, the former influencing the general centres to increased activity, and the latter to diminished activity. The thermo-accel- 1 University Medical Magazine, 1894, vol. v. p. 406. 2 Reichert: University Medical Magazine, 1894, vol. 6, p. 303. Ott : Journal of Nervous and Mental Diseases, 1884, vol. 11, ]>. 141; 1887, vol. 14, p. 154; 1888, vol. 15, p. 85 ; Therapeutic Gazette, 1887, p. 592; Fever, Thermotaxia, CaC0 3 + C0 2 + 2H 2 , and this same reaction may be brought aboul by the action of metallic iridium, rhodium, or ruthenium on formic acid. Anenzyrm is a substance probably of proteid nature capa- ble of producing change in ether substances without itself undergoing apparent change (example, pepsin). Bunge* calls attention to the fact that the above reaction may he brought about by living cells (bacterial, by an organic substance (enzyme), and by an inorganic metal. This similarity of action between organized and unorganized material, between living and dead substances, is shown more and more conspicuously as science advances. Properties. — Hydrogen burns in the air, forming water, and if two volumes of hydrogen and one of oxygen be ignited, they unite with a loud explosion. Hydrogen will not support respiration, but, mixed with oxygen, may be respired, probably being dissolved in the fluids of the body as an inert gas, without effect upon the organism. Hydrogen may pass through the intes- tinal tissues into the blood-vessels, according to the laws of diffusion, in ex- change for some other gas, and may then be given off in the lungs. Nascent hydrogen — that is to say, hydrogen at the moment of generation — is a powerful reducing agent, uniting readily with oxygen (see p. 505). Oxygen, = 16. Oxygen is found free in the atmosphere to the amount of about 21 per cent, by volume, and is found dissolved in water and chemically combined in arterial blood. It is swallowed with the food and may be present in the stom- ach, but it entirely disappears in the intestinal canal, being absorbed by respir- atory exchange through the mucous membrane. It ocean's chemically com- bined with metals 80 that it forms one-hall' the weight of the earth's crust ; it likewise occurs combined in water and in most of the materials forming animal and vegetable organisms. It is found in the blood in loose chemical 1 It is not within the scope of this work to <.'ive more than typical methods of lahoratory preparation. For greater detail the reader is referred to works on general chemistry. 1 Physiolfxjuchi Chemie, 2d ed., L889, i>. 167. THE CHEMISTRY OE THE ANIMAL BODY. 501 combination as oxyhemoglobin. It is present dissolved in the saliva, so great is the amount of oxygen furnished by the blood to the salivary gland ; it is, however, not found in the urine or in the bile. Preparation. — (1) Through the electrolysis of water (see Hydrogen). (2) By heating manganese dioxide with sulphuric acid, I'MnO, - H 2 S0 4 = 2MnS0 4 + 2H 2 + 2 . (3) By heating potassium chlorate. 2KC10 3 = 2KCl+30 2 . (4) By the action of a vacuum, or an atmosphere containing no oxygen, on a solution of oxyhemoglobin, Hb-0 2 =Hb+0 2 . This latter is the method occurring in the higher animals. Any oxygen present in a cell in the body combines with the decomposition products formed there, consequently entailing in such a cell an oxygen vacuum, which now acts upon the oxyhemoglobin of the blood-corpuscles in an adjacent capillary, dissociating it into oxygen and hemoglobin. (5) Bv the action of sunlight on the leaf of the plant, transforming the carbonic oxide and water of the air into sugar, and setting oxygen free, 6C0 2 + 6H 2 = C 6 H 12 6 + 60 2 . Properties. — All the elements except fluorine unite with oxygen, and the products are known as oxides, the process being called oxidation. It is usually accompanied by the evolution of energy in the form of heat, and often the energy liberated is sufficiently great to cause the production of light. The light of a candle comes from vibrating particles of carbon in the flame, which particles collect as lampblack on a cold plate. In pure oxygen combustion is more violent than in the air; thus, iron burns brilliantly in pure oxygen, while in damp air it is only very slowly converted into oxide (rust). This latter process is called slow combustion, and animal metabolism is in the nature of a slow combustion. In the burning candle has been noted the liberation of heat, and motion of the smallest particles : in the cell there is likewise oxidation, with dependent liberation of heat and motion of the smallest particles in virtue of which the cell is active. Phenomena of life are phenomena of motion, and the energy supplying this motion comes from chemical decomposition. The amount of oxidation in the animal is not increased in an atmosphere of pure oxygen, nor, within wide limits, is it affected by variations in atmospheric pressure, for oxygen is not the cmtse of decomposition. In putrefaction it is known that bacteria cause decomposition, and the products subsequently unite with oxygen. But the cause of the decomposition in the cell remains unsolved, it being only known that the decomposition-products after being formed unite with oxygen. So the quantity of oxygen absorbed by the body depends on the decomposition going on, not the decomposition on the absorption of oxygen. This distinction is fundamental (see further under Ozone and Peroxide of Hydrogen). 502 J.V AMERICAN TEXT-BOOK OF PHYSIOLOGY. By reduction in it- simplest sense is meant the removal of oxygen wholly or in part from the molecule. Example: reduced haemoglobin from oxy- hsemoglobin, iron from oxide of iron ( Fc.Og). Reduction may likewise be accomplished by Bimple addition of hydrogen to the molecule, or by the sub- stitution of hydrogen for oxygen. These two processes may be represented respectively by the reactions : CH3CHO +H 2 =CH 3 CH 2 OH. Ethyl aldehyde. Ethyl alcohol. ciLcoolI 2H 2 (!I,('IL()M+H 2 0. Acetic acid. Ethyl alcohol. Ozone, 3 . — Ozone is a -econd form of oxygen possessing more active oxi- dizing properties than common oxygen. It is found in neighborhoods where large quantities of water evaporate, and after a thunder-storm. Preparation. — (1) An induction current in an oxygen atmosphere breaks up some of the molecules present into atoms of nascenl or ■"active"' oxygen — — , the powerful affinities of whose free bonds enter into combination with oxygen, = to form Q ozone. /\ (2) Through the slow oxidation of phosphorus, P 2 + 3H 2 + 20 2 - 2H3PO3 + (-0-). (-0-) + 2 = O s . (3) On the positive pole in the electrolysis of water. In each of the above cases ozone is formed by the action of nascent oxygen on oxygen. Properties. — Ozone is a colorless gas, hardly soluble in water, and having the peculiar smell noted in the air after thunder-storms. Ozone has powerful oxidizing properties due to its third unstable atom of oxygen, oxidizing silver, which oxygen of itself doe- not. Bui ozone is not as oxidizing as nascent or '"active" oxygen, which may convert carbon monoxide into dioxide, and nitrogen into nitrons acid. Ozone cannot occur in the cell, as any nascent oxygen formed would naturally unite not with oxygen, but with the more readily oxidizable materials of the cell itself. Ozone acts on an alcoholic solu- tion of guaiacum, turning it blue; blood-corpuscles give the same reaction with guaiacum, hence it was thought that haemoglobin converted oxygen into ozone. However, this test is uol a test for ozone, but for "active" atomic oxygen, which is produced from the ozone and in the decomposing blood-cor- puscle (see theory of Traube below, and that of Hoppe-Seyler under Peroxide of Hydrogen). Ozone converts oxyhemoglobin into methaemoglobin. Theory of Traube as to the ('mis, of Oxidation in the Body. — Indigo-blue dissolved in a sugar-solution gives up oxygen in the atomic state for the oxida- tion of sugar, and the solution becomes white. If shaken in the air the blue coloration reappears, owing to the absorption of oxygen by the indigo. Hence indigo has the power of splitting oxygen into atom-, and acts as an "oxygen- carrier" between the air and the sugar. Traube is of the opinion that an "oxygen-carrier" exists in the blood-corpuscles. Sugar i- destroyed by stand- ing in fresh defibrinated blood ; serum alone doe- not effect this, nor does a solution of oxyhemoglobin, but it may take place in the extract obtained by THE CHEMISTRY OF THE ANIMAL BODY. 503 the action of a 0.6 per cent, sodium-chloride solution on blood -corpuscles. 1 The action here has been described as that of catalysis, that is, an action by which some substance effects decomposition in another substance without per- manent change in itself. In this case the substance in the blood-corpuscle is defined as an " ox ygen-carrier," taking molecules of oxygen from oxy- hemoglobin and giving atomic oxygen for the oxidation of the sugar. Spitzer 2 has shown that these oxygen-carriers are iron-containing nucleo- proteids which are characteristic constituents of the cellular nucleus. Hence the nucleus is the principal oxidation organ of living matter. Separation of protoplasm from its nucleus causes the death of the protoplasm on account of decreased oxidative capacity. 3 Old turpentine is highly oxidizing. This action was once believed to be due to absorbed ozone. If old turpentine be mixed with water and filtered, the aqueous extract has the same properties, due to the fact that an oxidized product which is soluble in water, gives off', under favorable conditions, atomic oxygen. * Water, H 2 0. — Water is found on the earth in large quantities, and its vapor is a constant constituent of the atmosphere. It is a product of the combustion of animal matter, and occurs in expired air almost to the point of saturation. It is furthermore given off by the kidneys and by the skin. It is a necessary constituent of a living cell, and forms 67.6 per cent, of the weight of the human body (Moleschott). Removal of 5 to 6 per cent, of water from the body, as for example in cholera, causes the blood to become very viscid and to flow slowly, no urine is excreted, the nerves become excess- ively irritable, and violent convulsions result. 5 Preparation. — (1) Bypassing an electric spark through a mixture of one volume of oxygen and two volumes of hydrogen. (2) By the combustion of a food — as, for example, C 6 H 12 6 + 120 = 60O 2 + 6H 2 0. Sugar. (3) Distilled water is made in quantity by boiling ordinary water and condensing the vapors formed in another vessel. Properties. — Water is an odorless, tasteless fluid of neutral reaction, colorless in small quantities, but bluish when seen in large masses. It is a bad conductor of heat and electricity. It conducts electricity better when it contains .silts. It is nearly non-compressible and nun-expansible; thus in plant-life, through evaporation on the surface of the leaf, sap is continuously attracted from the mots of the tree. The solvent properties of water give to the blood many of its uses, soluble foods being carried to the tissues and soluble products of decomposition to the proper organs for elimination. When water is absorbed by any substance the process is called hydration, 1 Read W. Spitzer : Pflugefa Arehiv, 1S95, Bd. 60, S. 307. 2 Tbid., 1897, Bd. 67, S. 615. 3 J. Loel>: Arrliir fin- ErUwickelwngsmechanik der Organismen, 1899, Bd. 8, 8. 689. * N. Kowalewsky : Centralblatt fiir die medicinische Wissenschaft, 1889, S. 113. 5 C. Voit: Hermann's Handbuch, 1881, Bd. vi. 1, S. 349. 504 -l.V AMERICAN TEXT-BOOK OF PHYSIOLOGY. as an example of which may be cited the change of calcium oxide into hydroxide when thrown into water. When a substance breaks down into simpler bodies through absorption of water the process is called hydrolysis or hydrolytic cleavage. Thus cane-sugar may take up water and be resolved into a mixture of dextrose and levulose, which are called cleavage-products. So, likewise, starch and proteid are resolved into series of simpler bodies through hydrolytic cleavage — changes which take place in intestinal digestion. All forms of fermentation and putrefaction are characterized by hydrolysis (exam- ple-, p. 500), and hence complete drying prevents such processes. Alcoholic, butyric, and lactic fermentation are apparent though not real exceptions to the above. Alcoholic fermentation, for example, is usually represented by the reaction, C 6 H 12 6 = 2C 2 H 5 OH + 2C( ).,, but the C0 2 is in fact united with water, and hence the true reaction should read, C 6 H 12 6 - 2H 2 = 2CJT 5 OH + 2H 2 C0 3 . Sugar. Alcohol. Drinking-water contains salts and air dissolved, giving it an agreeable taste. One does not willingly take distilled water on account of its tastelessness. Dry animal membranes and cells absorb water in quantities varying with the concentra- tion and the quality of salts in the solution in which they are suspended (Liebig). This is called imbibition. Membranes will absorb a solution of potassium salts in greater quantity than of sodium salts, and so the potassium salts are found predominating in the cells, the sodium salts in the fluids of the body. A blood-corpuscle treated with distilled water swells because it can hold more distilled water than it can salt-containing plasma. A cor- puscle placed in a 0.65 percent, solution of sodium chloride (the physiological salt-solution) remains unchanged, for this corresponds in concentration to the plasma of the blood. If the corpuscle he placed in a strong solution of a salt it shrivels, because it cannot hold as much of that solution as it can one having the strength of the salts of the plasma. Oysters are often planted at the mouths of fresh-water rivers, since they imbibe more of the weaker solution and appear fatter. If salt lie placed on meat and left to itself, a brine is formed around the meat on account of the osmotic pressure exerted by the strong solution of -alt. which sets up an osmotic stream of water to the salt and thus deprives the meat of water. Different bodies require different quantities of heat to warm them to the same extent. The amount of heat required to raise the temperature of water is greater than that for any other substance. A calorie or heat-unit is the amount of heat required to raise 1 cubic centimeter of water from 0° to 1° ('. The specific heat of the human body— that is, the amount of heat required to raise 1 gram 1° C— is about 0.8 that of water. On the trans- formation of a substance from the Bolid to the liquid state, a certain amount of heat is absorbed, known as latent li<,. (2) Peroxide of hydrogen is a product of the oxidation of phosphorus, and generally exists wherever ozone is produced. (3) Peroxide of hydrogen exists wherever nascent hydrogen acts on oxygen. It is therefore found mixed with hydrogen evolved at the negative pole in the electrolysis of water. This action happens in putrefaction, where the nascent hydrogen unites with any oxygen present, and the resulting H 2 2 strongly oxidizes the organic matter through the free — O — atom liberated. 1 Properties. — Peroxide of hydrogen is a colorless, odorless, bitter-tasting fluid, which decomposes slowly at 20° F., and with great violence at higher temperatures. It oxidizes where ordinary oxygen is ineffective ; it is a powerful bleaching agent, and is used to produce blonde hair. It destroys bacteria. Blood- corpuscles brought into a solution of H 2 2 bring about its rapid decomposition into water and atomic oxygen, whereby oxygen is evolved and oxyhemoglobin is converted into methsemoglobin. If oxyhemoglobin be brought into a putrefying fluid, the nascent hydrogen withdraws oxygen from combination to form H 2 2 , and then the atomic oxygen reacts on haemoglobin to form methaemoglobin. 2 The formula for the peroxide is probably II — O — O — H. In certain cases peroxide of hydrogen has a reducing action. Theory of Hoppe-Seyler 3 to account for the Oxidation in the Body. — This maintains that, as in putrefaction, hydrogen is produced in the decomposition of the cell, and acting on the oxygen present converts it into peroxide with its unstable atom, which then splits off as active oxygen and effects the oxida- tion of the substances in the cell. This theory is easier to reconcile with the fact that oxidation is dependent on the amount of decomposition (see p. 501) than is the theory of Traube. Solutions of H 2 2 do not liberate iodine from potassium iodide immediately, but only on the addition of blood-corpuscles or of ferrous sulphate, which cause liberation of — — , and then any starch present may be colored blue (see p. 502). Gruaiacum is not affected by H,0 2 unless blood-corpuscles or ferrous sulphate be added to make the oxygen active. Sulphur, S = 32. Sulphur is built in the proteid molecule of the plant from the sulphates taken from the ground. It is found in albuminoids, especially in keratin. As taurin it occurs in muscle and in bile, as iron and alkaline sulphide in the 1 Hoppe-Seyler: Zeitschrift fur physwlogische Chemie, 1878, Bd. '_\ 8. 22. 2 Hoppe-Seyler, Op. cit., S. 26. 3 P0ijir.< ArchiVf Bd. L2, S. 16, 1876. See also Berichte der deutschen ehemischen QaeUaehqfl, Bd. 22, S. 2215. 506 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. feces, as sulphuretted hydrogen in the intestinal gas, as sulphate and other unknown compounds in the urine. Sulphuretted Hydrogen, II..S. — This gas is found in the intestines, and pathologically in the urine. Preparation. — (1) Action of hydrochloric or sulphuric acid on ferrous sulphide, FeS + H 2 SG 4 = FeS0 4 + H 2 S. This same reaction takes place by treating feces (which contain FeS) with acid. (2) From the putrefaction of proteids, and by boiling proteid with mineral acid. Properties. — Sulphuretted hydrogen unites readily with the alkalies and with iron salts, forming sulphide; hence little H 2 S is found in the intestinal tract. It is a strong poison when respired. It has been shown to enter into combination with oxyhemoglobin to form sulph-hsemoglobin, and likewise in frogs it rapidly kills the nerves. 1 Sulphuretted hydrogen diluted with hydrogen and introduced into the rectum of a dog produces symptoms of poisoning in one to two minutes (Planer). It has an offensive odor similar to foul eggs. Sulphurous Acid, H 2 SO :! . — This acid has been found in the urine of cats and dogs, and lias been detected by Striimpell in human urine in a case of typhoid fever. Sulphuric Acid, H 2 S0 4 . — This acid is found in the urine in combination with alkali (preformed sulphate), and with indol, skatol, cresol, and phenol (ethereal sulphates). It is found in the saliva of various gastropods. Preparation. — (1) By oxidation of sulphur with nitric acid, S + 2HND 3 = H 2 S0 4 + 2NO. (2) By oxidation of sulphur-containing proteid, Properties. — Sulphuric acid is a very powerful acid. It is produced in the body by the burning of the proteids (which contain 0.5 to 1.5 per cent. S), 80 per cent, or more being oxidized to acid, while the remainder appears in the urine in the unoxidized condition termed neutral sulphur. When proteid, fat, and starch free from ash are fed to dogs, they live only half as long as they would were they starving, 2 for, according to Bunge, 3 the sulphuric acid formed abstracts necessary salts from the tissue. (For further discussion of this see pp. 354 and 525). Tf 100 cubic centimeters of urine be treated with 5 cubic centimeters of hydrochloric a<-id and barium chloride be added, the 'preformed sulphuric acid is precipitated as barium sulphate (BaSOJ, which may be washed, dried, and weighed. It' 100 cubic centimeters of urine be mixed with an equal volume <>t' a Bolution containing barium chloride and hydrate, filtered, and one-half the fill rate ( = 50 cubic centimeters of urine, now free of preformed Bulphate) be strongly acidified with hydrochloric acid and boiled, the ethereal sulphates will be broken up, and the resulting precipitate of barium sulphate will corre- spond to the ethereal sulphuric acid. To determine the neutral sulphur, evaporate the 1 Harnack : Archiv fur expervmenteUe Paihdogie, wnd Pharmakofogie, 1894, Bd. 34, S. 156. 2 .1. Foster: Zeitschrifijur Biologie, 1873, Bd. 9, S. 297. 3 Physiologische Chemie, 2d ed., 1889, p. 104. THE CHEMISTRY OF THE ANIMAL BODY. 507 urine to dryness, fuse the residue with potassium nitrate (KN0 :t ), which oxidizes all the sulphur to sulphate, take up with water and hydrochloric acid, add barium chloride, and the precipitate (BaSOj represents the total sulphur present. Deduct the amount belong- ing to sulphuric acid, previously determined, and the remainder represents the neutral sulphur. Metabolism of Sulphur. — The total amount of sulphur in the urine runs proportionally parallel with the amount of nitrogen ; that is to say, the amount is proportional to the amount of proteid destroyed. The amount of ethereal sulphate is dependent upon the putrefactive production of indol, skatol, phenol, and cresol in the intestinal canal, which on absorption form a synthetical combination with the traces of sulphate in the blood. Concerning neutral sulphur it is known that taurin is one source of it. If taurin be fed directly, the amount of neutral sulphur in the urine increases (Salkowski), and in a dog with a biliary fistula the neutral sulphur decreases but does not en- tirely disappear. 1 In a well-fed dog with a biliary fistula Yoit 2 found the quantity of sulphur in the bile to be about 10 to 13 per cent, of that in the urine. This biliary sulphur (taurin) is normally reabsorbed, as the quantity of sulphur in the feces (FeS, Na 2 S) is small and derived principally from pro- teid putrefaction. The amount of neutral sulphur in the urine is greatest under a meat diet, least when fat or gelatin is fed; the sulphur of gelatin is very small in quantity. In dyspncea the amount of neutral sulphur in- creases in the urine, on account of insufficient oxidation. 3 The neutral sul- phur of the urine includes potassium sulphocyanide (originally derived from the saliva), likewise a substance which on treatment with calcium hydrate yields ethyl sulphide, (C 2 H 5 ) 2 S, 4 and there are present other unknown com- pounds (see p. 547). When an animal eats proteid and neither gains nor loses the same in his body, the amount of sulphur ingested is equal to the sum of that found in the urine and feces. If sulphur be eaten, it partially appears as sulphate in the urine. Sulphates eaten pass out through the urine. They play no part in the life of the cell. Chlorine, CI = 35.5. Free chlorine is not found in the organism, and when 1 neat lied it vigor- ously attacks the respiratory mucous membranes. Chlorine is found combined in the body as sodium, potassium, and calcium chlorides, as hydrochloric acid, and it is said to belong to the constitution of pepsin. 8 Hydrochloric Acid, HC1, is found to a small extent in the gastric juice. Preparation. — (1) If sunlight acts on a mixture of equal volumes of chlorine and hydrogen, they unite with a loud explosion. 1 Kunkel : Archivfur < gesammte Physiologic, 1877, Bd. 14, S. 353. 2 Zeitsekrifi fur Biologie, 1894, Bd. 30, S. 554. 3 Harnack and Kleine: Zeitachrift fur Biologie, 1899, Bd. 37, S. 417. 4 J. J. Abel : Kitsch rift fur physiologisehe ('hemic, 1894, 1!<1. 'Jo, S. 253. 5 E. O. Schoumow -Simanowski : Archiv fiir exper. Pathologie und Pharmakologie, 1894, Bd. 33, S. 336. 508 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. (2) By the art ion of strong sulphuric acid on common salt. L'XaCl + H 2 S0 4 = Na 2 S0 4 + 2HC1. (3) By the action of primary acid phosphate of sodium on common salt, NaCl NaH 2 P0 4 = Na 2 HP0 4 + HCl. This, according to Maly, represents the process in the cells of the gastric glands. Properties. — Hydrochloric acid readily unites with most metals, forming chlorides. It causes a gelatinization of the proteids and seems to unite with them chemically. Such gelatinization is a necessary forerunner of peptic di- gestion. The cleavage products of peptic digestion (peptones, proteoses, etc.) combine with more hydrochloric acid than the original more complex proteid. 1 Free hydrochloric acid of the strength of the gastric juice (0.2 per cent.) inverts cane-sugar at the temperature of the body, 2 and inhibits the action of bacteria. Hydrochloric acid is derived from decomposition of chlorides in the secreting cells of the stomach. It has been shown that the excretion of common salt in the urine is decreased during those hours that the stomach is active, while the acidity of the urine decreases. If, in a dog with a gastric fistula, the mucous membrane of the stomach be stimulated and the gastric juice be removed as soon as formed, the urine becomes strongly alkaline with sodium carbonate (the excess of Na liberated taking this form) while the chlo- rides may entirely disappear from the urine. 3 Respiration in an atmosphere containing 0.5 per cent. HC1 gas becomes very uncomfortable after twelve minutes/ It' the bases (K, Na. Ca. M>. r , Fe) of gastric juice and then the acid radicals (CI and P 2 5 ) be determined, and the phosphoric anhydride be united with the proper bases, and then chlorine with the rest of the bases, there still remains an excess of chlorine which can only have belonged to the hydrochloric acid present. To detect free hydrochloric acid put three or four drops of a saturated alcoholic solution of tropseolin 00 in a small white porcelain cover, add to this an equal quantity of gastric juice, evaporate slowly, and the presence of hydrochloric acid is shown by a beautiful violet color, not given by any organic acid. 5 Griinzburg's reagent consisting of phloroglucin and vanillin in alcoholic solution, warmed (as above) with gastric juice containing tree hydrochloric acid, gives a carmine-red mirror on the porcelain, not given by an organic acid. 6 CHLORINE in THE body is ingested as chloride, and leaves the body as such, principally in the urine, likewise through the sweat and tears, and in traces in the feces. Bromine, Br = 80. Salts of bromine are found in marine plants and animals, but their physiological im- portance has not been established. Bromine is a fluid of intensely disagreeable odor, 1 Chittenden: Qartwrighl Lectures on Digestive Proteolysis, 1895, p. 52. * Ferris and Lusk : American Journal of Physiology, 1898, vol. i. p. 277. 3 E O. Schoumow-Simanowski : Arckiv fur a/per. Pathologie und Pharmakologie, 1894, Bd. 33, S. 336. * Lehmann : Archiv fur Hygiene, Bd. 5, S. 1. ' Boas: Deutsche medicinische Wocketnschrift, 1887, No. 39. '• < iiinzburg : Centralblatt fiir Iclinische Medicin, 1887, No. 40. THE CHEMISTRY OF THE ANIMAL BODY. 509 whose vapors strongly attack the skin, turning it brown, and likewise the mucous mem- branes of the respiratory passages. Hydrobromic Acid, HBr, may be prepared by the action of water on phosphorus tribromide, PBr 3 + 3H 2 - 3HBr + H 3 P0 3 . It is a colorless gas of penetrating odor. If sodium bromide be given to a dog in the place of sodium chloride, fifty per cent, and more of the hydrochloric acid may be sup- planted by hydrobromic acid in the gastric juice. 1 The various organs are then found to contain bromine, especially the kidneys' through which it may be eliminated. Iodine, I = 127. Like bromine, the salts of iodine ai'e found in many marine plants and animals, espe- cially in the algae. It is found in the thyroid gland. Iodine is prepared in metallic-looking plates, almost insoluble in water, but soluble in alcohol (tincture of iodine). Iodine is still more strongly corrosive in its action on animal tissue than is chlorine or bromine, and is an antiseptic and disinfectant. A slight trace of free iodine turns starch blue. Hydriodic Acid, HI, is prepared like hydrobromic acid, by the action of water on tri-iodide of phosphorus. An aqueous solution of hydriodic acid introduced into the stomach is absorbed, and shortly afterward iodine, as alkaline iodide, may be detected in the urine. On administration of sodium iodide to a dog with his food, only very little hydriodic acid appears in the gastric juice.* Circulation in the Body. — Iodine or iodides given are rapidly eliminated in the urine, in smaller amounts in saliva, gastric juice, sweat, milk, etc. It is noticed that ti »r weeks after the administration of the last dose of potassium iodide, traces of iodine are found in the saliva, and none in the urine. The explanation lies in the presumption that iodine has been united with proteid to a certain extent, and appears in such secretions as saliva, which contains materials derived from proteid through glandular manufacture. 4 A similar explanation avails in the case of Drechsel's 5 discovery that, in patients who have been treated with iodides, iodine may be detected in the hair (the keratin of hair being derived from other proteid bodies.) Whether free iodine or hydriodic acid is liber- ated in the tissues from ingested iodides are disputed points. Baumann 6 discovered an organic compound of iodine occurring in the thyroid gland and containing as much as 9.3 percent, of iodine. Roos 7 states that this thyroiodine from sheep's thyroid constantly contains about 5 per cent, of iodine. When fed it increases the metabolism of proteid and fat 8 and acts as an antitoxine. According to Blum, 9 the iodine is combined with the pro- teids of the thyroid in varying quantity, and any liberated iodine may act within the thy- roid to destroy toxic bodies, especially nerve toxines. 10 Oswald, 11 on the contrary, states that the effective principle of the thyroid is a thyroglobulin containing L.66 per cent, of iodine. This thyroglobulin treated with acids yields thyroiodine. which contains 14.4 per cent, of iodine. Thyroids which contain no iodine have no physiological effect upon metabolism. 12 1 Nencki and Schoumow-Simanowski : Arehivfiir exper. Pathologie wnd Pharmakologie, 1895, Bd. 34, S. 320. 2 Rosenthal: Zeitschrift fur physiologische Chemie, 1896, Bd. 22, S. 227. 3 Nencki and Schoumow-Simanowski : Lor. cit. * Schmiedeberg : Qrundriss der Arzeinmittellehre, 2d ed., 1888, S. 197. 5 Cailralblatt fur Physiologic, 1896, Bd. 9, S. 704. 6 Zeitschrift fur physiologische Chemie, 1895, Bd. 21, S. 319. 7 Ibid., 1898, Bd. 25, S. 1. 8 Voit, F. : Zeitschrift fur Biologie, 1897, Bd. 35, S. 116. » Zeitschrift fiir physiologische Chemie, 1898, Bd. 26, S. 160. 10 Blum: Pfluger'a Archiv, 1899, Bd. 77, S. 70. 11 Zeitschrift fiir physiologische ('/ionic, 1899, Bd. 27, S. 14. u Boss, E. : Ibid., 1899, Bd. 28, S. 40. 510 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Fluorine, F = 19. Fluorine is found in the bones and teeth, in muscle, brain, blood, and in all investigated tissues of the body, though in minute quantities. In one liter of milk 0.0003 gram of fluorine have been detected. 1 Fluorine is found in plants, and in soil without fluorine plants do not flourish. It seems to be a necessary constituent of protoplasm. Free fluorine is a gas which cannot be preserved, as it unite- with any vessel in which it is prepared. Hydrofluoric Acid, 1II\ is prepared by heating a fluoride with concentrated sul- phuric acid, in a platinum or lead dish. CaF,+ H a S0 4 = CaS0 4 + 2HF. Properties. — Hydrofluoric acid is a colorless gas, so powerfully corrosive that breathing its fumes results fatally. Its aqueous solutions are stable, but can be kept only in vessels of platinum, gold, lead, or india-rubber. It etches glass, uniting to form volatile silicon fluoride, Si0 2 + 4HF = SiF 4 -f-2H 2 0. Circulation in the Body. — Tappeiner and Brandl 2 have shown, on feeding sodium fluoride (NaF) to a dog in doses varying between 0.1 and 1 gram daily, that the fluorine fed was not all recoverable in the urine and feces, but was partially stored in the body. On subsequently killing the dog, fluorine was found in all the organs investigated, and was especially found in the dry skeletal ash to the extent of 5.19 per cent, reckoned as sodium fluoride. From the microscopic appearance of the crystals seen deposited in the bone, the presence of calcium fluoride was concluded. In this form it normally occurs iu bones and teeth. Nitrogen, N = 14. Free nitrogen constitutes 79 per cent, of the volume of atmospheric air. It is found dissolved in the fluids and tissues of the body to about the same extent as distilled water would dissolve it. It is swallowed with the food, may par- tially diffuse through the mucous membrane of the intestinal tract, but forms a considerable constituent of any final intestinal gas. It is found in the atmos- phere combined as ammonium nitrate and nitrite, which are useful in furnish- ing the roots of the plant with material from which to build up proteid. Bacteria upon the roots of certain vegetables combine and assimilate the free nitrogen (.ft he air (Hellriegel and Willforth). Cultures of alga do the same. 3 Preparation. — (1) By abstraction of oxygen from air through burning phosphorus in a bell jar over water, pentoxide of phosphorus being formed, which dissolves in the water and almost pure nitrogen remains. _• By heating nitrite of ammonium, NH 4 NO, = 2N+-2B O. Properties. — Nitrogen is especially distinguished by the absence of chemical affinity for other element-. It does not support combustion, and in it both a 1 i i. Tammann : Zeitschrifi fiir physiologiseht Chemie, 1888, Bd. 12, S. 322. 5 ZeUachrifi fur Biologic, 1892, Bd 28, S. 518. 3 P. Kosaowitch : Botaniaehe Zeitung, L894, Jahrg. 50, S. 97. THE CHEMISTRY OF THE ANIMAL BODY. 511 flame and animal life are extinguished, owing to lack of oxygen. It acts as a diluent of atmospheric oxygen, thereby retarding combustion, but on higher animal life it is certainly without direct influence. Ammonia, NH 3 , is found in the atmosphere as nitrate and nitrite to the extent of one part in one million. It is found in the urine in small quantities, is a constant product of the putrefaction of animal matter, and is a product of trypsin proteolysis. Preparation. — (1) Through the action of nascent hydrogen on nascent nitrogen. This may be brought about by dissolving zinc in nitric acid, 3Zn + 6HNO3 = 3Zn(M) 3 ) 2 + 6H. . 10H + 2HN0 3 = 6H 2 + 2N. N + 3H = NH 3 . Ammonia is produced in a similar way in the dry distillation of nitro- genous organic substances in absence of oxygen, being therefore a by-product in the manufacture of coal-gas. In putrefaction nascent hydrogen acts on nascent nitrogen, producing ammonia, which in the presence of oxygen becomes oxidized to nitrate and nitrite, or in the presence of carbonic oxide is con- verted into ammonium carbonate. Ammonium nitrite is likewise formed on burning a nitrogenous body in the air, in the evaporation of water, and on the discharge of electricity in moist air, 2N + 2H 2 = NH 4 N0 2 . At the same time a small amount of nitrate is formed in the above three processes, 2N + 2H 2 + O = NH 4 NO s . Hence these substances find their way into every water and soil, and furnish nitrogen to the plant. The value of decaying organic matter as a fertilizer is likewise obvious. Properties. — Ammonia is a colorless gas of pungent odor. It readily dis- solves in water and in acids, entering into chemical combination, the radical NH 4 appearing to act like a metal with properties like the alkalies, and its salts will be described with them. Very small amounts of ammonia instantly kill a nerve, but upon muscular substance it acts first as a stimulant, provok- ing contractions: 1 part of ammonia in 500 of water will kill an amoeba, and 1 part in 10,000 will slow and finally arrest ciliary motion. 1 Ammonia in the Body. — If it be agreed with Hoppe-Seyler licit normal decomposition in the tissues is analogous to putrefaction, then nascent hydrogen acting on nascent nitrogen in the cell produces ammonia, which in the presence of carbonic acid becomes ammonium carbonate, and in turn may be converted into urea by the liver. If acids (1IC1) be fed to carnivore (dogs) the amount of ammonia present in the urine is increased, which indicates that an amount of ammonia usually converted into urea has been taken for the neutralization 1 Bokorny : Pjliiyer's Archiv, 1895, Bd. 59, S, 557. 512 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. of the acid. 1 In a similar manner acids formed from decomposing proteid may be neutralized (see pp. 506 and 550). The ammoniacal fermentation of the urine consists in the decomposition of urea into ammonium carbonate by the micrococcus urince, the urine becoming alkaline. Compounds of Nitrogen with Oxygen. — There are various oxides of nitrogen, the higher ones being powerfully corrosive, and Borne of these unite with water to form acids, of which nitric arid I 1 1 N< ).. is the strongest. Only nitrous and nitric oxides are of physi- ological interest. Nitrous Oxide, N 2 0, likewise called "laughing-gas," is prepared by heating ammo- nium nitrate, NH 4 NO s = N s O + 2H a O. It supports ordinary combustion almost as well as pure oxygen, but it will not sustain life. Mixed with oxygen it may be respired, producing a state of unconsciousness preceded by hysterical laughter. Nitric Oxide, NO, is prepared by dissolving copper in nitric acid, 3Cu + 8IIN0 3 = 3Cu(N0 3 ) 2 + 4H, 2 + 2NO. Contact with oxygen converts it into peroxide of nitrogen (N0 2 ), which is an irritating irrespirable gas of reddish color. Nitric oxide in blood first unites with the oxygen of oxyhemoglobin, forming the peroxide 1 NO,), and then the nitric oxide combines with haemoglobin, forming a highly .-table compound, nitric-oxide haemoglobin (Hb-NO). Nitrogen en the Body. — Nitrogen is taken into the body combined in the great group of proteid substances, which are normally completely absorbed by the intestinal tract. It passes from the body in the form of simple decom- position-products, in larger part through the urine, but likewise through the juices which pour into the intestinal canal. The unabsorbed residues of these latter juices, mixed with intestinal epithelia constitute in greater part the feces. 2 An almost insignificant amount of nitrogen is further lost to the body through the hair, nails, and epidermis, but, generally speaking, the sum of the nitrogen in the urine and feces corresponds to the proteid decomposition for the same time (1 gram N = 6.25 grams proteid). When the nitrogen of the proteid eaten is equal in quantity to the sum of that in the urine and feces, the body is said to be in nitrogenous equilibrium. When the ingested nitrogen has been larger than that given off, proteid has been added to the substance of the body; when smaller, proteid has been lost. These propositions were established by Carl Voit. A small amount of urea and other nitrogenous substances may be excreted in profuse sweating. Proteid nitrogen never leaves the body in the form of free nitrogen or of ammonia. That ammonia is not given off by the lungs may be demonstrated by perform- ing tracheotomy on a rabbit, and passing the expired air first through pure potassium hydrate (to absorb CO.,] and then through Nessler's reagent. The experiment maybe continued for hours with negative result. 3 1 Fr. Walther: Archiv fur exper. Pathologie und Pharmakologie, 1877, Bd. 7, S. 164. 1 Menichanti and Prausnitz : Zeitechrifi fur Biologic, 1894, Bd. 30, S. 353. 1 Bachl : Zeitechrifi fur Biologic, 1869, Bd. 5, S. 61. THE CHEMISTRY OF THE ANIMAL BODY. 513 Phosphorus, P =-32. Phosphorus is found combined as phosphate in the soil ; it is necessary to the development of plants. As phosphate it is present in large quantity in the bones, and is found also in all the cells, tissues, and fluids of the body, probably in loose chemical combination with the proteid molecule. It is pres- ent in nuclein, protagon, and lecithin. Preparation. — Phosphorus was first prepared by igniting evaporated urine, 3NaH 2 P0 4 + 5C = 3H 2 + 5C0 + 2P + Na 3 P0 4 . In a similar way it may be obtained by chemical treatment of bones. The vapors of phosphorus may be condensed by passing them under water, where at a temperature of 44.4° the phosphorus melts and may be cast into stieks. Properties. — Phosphorus is a yellow, crystalline substance, soluble in oils and carbon disulphide. It is insoluble in water, in which it is kept, since in moist air it gives off a feeble glowing light, accompanied by white fumes of phosphorous acid (H 3 PO :) ) and small amounts of ammonium nitrate, peroxide of hydrogen, and ozone, to which latter the peculiar odor is ascribed. Phosphorus ignites spontaneously at a temperature of 60°, and this may be produced by mere handling, the resulting burns being severe and dangerous. This form of phosphorus is poisonous, but if it be heated to 250° in a neutral gas (nitrogen) it is changed into red phosphorus, which has different properties and is not poisonous. Phosphorus-poisoning. — On injecting phosphorus dissolved in oil into the jugular vein, embolisms are produced by the oil in the capillaries of the lungs, the expired air contains fumes of phosphorous acid, and the lungs glow when cut out (Magendie). If the phosphorus oil be injected in the form of a fine emulsion, embolism is avoided, 1 and the fine particles of phosphorus are generally distributed throughout the circulation. On autopsy of a rabbit alter such injec- tion in the femoral vein, all the organs and blood-vessels glow on exposure to the air. 2 If two portions of arterial blood be taken, and one of them be mixed with phosphorus oil, and they be let stand, both portions become venous in the same time. 3 Hence phosphorus in blood, as in water, is not readily oxidized. Persons breathing vapor of phosphorus acquire phosphorus-poisoning. What the direct action of phosphorus is, is unknown, but the results are most inter- esting. To understand the results it maybe supposed that proteid in decompos- ing in the body splits up into a nitrogenous portion, the nitrogen of w hioh finds it- exit through the urine and feces, and a non-nitrogenous portion, which i- re- solved into carbonic oxide and water, just as arc the sugars ami the fats. Phis carbonic acid is given off, for the most part, through the lungs. Now if a starv- ing dog, which lives on his own flesh and tilt, be poisoned with phosphorus, the proteid decomposition as indicated by the nitrogen in the urine is largely increased, while the amounts of carbonic acid given oil' and oxygen absorbed are largely decreased ; on post-mortem examination the organs arc found to contain excessive quantities of fat. We have here presumptive evidence that a part of the proteid molecule usually completely oxidized has not been burned, 1 L. Hermann: Pjlugei'i Archiv, 1870, Bd. :'>, S. 1. 1 II. Meyer: Archiv fur exper. Pathologic and Pharmakologie, L881, 1U1. 1 1, S. 327. 3 Meyer, Op. cit., S. 329. Vol. I.— 33 514 AN AM ERIC AX TEXT-BOOK OF PHYSIOLOGY. l»ut has been converted into fat. 1 Similar results are characteristic of arsenic and antimony poisoning, and of yellow atrophy of the liver. Rosenfeld has recently shown that much of the tat found in the liver of a dog poisoned with phosphorus is fat transported from the fat repositories of the body (fatty infiltration). The high proteid metabolism, however, of itself would indicate the retention of an unburned part of the proteid molecule, which in this case probably appears as fat - (fatty degeneration, see p. 559). A parallel case of high proteid metabolism is seen in diabetes, where sugar from proteid remains unburned. Compounds of Phosphorus with Oxygen. — Of these compounds three oxides ami several acids exist, but only meta- and orthophosphoric acid need attention here. Phosphorus Peroxide, P 2 5 , is a white powder, which rapidly absorbs moisture; it is produced by burning phosphorus in dry air. Metaphosphoric Acid, HPO s , is said to occur combined in nuclein. Preparation. — (1) By dissolving P 2 O s in cold water, P 2 5 + H 2 = 2HP0 3 . (2) By fusing phosphoric acid, H 3 P0 4 = HP0 3 + H 3 0. It is converted slowly in the cold, rapidly on heating, into phosphoric acid. ( r\ stalline it forms ordinary glacial phosphoric acid. Metaphosphoric acid precipitates proteid from solution, yielding a body said to be pseudonuclein, 3 but this seems to be untrue* (see p. 579). Orthophosphoric Acid, H 3 P0 4 . — Salts of this acid constitute all the in- organic compounds of phosphorus in the body, and are called phosphates. Preparation. — (1) By heating solutions of metaphosphoric acid, HP0 3 + H 2 = H 3 P0 4 . (2) By treating bone-ash with sulphuric acid, 0a ,(P0 4 ) 2 + 3H 2 S0 4 = 3CaS0 4 + 2H 3 P0 4 . Properties. — On evaporation of the liquors obtained above, the acid separates in color- less hydroscopic crystals. Phosphoric acid forms different salts according as one, two, or three atoms of hydrogen arc supplanted by a metal. Thus there exist primary sodium or calcium phosphates, Nail, PO, and Ca ( >' ; the secondary phosphates. Na 2 IIP0 4 and CaHP0 4 : and the tertiary phosphates, Na t l'<) 4 and Ca*(P0 4 ) s . On account of their reaction to litmus these salts have been falsely called acid, neutral, and basic, but the secondary salts are, chemically speaking, acid salts. The bones contain a large quantity of tertiary phosphate of calcium ; the fluids and cells of the body contain likewise the primary and secondary phos- 1 J. Bauer: Zeitschrifl fur Biolnrjie, 1871, Bd. 7, S. 63. 2 Kay, McDermott, and Ltisk : American Journal of Physiology, 1899, vol. iii. p. 139. 3 L. Liebermann : Berichte der deutschen chemischen Gesellschaft, Bd. 22, S. 598. 'Salkowski: Pfiuger's Archiv, 1894, Bd. 59, S. 245; also, Giertz: Zeitschrift fitr physiv- logische Chemie, 1899, Bd. 28, S. 115. THE CHEMISTRY OE THE ANIMAL BODY. 515 phates, while to primary sodium phosphate carnivorous urine mainly owes its acid reaction. In speaking of the ash of protoplasm, Nencki 1 advocates the idea of separate combinations of the base and acid radicles with the proteid molecule, as, for example, the sepauate union of potassium with proteid and of phosphoric acid with proteid, in the functionally active cell. However combined, phosphoric acid is necessary for the organism. Phosphorus in the Body. — The principal source of supply is derived from the phosphates of the alkalies and alkaline earths in the foods ; it may be absorbed in organic combinations in nuclein, casein, and caseoses ; and it may perhaps be absorbed as glycerin phosphoric acid, which is an intestinal decompo- sition product of lecithin 2 and probably also of protagon. Phosphorus leaves the body almost entirely in the form of inorganic phosphate, the only exception being glycerin phosphoric acid, which has been detected in traces in the urine. In man and carnivora the soluble primary and secondary phosphates of the alkalies are found in the urine, together with much smaller amounts of the less soluble primary and secondary phosphates of the alkaline earths. There is likewise, even during hunger, a continuous excretion of tertiary phosphate of calcium, magnesium, and iron in the intestinal tract. In herbivora the ex- cretion is normally into the intestinal tract, and no phosphates occur in the urine. This is because herbivora eat large quantities of calcium salts which bind the phosphate in the blood, and they likewise eat organic salts of the alkalies, which become converted into carbonate and appear in the urine as acid carbonates ; such a urine has no solvent action on calcium phosphate. 3 In a similar manner a great reduction of phosphate in the urine of man may be effected by feeding alkaline citrate and calcium carbonate, the first to furnish the more alkaline reaction to blood and urine, the second to bind the phosphate in the blood. The more alkaline reaction itself is insufficient to prevent the appearance of phosphates in the urine. 4 On the other hand, starving herbiv- ora, or herbivora fed with animal food, give urines acid from primary phos- phate. 5 In diabetes where there is a large production of abnormal acids which tend to neutralize the blood, there is a more acid urine which contains an increased amount of calcium phosphate, and the excretion of the same through the intestinal wall correspondingly decreases. During lactation the amount of phosphate eliminated through the ordinary channels is decreased, for a considerable amount is used to form the milk. 7 Excreted phosphates may be originally derived from the phosphates of the bones, or from phosphates arising from the oxidation of nuclein, protagon, and lecithin, but by far the greater quantity is derived from the food, or from pro- 1 Archiv far exper. Pathologie und Pharmakologie, 1894, lid. 31, S. 334. - B6kay: Zeitichrift fur phynologisehe Chemie, l s 77 78, Bd. 1, S. 157. 3 J. Bertram : Zeitsehrift fur Biologie, 1878, Bd. 14, S. 354. * Op. cit., S. 354. 4 Weiske: Ibid., 1872, Bd. 8, S. 246. 6 Gerhardt und Schlesinger : Archiv far exper. Pdlhohf/ie und Pharmakologie, L899, Bd. 12, S. 83. 7 Paton, Donlop, and Aitchison : Journal of Physiology, 70 . xxv. p. 212. 516 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. tt id metabolism. In a starving dog, which feeds on its own proteid, it was found that a ratio existed between nitrogen and phosphoric acid in the urine as 0.4:1, which approximates that in muscle, i.e. 7.6:1. On feeding meat till nitrogenous equilibrium was established, the ratio became 8.1 : l. 1 On addi- tion of proteid to the body, a proportionate amount of phosphoric acid is re- tained for the new protoplasm, while on destruction of proteid the phosphoric acid corresponding to it is eliminated. In diabetes where the proteid metab- olism i> far above the normal, the phosphorus excretion remains propor- tional to the proteid destroyed. 2 The larger excretion of phosphoric acid during hunger shown in the ratio above, has been ascribed to the decomposi- tion of the bones. 3 Thus Munk found on Cetti, who lived many days without food, a ratio as low as 4.5:1. In starvation the brain and nerves do not decrease in weight, so the protagon can hardly yield any great amount of phos- phoric acid (Voit). Casein and other nucleo-albumins, when fed, are oxidized and furnish phosphoric acid for the urine. Carbon, C = 12. This element is found combined in every organism, and in many decom- position-products of organized matter. Elementary carbon occurs as lamp- black, diamond, and graphite, the two latter having their origin from the action of high heat on coal. Carbon occurs combined in coal, petroleum, and natural gas, which are all products of the decomposition of wood out of contact with the air. Further it is found in vast masses, principally consisting of calcium car- bonate, having their origin from sea-shells. The maintenance of life depends, as will be shown, on the small percentage of carbon dioxide which is contained in the atmosphere. Lavoisier believed that compounds of carbon were all products of life, formed under the influence of a '" vital force," which was a property of the cell. It is now known that almost every constituent of the cell may be prepared from its elements in the laboratory without the aid of any "vital force" whatever. Notwithstanding its loss of strict scientific significance, the old term "organic" for a carbon compound is still in vogue, and conveniently describes a large number of bodies which are treated under the head of "or- ganic chemistry," while the term "inorganic" is applied to the rest of the chemical world. Elementary Carbon. — This burns only at a high heat. It is unaffected by the intestinal tract. This is shown by the fact that diamonds have been stolen by -wallowing them, and that finely divided particles of lampblack pass unchanged and unabsorbed to the feces, coloring them black (proof that the intestinal canal does not absorb solid particles). If lampblack be eaten with a meal its appearance in the feces may be used as a demarcation line between the 1 E. Bischoff: Zeilschrift jr,,- Bidogie, 1867, Bd. 3, S. 309. 2 Colaasanti e Bounani: Boll. r be pro- duced in the body after eating potassium carbonate or phosphate, since these salts may react with the sodium chloride. If fed, it is ordinarily balanced by its ex- cretion, but if 0.1 gram be introduced into the jugular vein of a medium-sized dog, immediately paralysis of the heart ensues. It is a powerful poison fornerves and nervous centres. It melts when heated to a low red heat, and volatilizes at a higher heat. 1 Bunge: Physiologixche Chemie, 3d ed., 1894, S. 25. 520 AS AMERICAS TEXT-BOOK OF PHYSIOLOGY. Potassium Phosphates. — The primary (K H 2 PG 4 ) and secondary (K 2 HP0 4 ) phosphate of potassium are the principal .silts <>f the cells of the body, and are likewise present in the urine, and to a very small extent in the blood-plasma. They are undoubtedly intimately connected with the functional activity of proto- plasm. Presence of carbonic acid causes the conversion of the secondary phos- phate into the primary salt, and this occurs in the blood-corpuscle as well as in the plasma : K 2 HP< ) 4 + C< ) 2 + H 2 = KH 2 P0 4 + KHCO3. Primary acid phosphate of potassium contributes to the acid reaction of the urine, though in presence of .-odium chloride there is a tendency to the forma- tion of primary sodium phosphate and potassium chloride. It is the cause of the acid reaction in muscle in rigor mortis (see p. 546). Potassium Carbonates. — The primary and secondary carbonates exist in the body only in trifling quantities. They may be produced as above de- scribed by the action of carbonic acid on the phosphates, they may be ingested with the food, or they may result in the body from the combustion of an organic salt of potassium, according to the same reaction as would take place by burn- ing it in the laboratory, KAH 4 O fl + 50 = K 2 CO s + 3C0 2 + 2H 2 0. K tartrate. Feeding potassium carbonate or an organic salt of potassium makes the urine alkaline owing to the excretion of potassium carbonate. Potassium salts are poisonous if introduced into the blood in too large quantities. In concentrated solutions in the stomach the} 7 produce gastritis, even with quickly fatal results.' Zuntz believes that potassium is combined with haemoglobin in the blood-corpuscle, and may be dissociated from it by the action of carbonic oxide. 2 Potassium in the Body. — The various salts of potassium are received with the food in the manner described ; the phosphate may be retained for new tissue, but the other salts are removed in the urine. They are all quite completely absorbed in the intestinal tract. In starvation, or in fever, where there is high tissue-metabolism, the body suffers greater loss of the potassium phosphate-containing tissue than it does of the sodium-rich blood, and potas- sium exceeds sodium in the urine (reverse of the usual proportion); also milk, which is prepared from tissue, contains more potassium than sodium. Bunge 3 has noted an important influence of potassium salts. If a potassium sail be in solution together with .-odium chloride, the two partially react on each other, with formation of potassium chloride. If now potassium carbon- ate, for example, be eaten, the same reaction occurs in the body, K 2 ( !< >, + 2Na< 11 = 2KC1 + Na 2 C0 3 . The kidney has the power of removing soluble substances which do not belong to the blood or are present in it to excess, and consequently the two salts 1 Bunge: Physiologiache CKemie, 3d ed., 1894, S. 136. s A. Loewy und X. Zuntz: Pfluger'i ArcMv, 1894, Bd. 58, S. 522. :; Op. cit., S. 108. THE CHEMISTRY OF THE ANIMAL BODY. 521 formed as above are excreted. Hence potassium carbonate has caused a direct loss of sodium and chlorine. For this reason, if potatoes and vegetables very rich in potassium salts are eaten, sodium chloride must be added to the food to compensate for the loss. Nations living on rice do not need salt, for here the potassium content is low. Tribes living solely on meat or fish do not use salt, but care is taken that the animals slaughtered for food shall not lose the blood, rich in sodium salts, and strips of meat dipped in blood are, by some races, considered a delicacy. 1 Sodium, Na = 23. Sodium salts belong particularly to the fluids of the body (see p. 504), blood-plasma containing 0.4 per cent, calculated to Na 2 < >. Sodium chloride, NaCl, is found in all the fluids of the body. It is found in blood and lymph to an extent of about 0.65 per cent., in the saliva, gastric juice, milk, sweat, urine, etc. Sodium chloride, like potassium chloride, melts at a low red heat, hence the fluids of the body yield a fluid ash, with the single exception of milk, which contains a high percentage of infusible calcium phos- phate. Sodium chloride is very readily soluble. In the blood it acts as a solvent on serum-globulin and other proteids, and its inert presence in proper concentration affords a medium in which the functional activity of cells and tissues is maintained. (For "physiological salt-solution" see p. 504.) From sodium chloride the hydrochloric acid of the gastric juice is prepared (sec p. 508) ; it is also a necessary addition to every food where potassium salts are in great preponderance (see p. 520), but it is taken by most races in amounts far above these physiological necessities. If a mixture of necessary food-stuffs — proteid, fats, starch, salts, and water — in proper proportion, but without flavor, be set before a dog, he will starve rather than touch it. A man will attempt its digestion, but the permanent support of life is impossible. A food to support life must be a well-tasting mixture of food-stuffs, lor. through the action of the flavor on the mucous membrane of the mouth and stomach there is established reflexly a nervous influence causing a proper flow of the various digestive juices. Hence salt, pepper, mustard, beer, wine, and other condiments are taken with the food. What the change is, when a substance acts on the taste-buds of the tongue, for example, start- ing a motion such as is afterwards interpreted in the brain as flavor, is unknown. Chemical constitution gives no hint how a body will taste or smell. In carnivora every trace of sodium chloride is absorbed by the villi from the intestinal tract. This is a proof that absorption does not depend on simple physical osmosis, in which case the intestinal contents would tend to have the same percentage composition as the blood, but upon the selective capacity of the exposed protoplasm of the villi. Sodium chloride is the principal solid con- stituent of sweat and of tears. Usually, however, it is lost to the body through the urine, of whose ash it forms the chief constituent. The quantity of salt in the urine is decreased during gastric digestion (sec p. 508). Sodium chloride if fed is largely excreted in the urine within the following twenty- four hours. 2 Experiments of abstention from .-ah have aever been carried 1 I'.unge: Op. cit., S. 116. 'Strajib: Zeitschrift fur Biologie, 1899, Bd. 37,S. 483. 522 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. so far as to produce vital disturbances, but the physiological minimum is probably very low. A dog weighing 35 kilograms may live on 0.6 gram of salt daily. 1 Sodium chloride, f'c> Physiologie, 1890, p. 739. 5 Hamtnarsten : Zetiachrifl fur physiologische Chemie, 1899, Bd. 28, S. 90. 4 Bowel! and Cooke: Journal of Phi/xiology, 1893, vol. 14, p. 219, note. 5 Howell : Ibid., 1894, vol. 16, p. 47<:. THE CHEMISTRY OF THE ANIMAL BODY. 525 the intimate relation between calcium salts and the functional activity of protoplasm. Howell 1 believes that calcium salts furnish the primary stim- ulus for the contraction of the heart. Calcium in the Body. — Calcium salts are especially needed in childhood for the growth of the bones. It has been estimated that the human suckling requires 0.32 gram CaO daily, and in the milk for that time is contained 0.55 gram to 2.37 grams, so that there may easily be lack of CaO when absorption is unfavorable. In children with rickets the bones contain too little calcium, and are abnormally weak and flexible. This same con- dition maybe reproduced in young growing dogs by feeding them entirely on meat and fat, which contain too little calcium for proper skeletal development. 2 Such dogs grow rapidly in size, especially around the thorax, while the pelvis remains ludicrously small, the extrem- ities become bent and finally incapable of supporting the weight of the body. A puppy of the same litter fed on the same food but with the addition of bones grows normally. In certain cases even when children are fed with sufficient calcium they still have the rickets. This might be due to a lack of ability to absorb the salts, but this Riidel 3 has disproved. To a child having rickets he administered a calcium salt, and confirmed its absorption by the increase in the calcium contents of the urine, the result being the same as with a normal child. (Example: Normal day, 0.0196 gram CaO in urine; after feeding 1.4 grams CaO dissolved in acetic acid the amount in the urine rises to 0.0396 gram for the twenty-four hours. ) Riidel therefore concludes that the cause of rickets may be in a local change of the bones themselves, whereby calcium salts are not deposited in the normal manner. In osteomalacia there occurs a solution of the salts of the bones in adult life, called softening of the bones. In osteoporosis, which is a simple atrophy of the bones, similar effects are produced. Voit* fed a pigeon for a year on washed wheat and distilled water. at the end of which time the pigeon apparently did not differ from the normal bird. A few months later a wing was broken, and the autopsy discovered osteoporosis in high degree, the skull being especially attacked. Weiske 5 has shown that rabbits ultimately die when fed on oats which are poor in calcium ; the oats yield an acid ash and produce an acid urine. On autopsy osteoporosis is found. This does not take place when calcium carbonate is added to the food. Whether the loss of salts to the bone is due ton normal metabolism, or to solution due to the production of acids in the metabolism of proteid, is an unanswered problem (see pp. 506, 511) the discussion of which lack of space forbids. 6 In such experiments as the above, the percentage of ash is always diminished, while the percentage of organic matter always rises, whereas the actual percentage composition of the ash itself remains the same. This is a strong argument in favor of the view that bone is a mineral of definite chemical composition. The mineral matter of bone is believed by some to be loosely combined with the organic material, principally ossein, but of this there is no proof. The exact amount of calcium salt necessary to keep up the supply in the adult body is unknown, but it must be exceedingly small. A dog of 3.8 kilograms eating with his food 0.043 gram CaO maintains his calcium equilibrium (Heiss). Regarding the absorption of calcium salts, it has long been questioned whether inorganic salts can lie absorbed, since, it was argued, insoluble 1 American .four/nil of Physiology, 1898, vol. '_', p. 17. 2 E. Voit : ZeiUchriftfSr Biologie, 18S0, Bd. 16, S. 70. 3 Archiv fur exper. Pathologie und Pharmakologie 1893, Bd. 33, S. 90. 1 Hermann's Handbueh, 1881, vi. 1, 8. 379. • Zeitschriftfur Biologie, 1894, Bd. 31, 8. 421. 6 See Weiske, Loc.cit.; Bunge, Physiologische Chemie, :!<1 ed., 1894, S. 104; V. Noorden, Path- ologie der Stoffweehsels, 1893, S. 48 and 413. 526 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. phosphate would immediately be precipitated in the blood. It has, however, been conclusively shown that such salts when eaten produce an increase in the calcium of the urine ' and it is known that blood has a special capability for carrying calcium phosphate. Calcium carbonate and chloride are capable of absorption, while absorption of the phosphate may be considered as still in doubt. If calcium chloride be given, a little of the calcium appears in the nine, and all of the chlorine, this being due to the conversion in the intes- tine of calcium chloride into calcium carbonate and sodium chloride, which latter is completely absorbed. Organic salts of calcium such as the acetate are absorbable, as are probably proteid combinations with calcium such as casein. Milk and egg-yolk are the foods richest in calcium salts, cow's milk containing more calcium to the liter than does lime-water. 2 The excretion of calcium takes place in major part as triple phosphate from the wall of the small intestine, 8 in minor part through the urine (for the latter see pp. 515 and 524). It is excreted during starvation, and is the principal inorganic constituent of starvation feces (Yoit). The secretions of the intes- tines, according to Fr. Miiller, 4 hardly contain enough calcium to account for that found in the feces, so that it is probably excreted by the epithelial cells of the villus. In starvation the source of excreted calcium is principally from the breaking down of tissue, but partially from the metabolism of the bones. The excretion is never large. On subcutaneous injection of small amounts of calcium acetate in dogs, 5 the calcium excretion may be raised for several days. On venous injection of 0.8 gram CaO as acetate, after one hour but 0.3 gram could be found above the normal in the blood, and analy- sis of the liver, kidney, spleen, and intestinal wall failed to reveal more than the usual minimal amounts of calcium. As it is never rapidly excreted, it must have been temporarily deposited in some unknown part of the body. Strontium, Sr = 87.5. Cremer 6 has shown, on adding strontium phosphate to almost calcium-free food of young growing dogs, that the strontium line could he detected in the suhsequent spectral analysis of their bones. Weiske, 7 on feeding young rabbits with food nearly free from calcium, and with addition of strontium carbonate, found the ash in some of the bones to contain, in the place of CaO, as high as 4.09 per cent, of SrO. In both of the above experiments the skeleton remained very undeveloped in comparison with the normal, so that strontium cannot be considered a physiological substitute for calcium. 1 Riidel, Op. cil., S. 79. 2 Bunge: I'liy.siologische Chemie, 3d ed., 1894, 8. 101. 3 Voit F. : Zeitachriftfur Biologie, 1893, Bd. 29, S. 325. 4 Zeitschrift fur Biologie, 1894, Bd. 20, S. 356. 5 Rev : Archiv fiir exper, Pathologie unci Pfiarmakologie, 1895, Bd. 35, S. 298. r ' SUzungtiberichte der Gesellschaft fiir Morphologic unci Physiologie in M'dnchen, 1891, Bd. 7, s. 124. 7 Zcitxrhrift fiir Biologie, 1894, Bd. 31, S. 437. THE CHEMISTRY OF THE ANIMAL BODY. 527 Magnesium, Mg = 24.3. This is the second in importance of the alkaline earths. It is present wherever calcium is found, but in comparison with calcium it has been little investigated. It occurs principally as phosphate, but is found as carbonate in herbivorous urine. Of the total quantity of magnesium in the dog, Heiss found that 71 per cent, belonged to the bones. It is found decidedly pre- dominating over calcium in muscle, but is less in quantity than calcium in the blood. Magnesium Phosphates. — Magnesium tertiary phosphate, Mg 3 (P0 4 ) 2 , is found in the ash of bones to the extent of about 1 per cent., is present in blood and especially in muscle, probably in combination with protcid, and contrib- utes to the functional activity of protoplasm. It is continuously excreted by the walls of the intestinal canal. The primary and secondary phosphates of magnesium are found in carnivorous urine, solution of the latter being aided by the presence of primary alkali phosphate and sodium chloride. Tertiary phosphate of magnesium is insoluble in water, the secondary very slightly so, the primary quite soluble ; but all are soluble in acids. In the am- moniacal fermentation of the urine, ammonium magnesium phosphate, MgNH 4 - P0 4 , is precipitated as a fine crystalline powder insoluble in alkalies. When- ever this fermentation takes place, whether in the bladder or, by similar reaction, in the intestines (herbivora especially), stones are formed. 1 Magnesium Carbonates. — The neutral carbonate, MgC0 3 , is insoluble in water, but soluble in water containing carbonic oxide, forming secondary or acid carbonate, MgH 2 (C0 3 ) 2 . This latter occurs in herbivorous urine. Magnesium in the Body. — Considerations regarding the absorption of calcium apply likewise to magnesium. It is absorbed by the iutestine as inor- ganic and probably as organic combinations. If growing rabbits be fed on a diet poor in calcium salts, but containing magnesium carbonate, the bones may be brought to contain double the normal quantity of magnesium, but the skeletal development remains far behind that of a normal rabbit, and there- fore magnesium can in no sense be considered a substitute for calcium. 2 The magnesium salts, whether phosphate or carbonate, being more soluble than the calcium salts, occur in the urine in greater abundance. Indeed, in carniv- orous urine the major part of excreted magnesium is found in the urine, the balance being given off through the intestinal wall to the feces. In starvation the source of the excreted magnesium is from the bones, and especially from destruction of its combination in proteid metabolism. Iron, Fe = 56. This is the one heavy metal which is an absolute necessity for the organ- ism. About three grams occur in the average man. It has been demon- strated of certain bacteria that they will not develop in the absence of iron, 1 For example in man see C. Th, Mdrner: Zeitschrift fw ]>hysiologische Chemie, 1897, Bd. 22, S. 522. 2 Weiske : Zeitschrift fur Biologie, 1894, Bd. 31, S 437. 528 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. and this is believed to be true of all protoplasm. Iron is found through- out the body, and is especially an ingredient of haemoglobin (0.4 per cent.), which carries oxygen to the tissues. It is found deposited in the liver and the spleen as fcrratin. hepatin, and other less investigated organic compounds. It is found in muscle washed free from blood. Iron appears in urine and in milk as organic compounds, and in the bile, gastric juice, and intestines as phosphate, in the feces as sulphide. Iron occurs in two forms, the ferro- and ferri- compounds, in which it has respectively two and three bonds. Ferrosulphide, FeS. — This is found in the feces and is the product of the action of sulphuretted hydrogen or alkaline sulphide on both inorganic iron and likewise, more slowly, on organic iron-containing compounds (fer- ratin, luematogen, etc.). Ammonium sulphide acts in a similar manner, and, in all cases, ferric salts arc reduced to ferrous: 2FeCl 3 + 3(NH 4 ) 2 S = 2FeS + 6NH 4 C1 + S. Ferric chloride. Ferric Phosphate, FeP() 4 . — This is found in the gastric juice, bile, and probably in the intestinal juice; 1 it is not, as many have believed, given off* by the epithelia of the intestines. It is soluble in mineral acids, but insoluble in water, alkalies, or acetic acid. Ikon ix the Body. — The amount of iron in the urine is very small, amounting daily in a large starving dog to 0.0013-0.0049 gram. 5 Feeding iron compounds does not increase the amount of iron in the urine. Forster 3 led a dog of 26 kilograms for thirty-eight days with washed meat containing 0.93 grams of iron, and in the feces were found 3.59 grams belonging to the same period. Here there was a loss of 2.66 grams 4 of iron from the body, and the necessity of iron as a food was established. Concerning the method ami the amount of iron-absorption, considerable difficulty has been encountered owing to the fact that both absorptive and secretive organs lie in the intestinal canal. < hi feeding a dog for thirteen days with meat containing 0. Isu gram Fe, there were found in urine and feces for the same time 0.1765 gram Fe : then to the same food lor a similar length of time were added 0.441 grain Fe (as sulphate), making in all 0.636 gram Fe, and of this 0.6084 gram were recovered in the excreta. 6 This experiment proves only that such absorption as may take place is pretty nearly balanced by the excre- tion. Alter eating hi 1 the feces are found to contain much hiematin. and it has been thought that iron could not be absorbed in that way. hut Abderhalden 8 has recently shown that there can he a small amount of iron absorption after feeding either haemoglobin or h;ematin. Bunge ha- sought for one of the antecedents of haemoglobin in egg-yolk, and ha> described it as an iron-containing nucleo-albumin, which he names haematogen. That and similar aucleo-albumins existing in plants he conceives to he the source of absorbable iron, while inorganic salts of iron aid only indirectly by forming iron sulphide, thus preventing the same formation from organic iron (see above). Small amounts of absorbable iron are found in all the ordinary cereal foods. 7 .Marion" has ' Macallum : Journal of Physiology, 1894. vol. 1.5, p. 268. 2 Forster: Zetochrifl fur Bioloijie, 1873, Bd. 9, S. 297. 3 Lor. cit. 1 This figure is probably too high, but the principle itself is fundamental. See Voit, Hermann* Handbook, 1881, vi. 1, S. 385. 5 Hamburger: Zeitschrifl fur physiologische Chemie, 1878, Bd. 2, S. 191. f ' Zeitschrifl fur Biohgie, 1900, Bd. 39, S. 487. 7 Bunge: Zeitschrifl j'iir ph>i.t/i..\ 1 Milkio(cow) K 2 0. Na 2 0. CaO. MgO. Fe 2 O s , CI. 0.202 4.341 0.176 0.041 0.01 3.961 5.543 0.158 1.504 0. "7:: 4.272 0.136 o.(i:;s 3.611 1 6 1 0.770 0.086 11,112 0.057 0.672 1.07 1.05 1.51 0.20 0.003 1.86 P 2 6 . 0.489 2.067 0.188 4.644 1.60 1 Pugliese: Archiv fur Phydologie, 1899, S. 80. 2 Op. cit., p. 278. :t Ilerter: Hoppe-Sevler's Physiologische Chemie, S. 192. 4 Kroger : Quoted by Halliburton, Chemistry, Physiological and Pathological, p. 656. 5 Bidder and Schmidt: Quoted by Halliburton, Op. cit., p. 638. ' Boppe-Seyler : Physiologische Chemie, S. 302. 7 Bunge : Bid., 3d ed., S. 265. 8 Op. rit., S. 222. For other similar blood analyses, see Abderhalden, Zeitschrift fur physiologische Chemie, 1898, Bd. 2-"), S. 65. 9 Bunge : Ibid., 1885, Bd. 9, S. 60. 10 Bunge : Physiologische Chemie, 3d ed., S. 100. THE CHEMISTRY OE THE ANIMAL BODY. 531 THE CHEMISTRY OP THE COMPOUNDS OF CARBON. Derivatives of Methane. The complicated structure aud the great variety of the compounds of car- bon are due to the fact that carbon-atoms have a greater power for union with one another than have the atoms of other elements. Saturated Hydrocarbons or Paraffins (formula, C„H 2n + 2 ). — Methane, CH 4 , gas. Pentane, C 5 H 12 , liquid at 38°. Ethane, C 2 H 6 , " Hexane, C 6 H 14 . " 71°. Propane, C 3 H 8 , " Heptane, C 7 H 16 , " 98°. Butane, C 4 H 10 , " etc. These are the constituents of petroleum and natural gas, and are formed by the action of low heat on coal under pressure in the absence of oxygen, and are probably derived from fossil animal fat, since it has been shown that the paraffins may be obtained in large quantity by beating fish oil at a pressure of ten atmospheres. 1 The paraffins may all be formed synthetically from methane by the action of sodium on halogen compounds of the group : 2CH 3 I + 2Na = C 2 H 6 + 2NaI. C 2 H 5 I + CH3I + 2Na = C 3 H 8 + 2NaI. This may be continued to form a theoretically endless number of compounds. Paraffins are notably resistant to chemical reagents, not being affected by either concentrated nitric or sulphuric acids. Vaseline contains a mixture of paraffins melting between 30° and 40°. By massage vaseline may be absorbed by the skin, through the epithelial cells of the seba- ceous glands. In rabbits and dogs, directly after such treatment, it may be detected de- posited especially in muscle, but it is for the greater part destroyed in the body. 2 Monatomic Alcohol Radicals. These are radicals which may be considered as paraffins less one atom of hydrogen, and therefore having one free bond. They form the basis of homologous series of alcohols and acids. Monatomic Alcohols (general formula, C n H 2n + jOH). — Methyl alcohol, CH,OH. Amyl alcohol, C 5 H„OH. Ethyl alcohol, C 2 H 5 01I. Hexyl alcohol, C„H 13 OH. Propyl alcohol, C B H T OH. Heptyl alcohol, C T H u OH. Butyl alcohol, C 4 H 9 OH. etc. General Reactions for Primary Alcohols.— (1) Alcohols treated with sulphuric acid give ethers (see Ethyl ether) : 2CH3OH + h 2 so 4 = ch:;>° + H *° + H2SOi< Methyl ether. (2) Alcohols oxidized give first aldehyde and then acid : CH s OH + = HC ^g + H 2 0. Methyl aldehyde. CH 2 + = HC<£J H Formic acid. 1 Engler: Berichte der deutschen chemischen OeseUachaft, 1888, Bil. 21, S. 1816. 1 Soubiranski : Archivfiir exper. Pathologie und Pharmakologie, 1893, Bd, 31, S. 329. 532 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. ■ Primary alcohols may be prepared 1 by reduction of the aldehyde with nascent hydrogen, , p. ,VJ3. Abstract in Malay's Jahresbericht iiber Thierchemie, 1886, Bd. 16, 8. 364. 4 A. Zeller: Zeitschrift fur physiologische Chemie, 1883, Bd. 8, S. 74. 5 Beriehte der dcutschen chemischen Gesellschaft, 1870, Bd. 3, S. 67. 6 Ibid., 1881, Bd. 14, S. 2144. 7 Ibid,, 1894, Bd. 26, S. 502 and 689. 8 Stocklasa: Zeitschrift fiir physiologische Chemie, 1896, Bd. 21, S. 83. 534 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. form synthetically and send to the beet root 31 grams of cane-sugar in thirty days. General Behavior of Aldehydes. — They act as reducing agents, being readily oxidized to the corresponding acid. With nascent hydrogen they are reduced to alcohols. A dis- tinctive reaction of aldehydes and ketones is their union with phenyl hydrazin, C 6 II 5 — NH — NIL. giving hydraxones : CH3CHO + C S H 5 XI1XII 2 = CH 3 .CH:N.NH.C«H S + H 2 0. Preparation. — By distillation of the salt of an acid with a salt of formic acid : CH 3 COONa + HCOONa = Na 2 C0 3 + CH 3 CHO. Aceto-aldehyde. Methyl Mercaptan, CH 3 SH. — This is a product of bacterial action on proteid, 1 and is found with H 2 S in the intestine. It is, furthermore, given off on fusing proteid with potash. 2 Methyl mercaptan boils at 5°, and has a strong odor. It is found in the urine, especially after eating asparagus, giving to it a peculiar smell. 3 According to Rubner i the smell of cooked cabbage, cauliflower, and the like, is due to methyl mercaptan. Methyl Telluride, (CH 8 ) 2 Te. — A gas of penetrating odor found in all excreta of an animal after feeding salts of telluric, H,Te0 4 . or tellurious, H 2 Te0 3 , acid. The salt is re- uuced to metallic tellurium in the body, which unites with a methyl group in some way liberated in the cells. 5 Metallic tellurium may be microscopically seen deposited in various cells, and the odor of (CH 3 ) 2 Te may be detected for months after the last dose has been given to a dog. 8 Methyl Selenide, (CH 3 ) 2 Se. — This is very similar to the last-named substance, but more poisonous. Formic Acid, HCOOH. — Found in ants, and obtained by distilling them with water. Present likewise in stinging-nettles and in the sting of honey- bees, wasps, and hornets, although not the essential poison. 7 Its salts are found in minute quantities in normal urine, and are present especially in both blood and urine in such diseases as leucocythsemia, fever, diabetes. 8 Formic acid may be obtained from the oxidation of methyl alcohol, of sugar, and of starch, but not from the latter two in the body. Likewise by heating oxalic acid, COOH cooii = HCOOH + co " It is found in the urine after feeding methyl alcohol and other methyl deriv- atives, such as oxymethyl-sulfonic acid, or formic; aldehyde. Ethyl alcohol, on the contrary, does not yield it. 9 It is the lowest member of the fatty-acid series, the most volatile, and the least readily oxidized in the body. If formates be 1 M. Nencki : Archiv fur exper. Pathologic und Pharmakologie, 1891, Bd. 28, S. 206. 2 M. Rubner : Archiv fiir Hygiene, 1S93. :t Nencki, loe. eit * Loc cit. Bofmeister: Archiv fiir exper. Pathologic wad Pharmakologie, ]s94, Bd. 33, S. 198. 8 Beyer: Archiv fur Physiologic, Jahrgang L895, S. 225. 7 Langer : Archiv fur exper. Pathologic und Pharmakologie, 1897, Bd. 38, S. 381. 8 See R. Jaksch : Zeitechrift fiir ph^ulnji^lt, ('/„ ,,,;,-, ism;, r,d. 10, S. 537. 9 Pohl: Archiv fur exper. Pathologic und Pharmakologie, 1893, Bd. 31, S. 298. THE CHEMISTRY OE THE ANIMAL BODY. 535 fed they appear readily in the urine. It has a penetrating odor, acts as a reducing agent (HCOOH -f- O = CO a + H 2 0), and therefore precipitates Fehling's solution. Outside of the body it readily undergoes oxidation to water and carbonic acid. It produces inflammation of the skin. A 7 per cent, solution given to a rabbit per os has a most powerful corrosive action and results fatally, formic acid being found in the urine. Ethyl Compounds. Ethyl Hydroxide, or Ethyl Alcohol, C 2 H 5 OH. — This has been detected in minute quantity in the normal muscle of rabbits, horses, and cattle. 1 Yeast-cells produce a ferment, zymase, which acts to split dextrose into alcohol and carbonic acid, producing likewise, to a very small extent, the higher alcohols, propyl, isobutyl, amyl, the esters of the fatty acids (fusel oil), glycerin, and succinic acid. Such fermentation may to a small extent take place in the intestine, 2 and likewise in the bladder (occurrence in diabetic- urine). Pure alcohol is a colorless, almost odorless liquid, having a burning taste. It is a valuable solvent of resins, fats, volatile oils, bromine, iodine, and many medicaments. Tinctures are alcoholic solutions of various drugs and salts. Liqueurs are manufactured from alcohol properly diluted, and treated with sugar and characteristic ethereal oils and aromatics. Distilled liquors are obtained by the distillation of the fermentative products of various substances, whiskey from corn and rye, rum from molasses, brandy from wine. The cha- racterizing taste depends on the different ethereal and fusel oils. Wines are produced from the natural fermentation of grape-juice. Sherry, madeira, and port are fortified by the further addition of alcohol and sugar. Beer is made by converting the starch of barley into maltose and dextrin through diastase. To an aqueous solution of the above hops are added, and the whole is boiled. After the settling of precipitated proteid, etc., the clear supernatant fluid is drawn oflf and treated with yeast, with ultimate conversion into beer. The taste is furnished by the hops. Alcohol in the Body. — Alcohol in the stomach at first prevents the gelatinization necessary in proteid for peptic digestion, but this difficulty is of no great moment because the absorption of alcohol is rapid and complete. It makes the mucous membrane hyperaemic, promotes the absorption of accompanying substances (sugar, peptone, potassium iodide), and stimulates the flow of the gastric juice. 3 In this matter it acts as do other condiments (salt, pepper, mustard, peppermint), 4 but if there be too great an irritation on the mucous membrane there is less activity (dyspepsia). The rapid absorption gives to alcohol its quick recuperative effect alter collapse, and it- value in administering drugs, especially antidotes. Alcoholic beverages combining alcohol and flavor promote gastric digestion and absorption, but often stimulate the appetite in excess of normal requirement Alcohol is ^ajewski: Pfliiger's Archiv, 1875, Bd II. S. 122 - Macfadyen, Nencki, and Sieber : Archiv fiir exper. Pathologic wnd Pharmakologie, 1891, Bd. 28, S. 347. 3 Brandl: Zeitsehrifl fur Biologie, L892, Bd. 29, S. 277. Chittenden, Mendel, and Jackson: American Journal of Physiology, 1808, vol. i. p. 164. 4 Brandl, Op. cit., 8. 292. 536 AN AMERICAN TEXT- HOOK OF PHYSIOLOGY. burned in the body, but may also be found in the breath, perspiration, urine, and milk. Alcohol has no effect on proteid decomposition, but acts to spare tat from combustion. 1 The addition of 50 to 80 grams of alcohol to the food has no apparent effect on the nitrogenous equilibrium. 2 Alcohol in the body acts as a paralyzant on certain portions of the brain, destroying the more delicate degrees of attention, judgment, and reflective thought, diminishing the sense of weariness (use after great exertion — furnished to armies in the last hours of battle) and raising the self-esteem ; it paralyzes the vaso-constrictor nerves, producing turgescence of the skin with accompanying feeling of warmth and therein' indirectly aiding the heart.' 5 Alcohol acts to stimulate the res- piration especially in the tired and weak, wine with a rich bouquet like sherry being more effective than plain alcohol.' The higher alcohols, propyl, butyl, amyl (sec p. 539), are more poisonous as the series ascends, and are less vol- atile, less easily burned, and therefore more tenaciously retained by the body, with more pernicious result-. Ethyl Ether, C 2 H 5 .O.C 2 H 5 . — This is formed by the action of sulphuric acid on alcohol, thus : C 2 H 5 OH - H 2 S0 4 = C 2 H 5 HS0 4 + H 2 0. C 2 H 5 HS0 4 + C 2 H 5 OH =(C 2 H 5 ) 2 + H 2 S0 4 . Ether is a solvent for fats, resins, and ethereal oils. Respired with air its action is like that of chloroform, producing temporary paralysis of the nerves and nervous centres. Since it boils at 35.5° its tension in the blood is always high, and it is probably not burned in the body to any great extent, but when present is eliminated through the breath. Ethers in general are neutral and very stable bodies, and may be considered oxides of organic radicles. They may all be prepared by boiling the corresponding alcohol with sul- phuric acid. Mixed ethers, in which the radicles are different, are prepared by boiling two different alcohols with sulphuric acid : CH 8 HSO, + C 2 H 5 OH = CH 3 OC 2 H 5 + H 2 S0 4 . Methyl-ethy] ether. Chloral Hydrate, CCl,CHO + H,0 or CCl s CH(OH) 2 .— This is thehydrated form of trichlor-ethyl aldehyde, CCl 3 CHO, and is used as an anaesthetic. It is an interesting fact that when fed it partially reappears in the urine as urochloralic acid, which consists of trichlor-ethyl alcohol, (T1 3 CH,0II, combined with glycuronic acid (which see). This is a notable illustration of reduction in the body, the change from an aldehyde to an alcohol. Acetic Acid, CH 3 COOH. — Acetic acid, the second of the fatty-acid series, is found in the intestinal tract and in the feces, being a product of putrefaction (see p. 545). It is more easily burned than formic acid, and when absorbed is resolved into C0 2 and water. It is found in traces in the urine, the total amount of fatty acids normally present being 0.008 gram per day. 6 Like formic acid, and accompanied further by the higher acids of the series, it is present in the blood, sweat, and urine in leucocythaemia and diabetes. The 1 See Rosemann : Pfluger'a Arehiv, 1899, Bd. 77, S. 405. 2 Strdm: Abstract in Centralblalt fur Physiologic, 1894, Bd. 8, S. 582. 3 Schmiedeberg : Grundriss der Arzneimittellehre, 2d ed., 1888. * Wendelstadt : Pfluger'a Arehiv, 1-99, Bd. 76, S. 226. & Gibbs and Reichert: Arehiv fur Physiologic, 1893, Suppl. Bd. S. 201. « V. Jaksch : Z( itschrift fur physiologische Chemie, 1880, Bd. 10, S. 536. THE CHEMISTRY OF THE ANIMAL BODY. 537 probability that acetone is derived from fat renders it possible that these aeids may also be derived from fat, and not from abnormal proteid decomposition, as was formerly supposed. Acetic acid is the product of the oxidation of alcohol. This may be brought about through the presence of spongy platinum, or through the action of bacteria (Mycoderma aceti) on dilute alcohol (preparation of vinegar, sour- ing of wine : for reaction see p. 532). Acetic acid, as well as other higher fatty acids, is one of the products derived from proteid through its putrefaction, its dry distillation, its fusion with potash, and its digestion with baryta water in sealed tubes. Formic, acetic, and propionic acids are products of dry distillation of sugar (formation of caramel). These facts are of importance in their rela- tion to the question of the production of fat in the body. Acetic and the higher fatty acids are, further, products of the dry distillation of wood and of the fermentation of cellulose (see p. 532). Putrefaction of acetates may take place in the intestines, the reaction being as follows : 2CH 3 COONa + 2H 2 = Na 2 C0 3 + 2CH 4 + H 2 + C0 2 . These products are similar to those in the marsh-gas fermentation of cellulose. Vinegar, whose acidity is due to acetic acid, is used as a condiment. Acetyl-acetic Acid, or Aceto-acetic Acid, CH 3 .CO.CH 2 .COOH. — This may be considered as acetic acid in which one H atom is replaced by acetyl, CH 3 CO — ; or as /9-keto-butyric acid. Treated with hydrogen it is reduced to /2-oxybutyric acid (CH 3 .CHOH.CH 2 .COOH), which in turn may be oxi- dized to the original substance. Aceto-acetic acid readily breaks up into acetone and carbonic acid : CH 3 COCH 2 COOH = CH 3 COCH 3 + C0 2 . Aceto-acetic acid, acetone, and /3-oxybutyric acid are found in the urine sometimes singly, sometimes together, and probably as the result of a metabolism of fat. In starvation and in diabetes there is an increased excretion of these bodies, for there is an Increased metabo- lism of fat. Feeding fat increases the acetonuria, whereas feeding sugar, which protects the fat from destruction, decreases it. 1 From their chemical relations already mentioned these substances may be regarded as of common origin, and in confirmation of this Araki 2 has shown that on feeding /3-oxybutyric acid it is oxidized and aceto-acetic acid and acetone may be detected in the urine. The production of the two aeids seems to further a gradual neutralization of the blood, ultimately causing coma. 3 In the presence of these substances ammonia runs high in the urine, and in amounts proportional to their excretion * (compare p. 550). Aceto-acetic acid gives to urine in the absence of phosphates a red coloration with ferric chloride (principle of the reaction of Gerhardt). Amido-acetic Acid, or Glycocoll, CH 2 .NH 2 .COOH, — This is a substance obtained by boiling gelatin with acids or alkalies. It is found in human bile and in that of other animals combined with cholic acid and called glycoeholie acid. Chittenden'' has found glycocoll in the muscles of Peeten irradiam. It is found in the urine combined with benzoic acid as hippuric acid after 'Literature by Waldvogel : Zeitsehrift fur klinische Mediein, 1899, Bd. 38, S. r>06. 2 Zeilschrift fiir physiologmhe Chemie, 1893, Bd. 18, S. 6. 3 Miinzer and Strasser: Archiv fur exper, Pathologie und Pharmakologie, 1893, Bd. 32, S. 372. * Loc. n't. 5 An»ii/rii der Chemie und Pharmakologie, 1875, Bd. 178, S. 266. 538 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. feeding benzoic acid or compounds which the body converts into benzoic acid. In a similar manner phenaceturic acid is found in the urine from the grouping together of glycocoll and phenyl aeetic acid. Glycocoll and urea are to be obtained by the decomposition of uric acid through hydriodic acid. Glycocoll form.- colorless crystals, soluble in water and having a sweet taste. Glycocoll in th< Body. — If glycocoll be fed it is absorbed, burned, and appears as urea in the urine. The fact that dogs, whose bile never contains glycocholic acid, nevertheless excrete hippuric acid after being fed with ben- zoic acid, indicates that, glycocoll may be considered a normal nitrogenous decomposition-product of proteid. Its easy cleavage from gelatin, a product manufactured from proteid in the body, confirms this. Heteroalbumose pre- pared from fibrin likewise yields glycocoll on decomposition. 1 Continual daily feeding of sufficient benzoic acid to fasting or casein-fed rabbits produces a con- stant excretion of hippuric acid in such a proportion to total urinary nitrogen as to indicate that 3 to 4 per cent, of the proteid molecule may be split off in metabolism as glycocoll. 2 Feeding gelatin will not increase the hippuric acid excretion as compared with the total urinary nitrogen. So glycocoll may be a cleavage product of both gelatin and proteid metabolism. Amido- Adds in (inn nil. — These acids, such as glycocoll. aspartic acid, glutamic acid, leucin, and tyrosin are found as putrefactive products of albumin and gelatin. Tn these acids the amido- group is very stable, and cannot be removed by boiling with KOH. Tliey are all converted in the body into the amide of carbonic acid (urea). Amido- acids may in general be synthetically formed by heating mono-halogen compounds of the fatty acids with ammonia: CH 2 C1C00H -f XH 3 = CH 2 NH 2 COOH + HC1. Methyl Amido-acetic Acid, or Sarcosin, CII 5 .NH.CH 2 .COOH.— This is not found in the body, but is derived from death), theobromin, and caffein by heating with barium hydroxide. Propyl Compounds. Normal or Primary Propyl Alcohol, CH 3 CH 2 CH 2 OH. — This is one of the higher alcohols formed in the fermentation of sugar, and on oxidation yields propyl aldehyde and propionic acid. Propionic Acid, CH 3 < II.,( '( >( )II. — Combined with glycerin this forms the simplest fat ; salts of this acid feel fatty to the touch. Propionic acid is a product of the dry distillation of sugar, of the butyric-acid fermentation of milk-sugar, and of the put refaction of proteid. It is said to be present in the sweat, in the bile, and sometimes in the contents of the stomach. Like others of the lower fatty acids, it may partially escape oxidation and appear in traces in the urine (see p. 536). ..^-Acetyl Propionic Acid, or Levulic Acid, CH 3 COCII 2 CH 2 COOH.— This is the next higher homologue to aceto-acetic acid. It has been obtained only by boiling sugars, espe- cially levulose, with acid and alkalies, and since Kossel and Neumann 3 found that it is yielded by some aucleins tiny conclude that this indicates the presence of the carbo- hydrate radical in these aucleins. 1 Spiro: Zeitschrift fiir physiologisehe Chemie, 1S99, Bd. 28, S. 174. 2 Parker ami Lusk : American Journal of Physiology, 1900, vol. iii. p. 472. 3 Verhandlung der Berliner physiologischen Gesellscbaft, Arehivfur Physiologic, 1894, S. 536. THE CHEMISTRY OF THE ANIMAL BODY. 539 Dimethyl Ketone, or Acetone, CH 3 CO( !H 3 . — This is found normally in the blood and urine, and in especially large quantities in patients suffering from an abnormally large decomposition of fat (see p. 537). During the first day of starvation by Cetti, the starvation artist, the amount of acetone in the urine rose to forty-eight times that of the day previous. 1 It may like- wise appear in the breath, giving a characteristic odor. Acetone is a product of the dry distillation of tartaric and citric acids, of wood, and of sugar. Oxidized, acetone yields acetic and formic acids, whereas, treated with hydro- gen, it is resolved into secondary propyl alcohol. When acetone is in the urine it is also found in the intestinal canal and in the feces, probably by pas- sage through the intestinal wall. Butyl Compounds. Normal Butyric Acid, CH 3 CH 2 CH 2 COOH. — Butyric acid was first found in butter, combined with glycerin. When free it gives the rancid odor to butter, and likewise contributes to the odor of sweat. It has been detected in the spleen, in the blood, and in the urine, but usually only in traces. As a pro- duct of putrefaction of proteid, and especially of carbohydrates, it is found in the intestines and in the stomach when the acidity is insufficient to be bacteri- cidal. It contributes to the unpleasant taste after indigestion, through the return of a small portion of the chyme to the mouth. In cheese it is a product of the putrefaction of casein. If starch, sugar, or dextrin be treated with water, calcium carbonate, and foul cheese, the carbohydrates are slowly converted into a mass of calcium lactate. On further standing the lactic acid is resolved into butyric acid : 2CH 3 CHOHCOOH = C 3 H 7 COOH + 4H + CO,.* Lactic acid. Calcium salts are found to putrefy more readily than others, and the carbon- ate is added above to neutralize any acids formed in the putrefactive process which might inhibit the action of the spores. This same fermentation takes place in the intestinal tract. Iso-butyl Alcohol, (CH 3 ) 2 : CH.CH 2 OH.— This is found in fusel oil. Iso-butyric Acid, (CH 3 ) 2 : CH.COOH. — This is a product of proteid putrefaction and is found in the feces. Pentyl Compounds. Iso-pentyl Alcohol, or Amyl Alcohol, (( , II,),( 1 II( , II,( , II,()II.— This is the principal constituent id' fusel oil, producing the after-effects of distilled-liquor intoxication. The poisonous dose in the dog per kilogram for the different alcohols has been found n> lie — for ethyl alcohol 5-6 grams, for propyl alcohol '■'> grams, tor butyl alcohol 1. 7 grams, fur amyl alcohol L.5 grams 1 (see p. 535). Iso-pentoic or Iso- valerianic Acid, (CII 3 ) 2 CH( Ih,( ( )( HI. — This is found in cheese, in the sweat of the foot, likewise in the urine in small-pox, in typhus, and in acute atrophy of the liver. It is a product of proteid putrefaction, and has a most unpleasant odor. 1 Fr. Miiller: Berliner Minische Wochemchrif^ 1887, S. 128. 2 Dujardin-Beaumetz et Audig6: Comptea rendus, t. 81, p. 19. 540 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Alcohols containing More than Five Carbon Atoms. Of these, cetyl alcohol, C„dl,,< )II. is found combined with palmitic acid in spermaceti; cerotyl alcohol^ C., 7 II sin) are normal products of tryptic digestion. In certain diseases of the liver leucin (and tyrosin) appear in the urine, which may be interpreted to mean that these substances, normally produced from proteid metabolism in the tissues, are not normally burned but accumulate within the body, and are excreted (see below). Proteid on chemical treatment may yield as much as 50 per cent, of leucin. Since leucin contains six atoms of carbon it has been suggested by Fr. Miiller that this substance and other proteid cleavage products con- taining six carbon atoms may be the mother substances of the sugar produced in diabetes. Cohn 2 asserts that feeding leucin to rabbits will increase the glycogen in their livers, but this increase is very slight. But Halsey 3 shows that there is no increase in sugar in the urine after feeding leucin in diabetes. It may be that a sugar radicle in proteid may be the mother-substance of leucin (see p. 581). Leucin and tyrosin are found in yellow atrophy of the liver both in the urine and in the liver itself, under conditions indicating their production by bacteria and their non- combustion after production. In phosphorus-poisoning and acute anaemia leucin and tyrosin occur in the urine, but apparently without good ground for considering them of bacterial oriuin. Leucin crystallizes in characteristic hall-shaped crystals. It was formerly supposed to be amido-caproic acid, but Schulze 4 has shown its true composition. Inactive leucin con- - 3tfi of a mixture of . 102. 1 Berichte der deutschen chemischen OeselUchaft, 1891, Bd. 24, S. 669 ; also, Gmelin: Zeitxchrift fiir physiologische Chemie, 1893, Bd. 18, S. 38. THE CHEMISTRY OF THE ANIMAL BODY. 541 Ba(OH) 2 . The two leucine may be separated by fermentation of cZ-leucin with PeniciUium glaucum. Cleavage of proteid by acids and by putrefaction seems to yield cZ-leucin. 1 Cohn 2 states that several varieties of leucin arise in tryptic digestion. Caprylic, C 8 H 16 2 , and Capric, C 10 H 20 O 2 , Acids. — These are found as glycerin esters in milk-fat. They are likewise present in sweat and in cheese. Palmitic, C 16 H 32 2 , and Stearic, C 18 H 36 2 , Acids. — As glycerin esters these two acids are found in the ordinary fat of adipose tissue, and in the fat of milk. The acids may occur in the feces, and are found combined with calcium in adipocere (p. 560). Wool-fat consists of the cholesterin esters of these acids. The bile contains palmitic, stearic, and oleic acids, 3 and to these have been attributed its very slight acid reaction. 4 Compounds of the Alcohol Radicals with Nitrogen. Amines. — These are bodies in which either one, two, or three of the hydrogen atoms in ammonia are replaced by an alcohol radical, and are termed respectively primary, second- ary, and tertiary amines. Methyl, ethyl, and propyl amine bases are the products of pro- teid putrefaction. They resemble ammonia in their basic properties. Methylamine, NH 2 (CH 3 ). — This is found in herring-brine. It lias the fishy smell noted in decaying fish. It is a product of the distillation of wood and of animal matter. Feeding methylamine hydrochloride is said to cause the appearance of methylated urea in a rabbit's urine 5 (analogous to the formation of urea from ammonia salts) : 2HC1.NH 2 (CH 3 ) + C0 2 = OC(NHCH 3 ) 2 + 2HC1 + H 2 0. According to Sehiffer, 6 the body, probably through intestinal putrefaction, has the power of partially converting creatin into oxalic acid, ammonia, carbonic acid, and methylamine, which last is finally excreted as methylated urea in the urine. Ethylamine, C 2 H 5 NH 2 , when fed as carbonate appears in part as ethylated urea in the urine. 7 Trimethylamine, N(CH 3 ) 3 . — Like ethylamine, this is found in herring-brine and among the products of proteid putrefaction and distillation. In the putrefaction of meat the first ptomaine appearing is cholin, which certainly is derived from lecithin ; the cholin (see p. 543) gradually disappears, and in its place trimethylamine may be detected. 8 Compounds with Cyanogen. The radicle NC — forms a series of bodies not unlike the halogen com- pounds. Owing to the mobility of the cyanogen group, Pfltiger 9 has sought to attribute the properties of living proteid to its presence in ili«' molecule, whereas in the dead proteid of the blood-plasma, for example, he imagines that the nitrogen is contained in an amido- group. When the cyanogen radical occurs in a compound in the form of N==C — the body is called a nitril, when in the form of C=N — an iso-nitril. Cyanogen Gas, NC — CN. — A very poisonous gas. 1 Gmelin: Zeitsehrift fiir physiologisehe Chemie, 1893, I'd. 18, 8.28. 2 Ibid., 1895, Bd. 20, S. 203. 3 Lassar-Cohn : Ibid., 1891, Bd. 19, S. 571. 4 Jolles: Pfliiger's Archiv, 1894, Bd. 57, S. 13. * Sehin'er : ZeUsehrift fur physiologisehe Chemie, 1880, Bd. -1, S. 2 )■">. 6 L<>c cit. T Schmiedeberg : Archiv fiir exper. Pathologic and Pharmakologie, 1877, I'>d. 8, S. 5. 8 Brieger: Abstract in Jahresberichi iiber Thierehemie, L885, 8. 101. s Pfliiger's Archiv, 1875, Bd. 10, S. 251. 54:2 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Hydrocyanic Acid, HON. — This is likewise a strong poison. Amygdalin is a glucoside occurring in cherry-pits, in bitter almonds, etc., together with a ferment ealled emulsin, which hitter hasthe power of transforming amygdalin intodexfcrose, benzaldehyde, and hydro- cyanic acid. Bydrocyanic acid, therefore, gives its taste to oil of bitter almonds, and it may likewise be detected ill cherry brandy. Potassium Cyanide, KCN. — This and all other soluble cyanides arc fatal poisons. Acetonitril, or Methyl Cyanide, CH S CN. — This and its higher homologous nitrils are violent poisons. After feeding acetonitril in small doses, formic acid (see p. 534) and thiocyanic acid (see below) appear in the urine, the thiocyanic acid being a synthetic prod- uct of the ingested cyanogen radical, and the HS — group of decomposing proteid. 1 After feeding higher homologues of acetonitril or hydrocyanic acid, thiocyanide likewise appears in the urine. Since the amount of thiocyanide in the urine is normally very small, there is no reason for believing that cyanogen radicals similar to those described above are ever, to any great extent, cleavage-products of proteid. 8 Through intravenous injections of sodium sulphide, and especially of sodium thiosulphate, poisonous cyanogen compounds may be administered much beyond the dose ordinarily fatal: 8 NaCN + S0 2 < |^ a a + = NCSNa + Na 2 S0 4 . Cyanamide, NC.NH 2 . — This is a laboratory decomposition-product of creatin, but does not occur in the body. It is poisonous when administered. When boiled with dilute sulphuric or nitric acids it is converted into urea : NCNH, + H 2 = H 2 NCOXH 2 . It is to be remembered that creatin in the body is not converted into urea. Ammonium Cyanate, OCN(NH 4 ). — Boiling ammonium cyanate converts it into urea. This was shown by Wohler in 1828, and was the first authoritative laboratory production of a body characteristic of living organisms: OCNiNH 4 )=OC(NH 2 ) 2 . This reaction illustrates Pfliiger's idea of the transformation of the unstable cyanogen radical in living proteid into the amido- compound in the dead substance. According to Hoppe- Seyler, the urea-formation in the body is as indicated in the above reaction, but that no cyanic acid or ammonium cyanate is to be detected on account of their extreme instability. Potassium Thiocyanide, NCSK. — This substance is usually found in human saliva to the extent of about iU>] per cent., and in the urine. Since it contains nitrogen and sul- phur its original source must be from proteid. The amount in the urine is probably wholly and quantitatively derived from that in the saliva. 4 If thiocyanides be fed, they appear quickly in the urine without change. Thiocyanides are less poisonous than the simple cyanides (see discussion under Acetonitril above). Thiocyanides give a red color with ferric chloride in acid solution. Diatomic Alcohol Radicals. Thus far onlv derivatives of monatomic radicals have been discussed ; next in order follow diatomic alcohol radicals, represented by the formula C„H 2I1 , and including the bodies ethylene, H 2 C — CH 2 , propylene, CH 3 — HC = CH 2 , etc. This set of hydrocarbons is called the olefines. The first series of compounds which are of physiological interest are the amines of the olefines. Amines of the Olefines. These include the group of ptomames — basic substances which are formed from proteid through bacterial putrefaction. Those which are poisonous are 1 Lang: Arrhiv fur exper. Pathologic wad Pharmakologie, 1894, P>d. 34, S. 247. 2 Op. cit., S. 256. ■ Lang: Archiv fur exper. Pathologic und Pharmakologie, 1895, Bd. 36, S. 75. *Gscheidlen: Pfliigei's Archiv, 1S77, Bd. 14, 8. 411. THE CHEMISTRY OF THE ANIMAL BODY. 543 called toxines. These bodies are diamines of the olefmes, and have been investigated especially by Brieger. 1 Tetramethylene-diamin, or Putrescin, H 2 N.CH 2 .CH 2 .CH,.CH, Nil,.— This com- pound is found in putrefying proteid, and has been detected in the urine and feces in cystitis. Pentamethylene-diamin, or Cadaverin, H,N.C 5 TI 10 .NH 2 .— This is found with putrescine wherever produced. They are both found in cultivations of Koch's cholera bacil- lus and in cholera feces. In cystitis they are a result of special infection of the intestinal tract, are principally excreted in the feces, but are partially absorbed, and prevent, perhaps through chemical union, the burning of cystein normally produced. 2 Diamines are not normally present in the urine. Neuridin. and Saprin. — These are isomers of cadaverin and are produced by the same putrefactive processes. Cholin. — This is trimethyl oxyethyl ammonium hydroxide, (CH 3 )3-N< CH2CHOH and has its source in lecithin decomposition, and putrefaction (see p. 559). Cholin has been found in the cerebrospinal fluid in cases of general paralysis in the insane, and is regarded as the effective poison. 3 Muscarin, or Oxycholin. — This is a violent heart-poison, and may be obtained by treating cholin with nitric acid. Neurin. — This is trimethyl-vinyl ammonium hydroxide, (CH 3 ) 3 ~ N < p jj _ q jj and is derived from lecithin. It may be considered as derived from cholin, with the elimination of a molecule of water, and it has been shown that bacteria make this conver- sion. It is a powerful poison. After feeding lecithin and occluding the intestinal canal, cholin and neurit] have been found within the intestinal contents. 4 Derivatives of Diatomic Alcohols. Taurin, or Amido-ethyl Sulphonic Acid, H 2 N.CH 2 .CH 2 .S0 3 H.— This lias been detected in muscle, 5 in the spleen, and in the suprarenal capsules. It is likewise a usual constituent of the human bile in combination with cholic acid, the salt present being known as sodium tauroeholate. Taurin is of proteid origin as is shown by its nitrogen and sulphur content. Little is known regarding its fate in the body, except as is indicated through the behavior of its sulphur atom (see p. 507). The Biliary Salts. — Taurin and glycocoll are found in the bile of cattle in combination with cholic acid (C^H^O^. In human bile, according to Lassar- Cohn," there is more fellic acid (C^H^OJ present than cholic, and there is likewise present some choleic acid, (C^H^C^). These acids arc of similar chemi- cal structure, though what the structure is, is unknown. Still other acids occur in the bile of pigs, geese, etc. Taurin and glycocoll form compounds with these acids, the sodium salts of which usually make up the major part of 1 Abstract, Jahresbcricht iiber I'hierchemie, 1885. S. 101. * Baum.inn und Udranszky : Zeitschrift fur phygiologische Chemie, 1889, Bd. 13,8. 562, and 1891, Bd. 15, 8. 77. 3 Mott and Halliburton : Journal of Physiology, 1899, vol. xxiv. p. ix. * Nesbitt, B. : American Journal of Physiology, 1899, vol. ii. p. viii. 5 Keed, Kunkenberg, and Wagner: Zeitschrift fiir Biologic, 1885, Bd. 21, B. 30. 6 Z> itschrift fiir physiologische Chemie, 1894, Bd. 19, S. 570. 544 AN AMERICAN TEXT- HOOK OF 1'HYSloLOGY. the solids of the bile. It has been shown that glycocoll and taurin are found in various parts of the body. Cholic, fellic, etc. acids are only found as products of hepatic activity. In a dog with a biliary fistula the solids of the bile increase on feeding much meat, but the hourly record of the solids compared with the nitrogen in the urine shows that the great production of biliary salts con- tinues after the nitrogen in the urine has beguu to decrease. 1 The experiments of Feder 2 have shown that the greater part of the nitrogen in proteid eaten by a dog leaves the body within the first fourteen hours, whereas the excretion of the non-nitrogenous moiety is more evenly distributed over twenty-four hours. It may be fairly concluded that cholic and fellic acids are produced from the non-nitrogenous portion, or from sugar or fat.' Furthermore Tappeiner ' has 6ho\\^i that cholic acid on oxidation yields fatty acids. A synthesis may there- fore be effected in the liver bit ween the non-nitrogenous cholic acid formed in the liver from fat or materials convertible into fat, and glycocoll and taurin formed from proteids, whether the latter be produced in the liver or brought to it from tlu 1 tissues by the blood. That the liver is the place for the synthesis is shown by the fact that the biliary salts do not collect in the body after extir- pation of the liver. The biliary salts in part may be absorbed by the intestine, and a part of these absorbed salts may be again excreted through the bile, forming a circu- lation of the bile salts. In the intestine either the acid of the gastric juice or bacteria may split up the biliary salt through hydrolysis: C 26 H, 3 M\+ H 2 - C 2 H 6 N0 2 + C.^H^O,. Glycocholic acid. Glycocoll. Cholic acid. Taurin and glycocoll may be absorbed, while cholic acid is precipitated if in an acid medium, but may be dissolved and absorbed in an alkaline intestine. Hence cholic acid, fellic acid, etc., may often be found in the feces in small amount-. .Meconium, that is. the fecal matter of the fetus, contains quantities of the biliary salts, but unaltered, since putrefaction is absent in the fetus. Kiihne has described dyslysin as a putrefactive product of cholic acid, but its existence is denied by Hoppe-Seyler and Yoit. In icterus (jaundice), a con- dition in which the biliary salts return to the blood from the liver, they are burned in the body, sometimes so completely that none appear in the urine. They have the power of dissolving haemoglobin from the blood-corpuscles, and in consequence the urine may be highly colored, perhaps from bilirubin. 5 The biliary salts have the power of dissolving the more insoluble fatty acids and soaps produced from the action of steapsin on fats. 1 ' Pettenkofer, experimenting once on the conversion of sugar into fat. warmed together cane-sugar, bile, and concentrated sulphuric acid. He obtained no fat, but a strong violet coloration. This is " Pettenkofer's test" for biliary acids (cholic acid, fellic acid, etc.). This coloration is likewise given by proteid, oleic acid, and other bodies. The test of'Neu- 1 Yoit : Zeitschrift fur Biologie, 1894, Bd. 30, S. 545. 2 Ibid., 1881, Bd. 15, S. 531. 5 Yoit, Op. ril., S. 556. 4 Zeitschrift fur Biologie, 1876, Bd. 12, S. 60. 5 Hoppe-Seyler: Physiohgische Chemie, 1877, S. 476. 6 Moore and Rockwood : Journal of Physiology, 1897, vol. xxi. p. 58. THE CHEMISTRY OE THE ANIMAL BODY. 545 konmi is a modification of this. Here a drop of a substance containing biliary acids is placed on a small white porcelain cover, with a drop id' dilute cane-sugar solution, and one of dilute sulphuric acid; the mixture is then very carefully evaporated over a flame and leaves a brilliant violet stain. Oxy- Fatty Acids, Lactic-acid Group. These are diatomic monobasic acids of the glycols. A glycol is a diatomic alcohol. The oxy- fatty acids have the general formula C n H 2I1 3 , and include : Carbonic acid, CH 2 3 . Oxy-butyric acid, C 4 H 8 3 . Glycollic acid, C 2 IT 4 3 . Oxy-valerianic acid, C 5 H 10 O 3 . Lactic acid, C 3 H 6 3 . etc. Carbonic Acid, or Oxy-formic Acid, HO.CO.OH. — This is, in reality, a dibasic acid on account of the symmetric structure of the two — OH radicals. It has already been considered. Lactic Acids, or Oxy-propionic Acids. — Of these there are two isomeres, which vary in the position of their — OH group, the a- and ft- lactic acids. Physiology is concerned only with the first. a-Lactic Acid, or Ethidene Lactic Acid, CH 3 .CHOH.COOH. — This is called fermentation lactic acid, being a product of the fermentation of carbo- hydrates (see p. 539) : C 6 H 12 6 = 2C 3 H 6 3 - On lactic fermentation of milk-sugar depends the souring of milk. This fer- mentation does not take place in the presence of sufficiently acid gastric juice, but maybe more active in the alkaline intestine. It has been noticed that the fecal excrements after a carbohydrate diet react acid, after proteid diet alkaline. The acid reaction is due chiefly if not wholly to acetic acid, since lactic acid, being the stronger acid, is first neutralized by the intestinal alkali. Lactic acid, when absorbed, is completely burned in the body. Lactic-acid fermenta- tion between the teeth dissolves the enamel, and gives bacteria access to the interior. The fermentation lactic acid is inactive to polarized light, and, since it has in its formula an asymmetric carbon atom,' it is necessary to assume that it consists of an equal mixture of right and left ethidene lactic acid. On 1 An asymmetric carbon atom is one in which the four atoms, or groups of atoms, united to CH a I it are all different. In lactic acid we find the following grouping, II — C — Oil. The central COOK carbon represents the asymmetric atom. Such an arrangement is always optically active. < me is able to conceive the arrangement of the atoms in space, according to the above grouping, >>r CI I, as follows: HO— C— H. This latter represents a different configuration. The two arrange- 1 coon ments are optically antagonistic. A mixture of the two is optically inactive. The reader is referred to a text-book on general chemistry for the suggestive illustrations of the tetrahedral space pictures. Vol. I.— 35 546 AN AMERICAN TEXT- HOOK OF PHYSIOLOGY. standing with PeniciUium glaucurn the left lactic acid is destroyed more freely than is the right, and the solution rotates polarized light to the right. 1 The right ethidene lactic acid, called also sarco- or para-lactic acid, is that which is found in muscle, blood, in various blood-glands, in the pericardial fluid, and in the aqueous humor. Likewise it is found in the urine after strenuous physical effort, after CO-poisoning, in yellow atrophy of the liver, in phosphorus-poisoning, in trichinosis, and in birds (geese and ducks) after the liver has been extirpated, and it is found in increased quantities in the blood and in all the organs of animals poisoned with arsenic.- It is some- times present in diabetic urine. Para-lactic acid is a normal constituent of the blood and increases in amount after work or tetanus. It accumulates in the dying muscle {rigor mortis), causing the formation of KH 2 P0 4 , which gives the acid reaction and causes coagulation. 3 Some believe that free lactic acid itself is present and aids in the coagulation. Regarding its origin, it has been shown that it increases in amount in the dying muscle without simultaneous decrease in the amount of glycogen. 4 It has also been shown that the large increase of lactic acid in the extirpated liver is only due to the production of fermentation lactic acid from glycogen.' On extirpation of the liver in geese, 6 ammonia and para-lactic acid replace the customary uric acid in the excreta, and previous ingestion of carbohydrates or of urea will not increase the amount of para-lactic acid. The lactic acid excreted is proportional in amount to the proteid destroyed and to the ammonia present. It may fairly be concluded that it always owes its origin to proteid. Hoppe-Seyler ' says that lactic acid appears in the urine only when there is insufficient oxidation in the body, and attributes its derivation to the decomposition of glycogen. In ( '( ^-poisoning Araki" finds as much as 2 per cent, of lactic acid (reckoned as zinc lactate in a rabbit's urine. Minkowski, 9 on the other hand, denies the insufficient-oxidation theory, and maintains that the destruction of lactic acid depends on a specific property of the liver, the normal action being either destruction in the liver itself or in other organs through the medium t>\' a substance (enzyme?) produced in the liver. One may interpret Araki's experiment as showing that considerable quantities of lactic acid arc constantly produced in metabolism, but are normally swept away and burned; the CO-poisoning would prevent the normal combustion. The accumulation in muscle after stoppage el' the blood current [rigor mortis) would then be only a continuation of the nor- mal process of decomposition. Cyste'in, a-Amido-a-thiopropionic Acid. — This substance has the formula 1 Berichte der deulschen chemischen Gesellschaft, Bd. L6, S. 2720. -' Morisbima : Archiv fiir exper. Pathologic umd Pharma/eologie, 1899, Bd. 43, S. 217. 3 Astaschewski : Zeitsehrifl fur physiologische Chemie, 1880, Bd. 4, S. 403; [risawa, Ibid., 1893, Bd. 17, S. 351. 'Boehm: P Irchiv, 1880, Bd. 23, S. 44. 5 Morisbima : Loe. cit. ,; Minkowski: Archiv fur exper. Pathologic mul Pharmacologic, 1S86, Bd. 21, S. 41. 7 /■ ttschrift zu /■'. Virchovfs 70. Geburtstag. - Zeitsehrifl fur physiologische Chemie, 1894, Bd. 19, S. 426. s hoc. cit., and Archiv fiir exper. Pathologic und Pharmakologie, 1893, Bd. 31, S. 214. THE CHEMISTRY OF THE AS IMA L BODY. 547 NH 2 CH 3 — C — COOH. It is a product of proteid metabolism and is normally SH destroyed in the body. On the introduction of a halogen derivative of benzol into the body, compounds are formed with cyste'in, called mercapturic acids, which appear in the urine : NH 2 NH 2 CH 3 -C— COOH + C,H 5 Br + O = CH 3 — C— COOH + H 2 0. I I 8H SC 6 H 4 Br. Broraophenyl-mereapturic acid. This proves that cystei'n (like glycocoll, for example) is at least an intermediary and possibly a primary product of proteid metabolism, [f cyste'in be fed, the greater part (two-thirds) of the sulphur appears in the urine as sulphuric acid, the rest as neutral sulphur. Thiolactic acid has been found 1 as a decomposition product of horn. Baumann 2 demonstrates the reduction of cyste'in to thiolactic acid, shows that the latter yields an odor of ethyl sulphide on evaporation, and asks if thiolactic acid be not the mother substance of Abel's compound (see p. 507) : NH 2 CH 3 — C— COOH + H 2 = CH 3 CH(SH)COOH + NH 3 . Thiolactic acid. SH Cyste'in itself is never directly detected in the urine or in the body. Cystin, Dithio-diamido-ethidene Lactic Acid. — Cyste'in is converted by atmospheric oxygen into cystin : NH, 2CH — C— COOH + 20 = CH 3 — CSNH 2 — COOH CH 3 — CSNH— COOH S 'I Cystin. Cystin is very insoluble in water. In particular cases it appears in considerable quantities as a urinary sediment, still more rarely as a stone in the bladder (see p. 543). It has been detected in the normal livers of horses.' It is Iaevo- rotatory. It is reported * that bodies having the composition (' S II ithio- acids, meivaptans) may form sulphuric acid, while most of those having the composition — S — C (ethyl sulphide) are not oxidized in the body. 1 Suter: ZeUaehrift fur physiologische Chemie, 1895, Bd. 20, S, 564. 2 Baumann: Tbid., 1895, Bd, 20, 6. 583. 3 Drechsel : Zeitsehrift fur Biologie, 1897, Bd. 33, S. B5. * W. .J. Smith : Pfliiger's Archiv, 1894, Bd. -V), S. 542, and 1894, Bd. 57, S. H8. 548 AN AMERICAN TEXT- BOOK OE PHYSIOLOGY. ,9-Oxybutyric Acid, CH 3 CHOHCH 2 COOH. — A lsevo-rotatory acid (see p. 539). Amido- Derivatives of Carbonic Acid. OC ' CO, the other of urea. The skeletal struc- ture of all alloxuric bodies may be written thus : N— C / 1 c c — N x \ 1 -K> N— C Alloxan. Urea. These bodies fall into three groups, that of hypoxanthin, of xanthin, and of uric acid. Bodies belonging to the first two groups are called alloxuric bases, or more commonly xanthin bases, or nuclei n bases, because they are derived from nucleiu. The strong family analogy of the three groups is shown by the following reactions — results of heating with hydrochloric acid in sealed tubes at 180° to 200° : 3 C 5 H 4 N 4 + 7H 2 = 3NH 3 + C 2 H 5 M) 2 + C0 2 + 20H 2 O 2 . Hypoxanthin. Glycocoll. Formic acid. 5 H 4 N 4 O 2 + 6H 2 = 3NH 3 + C 2 H 6 N0 2 + 2C0 2 + CH 2 2 . Xanthin. C 5 H 4 N 4 3 + 5H 2 = 3NH 3 + C 2 H 5 N0 2 + 3C0 2 . Uric acid. Reference to the formulae below will show that the molecules of C0 2 given off correspond t<» the number of CO radicals in the alloxuric body, while the molecules of formic acid correspond to the number of CH groups. Emil Fisher 4 has discovered a body called purin, and has given another classification. The chemical series of the purin bodies may thus be presented : 1 Drechsel: Archiv far Physiologie, 1891, S. 248. • Formula by Schulze and Winterstein : Zeitechrift far physiologische Chemie, 1899, Bd. 26, S. 12. s Kriiger: Ibid., 1894, Bd., 18, S. 463. * Berichte der deuUchen ehetnisrlicn <;,.« //,«■/, aft, 1899, Bd. 32, S. 435. THE CHEMISTRY OF THE ANIMAL BODY. 553 C 5 H 4 N 4 3 C 5 H 4 N 4 2 5 H 4 N 4 O C 5 H 4 N 4 . Uric acid. Xanthin. Hypoxanthin. Purin. To purin is given the following formula : N = C — H IN — 6C H — C C-XH 20 50 — N7 \ \ N— C— N '' 3N — 40- Purin. Purin nucleus // Q - For the convenience of chemical description the atoms of the purin nucleus are numbered as above, since the chemical constitution varies with the locality to which the atoms are attached to the nucleus. The purin deriv- atives number many hundreds, but only about a dozen are known at present to have physiological significance. Hypoxanthin is 6-oxypurin, xanthin is 2, 6-dioxypurin, uric acid is 2, 6, 8-trioxypurin, adenin is 6-amino-purin, while guanin is 2-amino- 6-oxypurin. Hypoxanthin, xanthin, adenin, and guanin are decomposition products of the nucleins, and from their oxidation uric acid is derived. (a) Purins. Purin, C 5 H 4 N 4 . This, according to Emil Fisher, is a substance which may occur in the body, but which on account of its ready decomposition has not yet been discovered there. (6) Monoxypurins. NH — C = I I Hypoxanthin, or Sarcin, H — C C — NH\ || || C — H.— This is found N — C— N in small amount in the tissues and fluids of the body and in the urine. Hypoxanthin is derived from some nucleins, especially those contained in the sperm of salmon and carp, through the action of water or dilute acids. (c) DlOXYPURINS. NH — = I I Xanthin, O = C C — NH \ C — H. — This substance, like hvpoxan- NH — C— N thin, is found in the tissues and fluids of the body and in the urine. It is a decomposition product of some nucleins and may be found in those of the pancreas, thymus, testicle, carp sperm, dr. Methyl Dioxypurins— The alkaloids theophyllin, theobromin, and caffein occur in tea, coffee, cocoa, etc., and are habitually taken in the food. Theophyllin ( 1. 3-dimethyl- 554 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. xanthin) probably loses its labile 3-methyl in the body, and occurs in the urine as 1-methyl- xanthin. In like manner theobromin (3, 7-dimethylxanthin) is converted into heteroxan- thin (7-methylxanthin). Caffein (I. 3, 7-trimethylxanthin) also parts with its 3-metbyl- radicle and appears in the urine as paraxanthin (1, 7-dimethylxanthin). Kriiger and Salomon 1 find 22. :: errams of heteroxanthin, 31.3 grams of l-methylxanthin, and 15.3 grams of para-xanthin in L0,000 liters of urine, or much more in quantity than the true nuclein bases (xanthin. etc.). That theophyllin, theobromin, and caffein may be demethylated in the tissue is an interesting commentary on the methylation of tellurium, selenium, and pyridin by the tissues. (d) MONOAMINOPURINS. N = C — XH, I I Adenin, or 6-Aminopurin, H — C C — NH\ II II C-H. X — C — X Adenin is found in the blood, the tissues, and the urine. It is especially a decomposition product of thymus nuclein, although other nucleins may con- tain it. Nitrous oxide converts it into hypoxanthin. (e) Amlnoxyptjrins. NH- C=0 I I Guanin, or 2-Amino-6-Oxypurin, H 2 N — C C — NH\ II II C-H N C— N S This also is found as a decomposition product of some nucleins, especially that of the pancreas. Combined with calcium it gives the brilliant irides- cence to fish-scales. 2 It is found in the fresher layers of guano, and, accord- ing to Voit, is here very probably derived from the fish eaten by the water- fowl. • Epiguanin, or 7-Methyl-g-uanin. — This has been found in the urine, and like the other methylated purins may very likely Vie derived from the fund fed. 3 Episarcin is a purin hase which has been found in the urine, but whose configura- tion has nol yel been made out. Carnin is said to occur in the urine. Its composition is unknown. (/) Trioxypurins. NH— C - O / I Uric Acid, O = C C— XH >CO. — This acid is found in the nor- MI_( _xh mal urine in small amounts, and may be detected in the blood and tissues, 1 Zeitschriftfiir physidogische Chemie, 1898, Bd. 26, S. 350. 2 Voil : Zeilschrifi fur wtssensehaftliche Zodlogie, Bd. 15, S. 515. ' Kriiger and Salomon: Zeitschriftfiir physiologische Chemie, 1898, Bd. 26, S. 389. THE CHEMISTRY OE THE ANIMAL BODY. 555 especially in gout. It is the principal excrement of birds and snakes, that of the latter being almost pure ammonium urate. Preparation. — (1) By heating glycocoll with urea at 200° : C 2 H 5 N0 2 + 3CO(NH 2 ) 2 == C 5 H 4 N 4 3 + 3NH 3 + 2H 2 0. (2) By heating the amide of trichlorlactic acid with urea : CCl 3 CHOH.CO.NH 2 + 2CO(NH 2 ) 2 - C 5 H 4 X 4 C) 3 + 3HC1 + NH 3 + H 2 0. Properties. — Uric acid may be deposited in white hard crystals, which are tasteless, odorless, and almost insoluble in water, alcohol, or ether. (For its solution in the urine see p. 522.) Preseuce of urea adds to its solubility. 1 Its most soluble salts are those of lithium and piperazin. Uric acid is dibasic — that is, two of its hydrogen atoms may be replaced by monad elements. (1) Nitric acid in the cold converts uric acid into urea and alloxan: C 5 H 4 N 4 3 + + H 2 = OC<^gZco> co + OC(NH 2 ) 2 . Alloxan. (2) Whereas, if the hot acid acts, it produces parabanic acid: /NH — CO\ /NH — CO OC< >CO + = OC< j +co 2 . \nh-cck \NH-eo Parabanic acid. (3) Through water addition parabanic acid becomes oxaluric acid: /NH — C = /NH 2 OC< I + H,0 = OC< \NH-C = \NH.CO.COOH Oxaluric acid. (4) And still another molecule of water added produces oxalic acid and urea: ' /NH 2 COOH OC< +H 2 0=| +OC(NH 2 ) 2 . Nmco.cooH cooH Oxalic acid. The above reactions lead up to the constitutional formula of uric acid, and show its decomposition into urea and oxalic acid through oxidation ami hydrolysis. It is known that uric acid when fed increases the amount of urea in the urine, and it is possible that the oxalic acid in the urine may have the same source. Uric acid oxidized with permanganate of potassium is converted into ht, /NH— CH— NH\ OC< | >co. V\ll, co-Nil/ a substance which is found in the allantoic fluid, ami in the urine ofpregnanl women ami of newborn children, and in the urine of dogs alter feeding thymus (see below). If uric acid be carefully evaporated with nitric acid on a small white porcelain cover, a reddish residue remains, which moistened with ammonia gives a brilliant purple color, due to the formation of murexid, C 8 H 4 (NH 4 )N 6 8 ; subsequent addition of alkali gives a red coloration. This is known as the murexid test and is very delicate, The Purin Bases in the Body. — All true nucleins yield one or more of the purin bases. Nucleins are combinations of nucleic acid and proteid, ' G. Riidel : Archiv fur exper. Pathologic unl<»jie, 1S93, lid. 30, S. 469. 3 See Bunge: Physiologische Chemie, L894, S. 312. 556 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. except the nuclein from spermatozoa in which the acid combines with pro- tamin. The simplest indication of the cleavage of nuclein (see Nuclein) on chemical treatment, may be written as follows: Nuclein. Proteid. Nucleic acid. Phosphoric acid. Adenin. Guanin. Xanthin. Hypoxanthin. The idea that the purin bodies occurring in the urine of mammals are the metabolic products of nuoleins, the uric acid being derived from the oxidation of the bases, was made especially clear by the experiments of Horbaczewski. 1 His statement that feeding nucleins increases the purin bases and the uric acid in the urine has been frequently confirmed. He also showed that if fresh spleen pulp, which contains no purin bodies, be per- mitted to putrefy, the extract will contain xanthin and hypoxanthin, whereas if the spleen pulp be shaken with the air uric acid is produced, being oxi- dized from these bases. Spitzer 2 finds, if air be passed through spleen and liver extracts digested at 40° with the exclusion of putrefaction, that uric acid is produced. The nuclein bases formed decrease with the increase of uric acid. Hypoxanthin and xanthin added to such digests are readily oxi- dized to uric acid, as are adenin and guanin, although with greater difficulty. Extracts of the kidney, pancreas, thymus, and blood have no such power. Feeding uric acid and nuclein bases increases the amount of urea in the urine. Minkowski 3 has proved that after feediug hypoxanthin uric acid increases in the urine, showing its oxidation. Minkowski also showed after feeding a man with thymus, the nuclein of which yields principally adenin with some guanin, that the amount of uric acid was increased in the urine; the same food fed to a dog increased the uric acid, and allantoin, an oxidation product of uric acid, also appeared. Feeding adenin to a dog did not in- crease the uric acid or allantoin excretion, but on autopsy of the dog there was found a deposit of uric acid in the uriniferous tubules with indications of inflammatory processes. This is the first known artificial production of a deposition of uric acid. It would seem that the adenin in combination with nucleic acid in thymus may be readily burned to uric acid in such a way that it is readily excreted, whereas adenin itself behaves differently. Loewi 4 finds that the same amount of nuclei]] food fed to different people results in tin r- at., 8. 132. 4 Deutsches ArcMvfur klinische Medizin, 1899, Bd. til'., S. 599. 558 AJV AMERICAN TEXT-BOOK OF PHYSIOLOGY. Monamide of Amido-succinic Acid, or Asparagin, IT,NOC.C,H 3 NH. 2 .COOH — This is found widely distributed in plants, especially in the germinating seed. If a plant be placed in the dark its proteid nitrogen decreases, whereas the non-proteid nitrogen increases, 1 the cause of this being attributed to proteid metabolism with the production of amido- acids, i. < . aspartic and glutamic acids, leucin, and tyrosin. In the sunlight, it is believed, these bodies arc later reconverted into proteid. One view regarding the for- mation of asparagin is based theoretically on the production of succinic acid from carbo- hydrates (as in alcoholic fermentation) and the subsequent formation of oxysucrinic acid (or malic acid, HOOC.C,H 3 OH.COOH), which the inorganic nitrogenous salts change to asparagin. 2 At any rate asparagin in the plant has the power of being constructed into proteid. Since proteid in the animal body may yield 60 per cent, of dextrose in its decomposition, as will be shown, it seems fair to surmise that the synthesis of proteid in the plant may in part depend upon the union of asparagin or similar amido- compounds wit li the carbohydrates present. Asparagin if fed is converted into urea. It forms no proteid synthesis in tin' animal, and lias only a very small effect as a food-stuff. 3 Glutamic acid, H00C.( , I1NI1,.( , II,.*CH 2 .C001I.— This is found as a cleavage- product of tryptic digestion in the intestinal canal. Glutamin, its amido- compound, is, like asparagin, widely distributed in the vegetable kingdom and in considerable amounts. It probably plays the same role as asparagin in the plant. Glutamin is more soluble than asparagin and is therefore less easily detected. Compounds of Triatomic Alcohol Radicals. Glycerin, or Propenyl Alcohol, CH 2 OH.CHOH.CH 2 OH. The glycerin esters of the fatty acids form the basis of all animal and vegetable fats. Glycerin is furthermore formed in small quantities in alcoholic fermentation. Preparation. — (1) Through the action of an alkali on a fat, glycerin and a soap are formed, a process called saponification: 2C 3 H 5 (C 18 H 35 2 ) 3 + 6XaOH = 2C 3 H 5 (OH) 3 + GNaC^O,. Stearin. Sodium stearate. (2) Fats may be decomposed into glycerin and fatty acid by superheated Steam, and likewise by the fat-splitting ferment in the pancreatic juice. Thus, if a thoroughly washed butter-ball, consisting of pure neutral fat, be colored with blue litmus, and a drop of pancreatic juice be placed upon it, the mass will gradually grow red in virtue of the fatty acid liberated from its glycerin combination. This reaction takes place in the intestine. If fatty acid la- led, the chyle in the thoracic duet is found to contain much neutral fat.' This synthesis indicates the presence of glycerin in the body — perhaps, in this case, in the villus of the intestine: the source of this glycerin, whether from proteid or carbohydrates, is problematical. If glycerin be 1'ed, only little is absorbed (since diarrhoea ensues), and of thai little some appears in the urine. It seems, therefore, to be oxidized with difficulty in the body. Glycerin Aldehyde, IIOCH 2 .CHOH.CHO, and Dioxyacetone, HOCH. 2 .CQ.CH 2 Oil. — These substances are formed by the careful oxidation of glycerin with nitric acid, and together are termed glycerose. They ha\e a sweet taste and are the lowest known 1 Schulze and Kisser: Landwirthschatfliche Versucks-Staiion, 1889, Bd. 36, S. 1. ' Miiller: Ibid., 1886, Bd. 33, S. 326. 3 See Voit : Zeitschrift fur Biologic, 1892, Bd. 29, B. 126. * Munk: Virchovfs Archiv, 1880, Bd. 80, S. 17. THE CHEMISTRY OF THE ANIMAL BODY. 559 members of the glycose (sugar) series — i. e. substances which are characterized by the presence of either aldehyde-alcohol, — CHOH — CHO, or ketone- alcohol, — CO — CH.< MI, radicals. The constituents of glycerose, from the number of their carbon atoms, are called trioses. On boiling glycerose with barium hydrate the twu constituents readily unite to form i- fructose (levulose). Glycerin Phosphoric Acid, (HO) 2 C 3 H 5 .H 2 P0 4 .— This is the only ethe- real phosphoric acid in the urine. It is luiind in mere traces. Lecithin, C 3H/ (C " H2U - A)2 3 3 \O.PO.(OH).O.C 2 H 4 .N(CH 3 ) 3 OH.— Lecithin is found in every cell, animal or vegetable, and especially in the brain and nerves. It is found in egg-yolk, in muscles, in blood-corpuscles, in lymph, pus-cells, in bile, and in milk. On boiling lecithin with acids or alkalies, or through putrefaction in the intestinal canal, it breaks up into its constituents, fatty acids, glycerin phosphoric acid, and cholin (see p. 543), substances which the intestine may absorb. The fatty acids may be stearic, palmitic, or oleic, two molecules of different fatty acids sometimes uniting in one molecule of lecithin : hence there are varieties of lecithins. Through further putrefaction cholin breaks up into carbonic oxide, methane, and ammonia. 1 Lecithin treated with distilled water swells, furnishing the reason for the " mvelin forms" of nervous tissue. Lecithin is readily soluble in alcohol and ether. It feels waxy to the touch. Protagon, which has been obtained especially from the brain, is a crystalline body containing lecithin and cerebri)} — which is a glucoside (a body separable into proteid and a sugar). The chemical identity of protagon is shown in that ether and alcohol will not extract lecithin from it. 2 Protagon readily breaks up into its constituents. While protagon seems to be regarded as the principal form in which lecithin occurs in the brain, simple lecithin is believed to be present in the nerves and other organs. This subject has not been properly worked out. Noll 1 states that the quantity of protagon in the spinal cord may amount to 2o per cent, of the dry solids, in the brain to 22 per cent., and in the sciatic nerve to 7.5 per cent. Regarding the synthesis of lecithin in the body, or the physiological importance of the substance, absolutely nothing is known. Fat in the Body. — Animal and vegetable fats consisl principally of a mixture of the triglycerides of palmitic, stearic, and oleic acids. In the intestines the fat-splitting ferments convert a small portion offal into glycerin and fatty acid ; the fatty acid unites with alkali to form a soap, in the presence of which the fat breaks up into fine globules called an emulsion : the fat-split- ting ferment then acts further on the fat, probably converting it all into tatty acid and glycerin.' A line emulsion of lanolin ( fatty acid in combination with cholesterin, isocholesterin, etc.) is not absorbed, because the intestine dues not break up the combination/ and the melted particles themselves cannot 1 JIasebroek: Zeitschrift fur physiologische Chemie, 1888, Bd. 12, 8. 1 18. 2 Gamgee and Blankenhorn: Journal of Physiology, 1881, vol. ii. p. 113. * Zeitschrift fur physiologische Chemie, L899, Bd. 27, S. 370. * Frank, ( ). : Zeitschrift fur Biologic, 1898, Bd. 36, 8. :><>*. 6 Counstein : Archiv fur Physiologie, L899, S. 30. 560 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. be absorbed. When the fatty acids arc produced they unite with the alkali of the intestines to form soaps. The solution of these soaps is greatly aided by the bile. 1 The tissue of the villus has the power to unite synthetically the absorbed soap and glycerin to form neutral fat. It should be remembered that the changes necessary for the absorption of fat may also take place in a cleansed isolated loop of the intestine. 2 Fat may likewise be derived from ingested carbohydrates. The chemical derivation of fatty acid from carbohydrates has already been mentioned in the case of formic, acetic, propionic (see p. 537), and butyric acids. The fatty acids of fusel oils are likewise formed from carbohydrates in fermentation. The laboratory synthesis of sugar from glycerin has been already related. These reactions, however, furnish only the smallest indication of the large transformation of carbohydrates into fat possible in the body. If geese be fed with rice in large quantity, and the excreta and air respired be ana- lyzed, it may be shown that carbon is retained in large amount by the body, in amount too great to be entirely duo to the formation of glycogen, and must therefore have been deposited in the form of fat. s Such fattening of geese produces the delicate pdti de foie gras. The principle has been established in the case of the dog as well. 4 The formation of fat from proteid (fatty degeneration) is believed to take place in some pathological cases (see p. 513). Recollection of the fact that proteid may yield 60 percent, of sugar aids in the comprehension of this problem. 8 Other usually cited proofs of the formation of fat from proteid include the conversion of casein into fat incident to the ripening of cheese ; and the transformation of muscle in a damp locality into a cheesedike mass called adipocere, which is probably effected by bacteria. 6 Adipocere contains double the original quantity of fatty acid, occurring as cal- cium, and sometimes as ammonium salts. Experiments of C. Voit show that on feeding large quantities of proteid. not all the carbonic acid is expired that belongs to the proteid destroyed as indicated by the nitrogen in the urine and feces. The conclusion follows that a non-nitrogenous substance has been stored in the body. Too much carbon is retained to be present only in the form of glyco- gen ; fat from proteid must therefore have been stored. 7 The formation of fat normally from proteid has been combated by Pfluger, it would seem without proper foundation. For behavior oi* fat in the cell see p. 558. Oleic Acid, C 1S II 34 2 . — This acid belongs to the series of fatty acids hav- ing the formula C D H 2n _ 2 2 . Its glyceride solidifies only as low as +4° C. It is the principal compound of liquid oils. Pure stearin is solid at the body's temperature, but mixed with olein the melting-point of the mixture is reduced below the temperature of the body and its absorption is thereby rendered possi- ble. The fat in the body is all in a fluid condition, due to the presence of olein. 1 Moore and Rockwood : Journal of Physiology, 1897, vol. xxi. p. 58. I lunningham : Ibid., 1898, vol. 23, p. 209. 5 Voit: Abstract in Jahresberichi fiber Thierchemie, 1885, lid. 15, S. 51. 4 Rubner: ZeUackrifi fur Biologie, 1886, Bd. 22, S. 272. 5 Kay, McDermott and Lusk : American Journal of Physiology, 1899, vol. 3, p. 139. '■ Bead Lehmann: Abstract in Jahresberirht fiber Thierchemie, 1889, Bd. 19, S. 51b. 7 Erwin Voit : Munchener medicinische Wochenschrift, No. 26, 1892 ; abstract in Jahresbericht iiber Thierchemie, 1892, S. 34 ; Cremer, M. : Zeitsehrift fur Biologic, 1899, Bd. 38, S. 309. THE CHEMISTRY OE THE ANIMAL BODY. 561 Carbohydrates. The important sugar of the blood and the tissues is dextrose. It is derived from the hydration of starchy foods, and from proteid metabolism. From dextrose the lactic glands probably manufacture another carbohydrate, milk-sugar. Cane-sugar forms an article highly prized as a food. Thestudy of the various sugars or carbohydrates is of especial interest, because their chemical nature is now well known. Carbohydrates were formerly denned as bodies which, like the sugars and substances of allied constitution, contain carbon, hydrogen, and oxygen, the carbon atoms being present to the number of six or multiples thereof, the hydrogen and oxygen being present in a proportion to form water. Glycoses include the monosaccharides like dextrose, C 6 II 12 6 ; disaccha rides include, for example, cane-sugar, C 12 H 22 O u , which breaks up into dextrose and levu- lose, while polysaccharides comprise such bodies as starch and dextrins, which have the formula (C 6 H 10 O 5 ) n . In recent years the term glycose has been extended to cover bodies having three to nine carbon atoms and possessing either the constitutiou of an aldehyde-alcohol, — CH(OH)CHO, called aldoses, or of a ketone-alcohol, — COCH 2 OH, called ketoses. These bodies also have hydrogen and oxygen present in a proportion to form water, and the number of carbon atoms always equals in number those of oxygen. According to their number of carbon atoms they are termed trioses, tetroses, pentoses, hexoses, heptoses, octoses. and non< >-i is. It has been shown (foot-note, p. 545) how from the asymmetric carbon atom in lactic acid two configurations are derived. If a body (such as trioxybutyric acid) contains two asymmetric carbon atoms, four configurations are possible, CH 2 OH CH 2 OH (I I, OH CILOH HCOH OHCH OHCH" HCOH HIM MI OHCH HCOH OHCH COOH COOH COOH COOH Similarly among the glycose-aldoses, a triose has two modifications ; a tetrose, four ; a pen- tose, eight: a hexose, sixteen, etc. Thus in the following formula by the variations of H and OH on the four asymmetric carbon atoms, sixteen possible hexoses may be obtained. CH 2 OH — C— — c— — c— -c— CHO The carbohydrates have well-defined optical properties, rotating polarized light to the right or left, and were therefore originally designated as d- (dextro-) and I- (lsevo-) respec- tively. An inactive (/-) form consists in an equal mixture of the two others; at present, however, thed- may signify a chemical relation to dextrose: thus levulose, which is ordinary fruit sugar and rotates polarized light to the left, is called d- fructose, on account ol its deriva- tion from dextrose. Where the Oil group is attached on the right it may he indicated by the sign +, on the left by — , or the | (Ml may he written below, th< — Oil above. II II Oil II orCH.,011 T C (' C (410 (Ml OH II (Ml Vol. I. CH( ) CIIO iiroii c+ ouch c— 1KMMI C+ ' HCOH C-f- CILOH CH 2 OH d-Glucose. 562 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. The Glycoses. The triose called glycerose has already been described. A tetrose called erythrose, which is the aldose of erythrite, C 4 H 6 (OH) 4 , a tetratomic alcohol, is known. Of the possible pentoses, arabinose, xylose, and rhamnose (methyl-arabinose) occur in the vegetable kingdoms in considerable quantity. They may be absorbed by the intestinal canal. 1 Pentoses are found in the urine in rare cases. 2 Some nucleins, especially those of the pancreas and thymus, yield pentoses on decomposition. Subcutaneous injection of arabinosc, xylose, and rhamnose results in their excretion to the extent of more than 50 per cent, in the urine. 3 The rest may be burned. Hexoses, or Glucoses. — Through the oxidation of hexatomic alcohols there may be obtained, first, glucoses, then monocarbonic acids, and lastly saccharic acid, or its isomer mucic acid : C 5 H 6 (OH) 5 CH 2 OH. C 5 H 6 (OH) 5 CHO. C 5 H 6 (OH) 5 COOH. Mannite. Mannose Mannonic acid, (and levulose). C 5 H 6 (OH) 4 (COOH) 2 . Saccharic acid. Mannose and levulose are respectively the aldose and ketose of mannite, galactose is the aldose of duleite, whereas glucose is probably the aldose of sorbite — duleite and sorbite being, like mannite, hexatomic alcohols. Properties. — (1) The hexoses are converted into their respective alcohols on reduction with sodium amalgam. (2) The hexoses act as reducing agents, converting alkaline solutions of cuprous oxide salts (obtained through presence of tartrate) into red cuprous oxide, which precipitates out (Trommer's test). Levulic acid is among the products formed (see p. 538). Of the higher saccharides only maltose and milk-sugar give this reaction. (3) Strongly characteristic are the insoluble crystalline compounds formed by all glycoses with phenvlhydrazin, called osazones (see p. 534) : 6 H 12 O 6 + 2ILX.X I I(C 6 H 5 ) = C 6 H 10 O 4 (:N.NH.C 6 H 5 ) 2 + 2H 2 + H 2 . Levulose. Phenvlhydrazin. Glycosazone. Levulose, dextrose, and mannose give the same glycosazone. The glycos- azones are decomposed into osones by fuming hydrochloric acid : C 6 H 10 O 4 (:N.NH.C 6 H 6 ) 2 + 2H 2 == C 6 H 10 O 6 + 2H 2 N.NH.C 6 H 5 . Glycosone. Osones are converted into sugar by nascent hydrogen. The osone de- rived from levulose, dextrose, and mannose yields levulose by this treatment, and the transformation of dextrose and mannose into levulose is therefore demonstrated. 1 Weiske: Zeitschrift fiir physiologischi Chemie, 1895, Bd. 20, S. 489. > Salkowski : Zeitschrift fiir phy&iologische Chemie, 1899, lid. 27, S. 507. 3 Vi.it. F. : Deutsche* Archiv fiir klinische Medizin, Bd. 58, S. 523. THE CHEMISTRY OF THE ANIMAL BODY. 563 (4) Only trioses, hexoses, and nonoses are capable of alcoholic fermenta- tion. Synthesis of the Glucoses. — Formose (see p. 533) may be purified by means of phenylhydrazin as above, so that pure /-fructose is obtained ; this treated with sodium amalgam yields /-mannite, which on oxidation is converted into /-man- nonicaeid ; this last is separated by a strychnin salt into its two components ■ the rf-mannonic acid is divided and one part treated with hydrogen, with result- ing d-mannose, which, as has been shown above, is convertible into (/-fructose or ordinary fruit-sugar ; the second part of the c/-mannonic acid treated with chinolin is transformed through change in configuration into its isomer, (/-gluconic acid, which on reduction yields (/-glucose, or ordinary dextrose. This shows the preparation of the common sugars from their elements. The transformation of levulose into dextrose is especially to be noted, since it takes place in the body. K H OHH (/-Glucose, Dextrose, Grape-sugar, CH 2 OH C C C C CHO.— OH OH H OH This is the sugar of the body. It is found in the blood and other fluids and in the tissues to the extent of 0.1 per cent, and more, even during starvation. The principal source of the dextrose of the blood is that derived from the digestion of starch, and also of cane-sugar, in the intestinal tract. Dextrose is likewise pro- duced from proteid, for a diabetic patient fed solely on proteid may still excrete sugar in the urine. Minkowski 1 finds that in starving dogs after extirpation of the pancreas the proportion of sugar to nitrogen is 2.8 : 1. The same ratio has been shown to exist in phlorhizin diabetes in fasting rabbits 2 and goats 3 when the drug is frequently administered. After frequent dosage of phlorhizin to fasting, meat-fed, or gelatin-fed dogs, the ratio dextrose : nitrogen approxi- mates 3.75 : 1. Since 1 gram of N in the urine corresponds (neglecting the faecal N) to 6.25 grams of proteid destroyed, therefore, 3.75 grams ot sugar must have arisen from <>.25 grams of proteid (including gelatin). In other words, there has been a production from the proteid molecule of 60 per cent. of dextrose, which contains nearly 60 per cent, of the physiologically avail- able energy of the proteid consumed. 4 A similar large excretion of dextrose has been noted in cases of human diabetes mellitus.* In pancreas diabetes the pancreas may perhaps manufacture a ferment which, supplied from the lymph of the pancreas'' to the tissues, becomes the first cause of the decomposition of dextrose, and in whose absence diabetes ensues. Excess of dextrose in the body is stored up, especially in the liver- cells, as glycogen, which is the anhydride of dextrose ) the glycogen may be afterwards reconverted into dextrose. The presence of sugar in the body in starvation, even when little urea may be detected there, shows the readier excre- 1 Arehivfiir Exper. Paihologie wnd Pharmakologie, L893, Bd. 31, 8. 85. a Lusk : Zeitachriftfiir Biologic, 1898, Bd. 36, S. 82. i busk: Unpublished. * Reilly, Nolan, and Lusk: American Journal of Physiology, 1898, vol. i. j>. 895. s Kmnpf: Berliner Minischer Wbchenschrift, 1898, Bd. 24, Heft 43. ■ Biedl : Centralbatt fur Physiologic, 1898, Bd. 12,8.624. 564 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. tioii of the nitrogenous radical of proteid. Traces of dextrose are found in normal urine. 1 >"\trose is a sweet-tasting- crystalline substance; its solutions rotate polar- ized light to the right. Jecorin, a substance found in the liver and the blood, yields dextrose on decomposition. It is said to be a glycose-lecithin. 1 Glucosainin, C 6 If u < >.X !!._,. — This is yielded as a decomposition product of some proteids. Egg albumin, for example, yields 8 percent, of gluco- sainin. It reduces copper solutions, and has been mistaken for dextrose. H H OH rZ-Fructose, Levulose, Fruit-sugar, CH 2 OH C C C COCH 2 OH. — OHOHH This occurs in many fruits and in honey. It is sweeter than dextrose, and rotates polarized light to the left. It is a product of the decomposition of cane-sugar in the intestinal canal. If levulose be fed. any excess in the blood may be converted into glycogen, and through the glycogen into dextrose. It is possible thus to convert 50 per cent, of the levulose fed into dextrose. 2 When levulose is fed to a diabetic patient, it may be burned, though power to burn dextrose has been lost. 3 H OHOHH d- Galactose, CH 2 OH C C C C CHO.— This is found combined OIIH H OH with proteid in the brain, forming the glucoside cerebrin. It is produced together with dextrose in the hydrolytic decomposition of milk-sugar. It does not undergo alcoholic fermentation, at least not with Saccharomyces apiculatus. When fed it may in part be directly burned or in part converted into glycogen. The Disaccharides, C 12 H 22 O n . These are di-multiple sugars in ether-like combination. To cane-sugar and milk-sugar, Fisher has ascribed the following formulae : 4 Cane-sugar. M ilk-sugar. .CH- — -__ n CH 2 OH n /CHOH U \C u \CIIOH CHOH CH O CHOH CHOH (II CHjOH CH 2 OH Dextrose group. Levulose group. Cane-sugar, or Saccharose. — Cane-sugar, obtained from the sugar-cane and the beet-root, is largely used to flavor the food, and likewise assumes importance as a food-stuff. On boiling with dilute acids, cane-sugar is con- verted through hydrolysis into a mixture of levulose and dextrose. The same 1 Bing : Omtralblatt fur Physiologie, 1898, Bd. 12, S. 209. 7 Minkowski : Archie fur Pathologic und PharmaJeologie, L893, Bd. 31, S. 157. 3 Loc. cit. * Berichte der deutschen chemischen Gesellschaft, 1894, Bd. 26, S. 2400. CH,OH CHOH CH n /CHOH u \CHOH CH — O- CHO CHOH CHOH CHOH CHOH -CH 2 Galactose group. Dextrose group, THE CHEMISTRY OF THE ANIMAL BODY. 565 result is obtained by warming with 0.05 to 0.2 per cent, hydrochloric acid at the temperature of the body. 1 This inversion, therefore, takes place in the stomach. In the intestinal canal the inversion is accomplished through the action of a ferment present in the intestinal juice. Subcutaneous injection of cane-sugar results in its quantitative excretion through the urine j 2 but fed per os, cane-sugar is converted into dextrose and levulose, which may be burned in the body. Milk-sugar, or Lactose. — This is found in the milk and in the amniotic fluid. It is probably manufactured from dextrose in the mammary glands, for the blood does not contain it. It is always present in the urine during the first days of lactation, but is not found there antepartum. 3 It readily undergoes lactic fermentation, producing lactic acid, which then causes clotting of the milk. This fermentation may take place in the intestinal tract. Boiling with dilute apids splits up milk-sugar into galactose and dextrose. This decom- position probably does not take place in the stomach. The intestinal juice causes this transformation, especially in suckling animals, 4 and lactase of the pancreatic juice will also split milk-sugar. 5 Milk-sugar injected subcutane- ously in man is quantitatively eliminated through the kidney. 6 It must, therefore, undergo inversion in the intestine into galactose and dextrose before it can be burned. Isomaltose. — This is the only disaccharide which has been synthetically obtained, having been produced by boiling dextrose with hydrochloric acid. It ferments with difficulty and forms an osazone which melts at 150°-15o°. It, with dextrin, is a product of the action of diastase and of the diastatic enzymes found in saliva, pancreatic juice, intestinal juice, and blood upon starch and glycogen. Through further action of the same ferments isomaltose is converted into maltose. Maltose. — Maltose (and dextrin) are the end-products of the action of diastase on starch and glycogen, the process being one of hydrolysis : 3C 6 H l0 O 5 + H 2 = Ci 2 H 22 O u + C 6 H J0 O 5 . Maltose. Dextrin. It is likewise a product of the diastatic action of ptyalin (saliva), amylopsin (pancreatic juice), and of ferments in the intestinal juice and in the blood. Maltose readily undergoes alcoholic fermentation and forms an osazone which melts at 206°. It is converted into dextrose by boiling with acids. Certain ferments convert maltose (and dextrin) into dextrose (see Starch). (Vj/lulose Group, (C 6 IT 10 O r ,) n . Cellulose. — This is a highly polymerized anhydride of dextrose, perhaps also of man- nose. It tonus the cell-wall in the plant. It undergoes putrefaction in the intestinal 1 Ferris and Lusk : American Journal <>j Physiology, L898, vol. 1, p. "J77 » Voit, F. : Deutsehes Archiv fur klinische Medizin, 1897, !'.. 229 : abstr. Jahresberichi uber Thiercfu 1884, S. 77. 570 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. ordinary hippuric acid is formed. After eating apple-parings and other vege- table substances, hippuric acid is found in human urine. It is further stated thai phenyl-aeetic acid and phenyl-propionic acids are normal products of proteid putrefaction, though in very small quantities ; hippuric acid and phen- aceturic acid must therefore be constantly present in traces in human urine. Hippuric acid is split into its constituents by hydrolysis through the action of the Micrococcus ureoe. p-Oxyphenyl-acetic Acid, 0, H,.OH.CH 2 COOH. — This is a product of the intestinal putrefaction of proteid and of tyrosin (which see). It occurs in the urine either paired with sulphuric acid or as an alkaline salt of oxyphenyl- acetic acid. 1 p-Hydrocumaric Acid, C t .H 4 .OH.C 2 H 4 COOH. — This second oxy- acid is likewise derived from proteid and tyrosin (which see) putrefaction. Its occur- rence in the urine is similar to the above oxy- acid. Tyrosin, Amido-hydrocumaric Acid, ^-Oxyphenyl-amido-propionic Acid, C 6 H 4 .OH.C 2 H 3 NH 2 COOH. — Tyrosin is a constant product of the putre- faction of all proteid bodies (except gelatin), and is therefore found in cheese. It may be formed in large quantities by boiling horn-shavings with sul- phuric acid. Leucin is always formed whenever tyrosin is. Tyrosin forms characteristic sheaf-shaped bundles of crystals. All the aromatic bodies thus far described have been eliminated in the urine with their benzol nucleus intact. Tyrosin, however, may be completely burned in the body. This seems to be because of the presence of the amido- group on the side chain, for phenyl-amido-propionic acid is likewise destroyed. Tyrosin is found in the urine in yellow atrophy of the liver, in phosphorus-poisoning, etc. (see Leucin, p. o40). Through cleavage, oxidation, or reduction, the following reactions take place, phenol being the final product. 2 The substances not found in intes- tinal putrefaction are named in italics: C 6 H 4 .OH.C 2 H 3 NH 2 COOH - H 2 C 6 H 4 .OH.C 2 H 4 COOH + NH 3 p-TIydrocumaric acid. C 6 H 4 .OH.C 2 H 4 COOH C 6 H 4 .OH.C 2 H 5 + C0 2 p-Ethylphenol. C 6 H 4 .0H.C 2 H 5 + 30 C 6 H 4 .0H.CH 2 C00H - H 2 p-Oxyphenyl-acetic acid. C 6 H 4 .0H.CH 2 C00H C 6 H 4 .0H.CH, + CO, /<-« resol. C 6 H 4 .OH.CH 3 + 30 CJLOHCOOH + H 2 p-Oxybenzoic acid. CeH 4 .0H.C!00H C 6 H 5 OH + C0 2 Phenol. It has never been shown that tyrosin i- a normal product of proteid metabolism within the tissues. With leucin it is a normal product of pancreatic diges- tion (see p. 540). Homogentisic Acid, Dioxyphenyl-acetic Acid, Hydroquinone-acetic Acid — Tlii^ i.- found in the urine in alcaptonuria. Feeding tyrosin in this disease increases the 1 Baumann: Zeitsehriftfur physiologische Chemie, 1886, Bd. 10, S. 125. J Baumann : Berichte der deidschen ehemisehen Gesellschaft, 1879, Bd. 12, S. 1450. THE CHEMISTRY OE THE ANIMAL BODY. 571 amount of homogentisic acid. It may arise from the reduction and oxidation of tyrosin according to the following reaction: 1 + H 2 OH/ \ NH 3 +C0 2 + 2H 2 + 50 2 = 'oh CH 2 CHNH 2 COOH CH 2 COOH Pyridin.— This hody has the accompanying formula, one of the CH groups in benzol H C HC CH being substituted by N : || • When pyridin is fed, methyl-pyridin ammonium HC CH V hydroxide, OH.CH 3 .NC 5 H 5 , is excreted in the urine. 2 This is another case, besides those of selenium and tellurium, of methylation in the body. H H C C HC C CH Chinolin. — The accompanying formula illustrates the composition HC C CH N C H of this body. Several of the methyl-chinolins burn readily in the body. 3 Cynurenic Acid, C 9 H 5 N.OH.COOH.— This is oxychinolin carbonic acid ; it is found normally in dog's urine, being derived from proteid in amounts proportional to proteid metabolism. It is, however, not derived from the metabolism of gelatin, 4 a body which does not yield the aromatic chain. Indol, or Benzopyrol, C 8 H 7 N. — The source of indol is surely from proteid putrefaction; it may also be obtained by melting proteid with potash. H H C C // \ /\ // \ y\ HC C CH HC C COH I II II I II II HC C CH HC C CH ^/\/ % /\/ C N C N H H H H Indol. Indoxyl. After its absorption it receives an oxy- group ju>t as benzol docs, and like benzol pairs with sulphuric acid with the loss of a molecule of water, and appears as ethereal sulphate in the urine. In preparing indol from feces the fecal odor clings to it. Pure indol, however, has no smell. An alcoholic 'Enibden: Zeittehrift fur physiologiscke Chemie, 189:2, I5d. 17, 8. 182. 2 His: Archiv fur exper. Pathologie wad Pharmafcologie, 1887, I'«d. 22,8.263. 3 Cohn: Zeiischrift fur phymlogische Chemie, 1804, I'.d. 20, S. 210. * Mendel and Jackson : American Journal of Physiology, 1899, vol. ii. p. 1. 572 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. solution of indol mixed with hydrochloric acid colors fir-wood cherry-red. If urine be mixed with an equal volume of hydrochloric acid, chloroform added, and then gradually an oxidizing agent (chloride of lime), any indoxyl- sulphuric acid present will be oxidized to indigo-blue, which gives a blue color to the chloroform in which it dissolves. Skatol, or ,3-Methyl Indol, C 8 H 6 CH 3 NH. — The history of skatol, H C // \ /\ HC C CCH 3 I II II , HC C CH % /\/ C N H H Skatol. is the same as that of indol. Its source is from proteid putrefaction ; after ab- sorption it unites with an oxy- group, and the skatoxyl thus produced pairs with sulphuric acid, and appears in the urine as ethereal skatoxyl-sulphuric acid. CH 3 Epinephrin.— C 6 H 4 ^C.CHOH.CO.C 6 H 3 (OH) 2 . The above is the X NH 7 formula for epinephrin, the active principle of the suprarenals, as proposed by Abel. 1 Abel has formed several distinct salts of this pyrrol base. Of the sulphate of epinephrin, only 0.000018 gram per kilogram of dog causes a sharp rise in blood-pressure. Aromatic Bodies in the Urine. — There have been named above as appearing in normal human urine the ethereal sulphates of phenol, jo-cresol, pyroeatechin, indoxyl, skatoxyl, hvdroparacumaric acid, and oxyphenyl-acetic acid, of which, however, the last two appear likewise as their salts without being combined with sulphuric acid. 2 These are derived from proteid putre- factive products formed almost entirely in the large intestine (see p. 545), which are partially absorbed and partially pass into the feces. The amount of ethereal sulphate in the urine gives an indication of the amount of intes- tinal putrefaction. It does not disappear in starvation, mucin and nucleo- proteid of bile and intestinal juice furnishing material. 3 If the intestinal tract be treated so as to make it antiseptic, the ethereal sulphates disappear from the urine. 4 Diarrhoea likewise decreases their amount, obviously from the short time given for putrefaction. The synthesis between the aromatic bodies and sulphuric acid probably occurs in the liver. The liver and the kidney both have the power of combining with a considerable amount of 1 ZeitsehriftJUr phyiriologische Chemie, 1899, Bd. 28, S. 318. 1 Baumann: Zeitschrifi fib- phi/xiolni/iarhr (Vn-mir. ism;, Bd. 10, S. 125. s Von Noorden : Pathologic des Stoffwechsels, 1893, S. 163. * Baumann : Op. cit., S. 129. THE CHEMISTRY OF THE ANIMAL BODY. 573 indol and phenol, holding them until the requisite synthesis between them and .sulphuric acid occurs, and thereby rendering them non-poisonous. 1 Inosit. — This is the hexatomic phenol of hexahvdrobenzol, C 6 H c (OH) 6 . It was long mistaken for a carbohydrate. It has been found in muscle, liver, spleen, suprarenals, lungs, brain, and testicles ; likewise in plants, in unripe peas and beans. After drinking much water it may be washed out in the urine, and perhaps for this reason is often found in the voluminous urine of the diabetic. When fed it is burned ; also by the diabetic. Its origin is unknown. Substances of Unknown Composition. Coloring Matters in the Body. Haemoglobin, C 712 H U30 N 2U FeS 2 O 24 5 (Zinoffsky's formula for haemoglobin in horse's blood). — Haemoglobin is found in the red blood-corpuscle, probably in chemical union with the stroma. 2 United with oxygen it forms oxyhaenioglobin, which gives the scarlet color to arterial blood ; haemoglobin itself is darker, more bluish, and therefore venous blood is of a less brilliant red. Methods for preparing oxyhemoglobin crystals are numerous, but all depend on getting the haemoglobin into solution. If the corpuscles in cruor be washed witli physiological salt-solution, and then treated with distilled water, the HbO will be dissolved; on shaking with a little ether the stroma will likewise dis- solve; after decantation and evaporation of the ether, at the room's temperature, the solution is cooled to — 10° and a one-fourth volume of alcohol at the same temperature added; after a few days rhombic crystals of oxyhaemoglobin may be collected, redis- solved in water, and re precipitated for purification. The crystals may be dried in vacuo over sulphuric acid. Once dry they may be heated to 100° without decomposition, but in aqueous solution they are decomposed at 70° into a globulin and haematin. the latter having a brown color. This difference in color gives the distinction between "rare " and "well-done" roast-beef. Gastric and pancreatic digestion likewise converts oxyhaemo- globin into a globulin, which may be absorbed, and haematin, which passes into the feces. Haemoglobin is without doubt formed in the body from simple proteids by a synthetic process, (for further information see pp. 529 and 574, and likewise under the sen ion on Blood.) CO-Haemoglobin (see p. 51 7). NO-Hsemoglobin (see p. 512). Methsemoglobin.— This is found in blood-stains, and may be considered as oxyhaemo- globin which has undergone a chemical change whereby some of the loosely combined oxygen has been liberated. 3 Haematin, C 32 H ;!2 N 4 0.,Fe. — This is a cleavage-product of haemoglobin in the presence of oxygen. (See above, under Haemoglobin). It is not itself a constituent of the body. It is insoluble in dilute acids, alcohol, ether, or chloroform, but is soluble in alkalies or in aeiditied alcohol or ether, showing characteristic absorption-bands. If a little dry blood be placed on a microscope slide with NaCl and moistened with glacial acetic acid, and wanned, characteristic brown microscopic crystals of licemin, I ' 1 1 N , Fe( I 1 1 1 '1. crystallize out. If these crystals and the spectroscopic test be obtained, one can be absolutely posi- ti\ c of the presence of Mood. Haemochromogen, (VJT^NgFe.^. — This substance has the same composition as haematin, only it contains less oxygen. 4 If reduced haemoglobin be heated in scaled tubes with dilute acids or alkali in absence of oxygen, a purple-red compound is produced called 1 Herter and Wakeman : Journal of Experimental Medicine, 1899, vol. iv. p. 307. 3 Read .Stewart, G. N.: Journal of Physiology, 1899, vol. xxiv. p. 238. 3 Zeynek: Archivfur Physiologic, 1899. S. 460. 4 Zeynek: Zeilschrift fiir physiologische Chemie, 1898, Bd. 25, S. 492. 7u [ AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. haemochromogen, which is a crystallizable cleavage-product of haemoglobin. According to Hoppe-Seyler the oxygen in oxyhaemoglobin is bound to the haemochromogen group. Haemochromogen treated with a strong dehydrating agent is converted, with elimination of iron, into Jioematoporphyrin, Ci 6 H, 8 N.,0 3 , an isomer of bilirubin. Haematoporphyrin is said to occur in normal urine. 1 Haematoporphyrin treated with nascent hydrogen is converted into a body believed to be identical with hydro- or urobilirubin. Analogous to this is the work of the liver in the body, manufacturing the biliary coloring matter from haemoglobin, and retaining the separated iron for the synthesis of fresh haemoglobin (see p. 5i29). Hcematoidin, found in old blood-stains, is believed to be identical with bilirubin. The Bile-pigments. — The ordinary coloring matter of yellow human bile is bilirubin, C ; JI: iB N 4 6 . The next higher oxidation-product is the green bit inn I in, C 32 H 36 N t O fe , which is the usual dominant color in the bile of herbivora. These coloring-matters and others derived from them have been found in gall-stones. Jolles 2 gives the following products of the oxidation of bilirubin: Bilirubin (red) t' 16 H I8 X 2 3 ; Biliverdin (green) C 16 H ls N 2 O i ; Bilicyanin (blue) ? — - — (violet) ? (red) ? (brown) ? Bilixanthin (brownish-yellow) C 16 H 18 N 2 0». If nitric acid containing a little nitrous acid be added to a solution ol bilirubin, a play of colors is observed at the juncture of the two fluids, undoubtedly depending upon various st; i -es of oxidation. Above is a ring of green (biliverdin), then blue and violet (bilicya- nin), red, yellowish-brown (bilixanthin). Bilixanthin (= choletelin) is the highest oxida- tion-product. The above is known as Gmelins test. 3 If bilirubin or biliverdin is subjected to the action either of nascent hydrogen or of putrefaction it is reduced to hydrobilirubin, C 32 H u N 4 7 . This substance is therefore formed in the intestinal tract, is in part absorbed, and appears in the urine, where it is called urobilin, though the two are identical. Urobilin gives a yellowish coloration to the urine. Injection into the blood-vessels of distilled water, ether, chloroform, the biliary salts, or arsenuretted hydrogen, produces a solution of the red blood-corpuscles and conver- sion of haemoglobin into biliary coloring matters which are thrown out in the urine. Bili- rubin, biliverdin, and bilicyanin give characteristic spectra. Melanins. — Under this name are classed the pigments of the skin, of the retina, and of the iris. In melanosis and kindred diseases they are deposited in black granules. Abel and Davis 1 prepared pure pigment from the skin of the negro and find that it con- tains no iron and 1.5 per cent, of sulphur. These pigments arise from proteid. On decomposition they yield two melaninic acids. 5 Tryptophan. — This is said to be a cleavage-product of hemipeptone in tryptic diges- tion ; 6 it gives a red color with chlorine and a violet color with bromine, due to halogen- addition compounds. Lipochromes. — These include lutein, the yellow pigment of the corpus luteum, of 1 Gar rod: Journal of Physiology, 1894, vol. 17, p. 348. 2 Pilii./.rs Archiv, 1899, Bd. 75, S. 446. 5 For a delicate modification of this test see Jolles: Zeitschrift fur physiologische Chemie, 1895, Bd. 20, S. 461. 4 Journal of Experimental Medicine, 1896, vol. i. p. 361. 1 . 1 ones: American Journal of Physiology, 1899, vol. ii. p. 380. delmann: Zeitschrift fur Biologie, 1890, Bd. 26, 8. 491. THE CHEMISTRY OF THE ANIMAL BODY. 575 blood-plasma, butter, egg-yolk, and of fat; likewise visual purplt of the retina, which is bleached by light, Solutions of the pure visual purple from rabbits or dogs become clear as water on exposure to light. 1 Cholesterin. Cholesterin, C 27 H 45 OH. — This is found in all animal and vegetable cells and in the milk. 2 It is especially present in nervous tissue and in blood-corpuscles. It is excreted through the bile and through the intestinal wall. 3 In the blood-plasma it is present as an ester combined with oleic and palmitic acids, while in the corpuscle it occurs as simple cholesterin.* It may be prepared by dissolving gall-stones in hot alcohol, from which solution the cholesterin crystallizes on cooling in characteristic plates. It is insoluble in water or acids, but soluble in the biliary salts, ether, and hot alcohol. Tt is probably not absorbed by the intestinal canal. In human feces stercorin appears instead of choles- terin. 5 This stercorin (the koprosterin of Bondzynski) is a dihydrocholesterin, 8 (\, 7 II, ; OH, and is the result of putrefactive change. 7 Cholesterin feels like a fat to the touch, but is in reality a monatomic alcohol. With concentrated sulphuric acid it yields a hydrocarbon, cholesterilin, C 26 H 4! „ coloring the sulphuric acid red (Salkowski's reaction i. Iso-cholesterin, an isomere, is found combined as an ester with fatty acid in wool-fat or lanolin. The physiological importance of cholesterin is unknown. The Proteids. Consideration of the proteids from a purely chemical standpoint is impos- sible, for their composition is unknown. There exist only the indices of com- position furnished by the products of cleavage and disintegration. Bodies at present classed as individuals may sometimes be shown to be identical, with characterizing impurities. It remains for the chemist to do for the proteid group what Emil Fischer with phenyl-hydrazin has accomplished for the sugars. As a characteristic proteid, egg-albumin may be mentioned. Proteid forms (after water) the largest part of the organized cell, and is found in all the fluids of the body except in urine, sweat, and bile. Proteid contains carbon, hydrogen, nitrogen, oxygen, sulphur, sometimes phosphorus and iron. General Reactions. — A neutral solution of proteid (with the exception of the peptones and proteoses) is partially precipitated on boiling, and is quite completely precipitated on careful addition of an acid (acetic) to the boiling solution. Proteids are precipitated in the cold by nitric and the other com- mon mineral acids, by metaphosphoric but not by orthophosphoric acid. Metallic salts, such as lead acetate, copper sulphate, and mercuric chloride, precipitate proteid; as do ferro- and ferricyanide of potassium in acetic-acid solution. Further, saturation of acid solutions of proteid with neutral salts (NaCl, Na 2 S0 4 , (NH 4 ) 2 S0 4 ) precipitates them, as docs likewise alcohol in 1 Kiihne : Zeitschrift fur Biologie, 1895, Bd. 32, S. 26. •Schmidt-Muhlheim: Pfluger's Arehiv, 1883, Bd. 30, S. 384. 3 Moraczewski : Zeitschrift fiir physiologische Chemie, 1898, Bd. 25, S. 122. * Hepner: Pfluger'a Arehiv, 1898, Bd. 73, S. 595. 5 Flint: American Journal of Medical Sciences, 1862. 6 Bondzynski and Hnmnicke: Zeitschrift fur physiologische Chemie, 1S96. Bd. 22, B. 39(5. : Miiller, P. : Ibid., 1900, Bd. 29, S. 129. :,7i; AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Albumins neutral or acid solutions. Proteid is also precipitated by tannic acid in acetic- acid solutions, by phospho-tuugstic and phospho-molybdic acids in the presence of free mineral acids, by picric acid in solutions acidified by organic acids. 1 The precipitation of proteid is also accomplished by nucleic acid, taurocholic acid, and chondroitic sulphuric acid in acid solutions. Of the eohr-readions the action of Millon's reagent has been described p. 569). Soluble proteids give the biuret test (see p. 549). With concen- trated sulphuric acid and a little cane-sugar a pink color is given when proteid is present (see p. 544). Proteid heated with moderately concentrated nitric acid gives yellow Makes, changing to orange-yellow on addition of alkalies (xantho-proteid reaction). Proteid in a mixture of one part of concentrated sulphuric acid and two parts of glacial acetic acid gives a reddish-violet color (Adamkiewicz), a reaction accelerated by heating. Finally, proteid dissolves after heating with concentrated hydrochloric acid, forming a violet-colored sol i i tion ( Lieberman n) . The following, taken in part from Chittenden, 2 is submitted as a general classification of the proteids : Simple Proteids. Serum-albumin ; Egg-albumin ; Lacto-albumin ; Mvo-albumin. Serum-globulin ; Fibrinogen ; Myosin ; Myo-globulin ; Paramyosinogeu ; Cell-fflobulin. Acid-albumin ; Alkali-albumin. Proteoses and Peptones. Coagulated Proteids < ' .. I Other coagulated proteids. Combined Proteids. Haemoglobin ; Histo-hsematins ; Ckromo-proteids J Chlorocruorin ; Haemerythrin ; Haemocyanin. Glyco-proteids < _ _ ' * { Mucoids. 1 The above list is given by Plammarsten, Physiological Chemistry, translated by Mandel, p. IS. - " Digestive Proteolysis," Cartwright Lectures, 1895, p. 30. Globulins Albuminates THE CHEMISTRY OF THE ANIMAL BODY. 577 c Casein ; ^ 1. Those yielding para-nuclein < Pyin ; Nudeo-proteids \ ' Vitdlin. ^ o T , • 1V , l • i Nucleo-histon ; v 2. Ihose yielding true nuclei n < - „ , . ' J I Gell-nuclein. Phospho-glyco-proteids. Helico-proteid. Albuminoids. Collagen (gelatin). Elastin. Keratin and Neurokeratin. Albumins. — Bodies of this group are soluble in water and precipitated by boiling, or on standing with alcohol. Serum-albumin is the principal proteid constituent of blood- plasma, while lacto-albumin and myo-albumin are similar bodies found respectively in milk and muscle. Globulins. — These are insoluble in water, but soluble in dilute salt-solutions. They are coagulated on heating. If blood-serum be dialyzed with distilled water to remove the salts present, serum-globulin formerly held in solution separates in flakes. Fibrinogen and serum-globulin are in blood-plasma and the lymph. Myosin is the principal constituent of dead muscles ; in the living muscle myosin is said to be present in the form of myosin- ogen. Myoglobulin in muscle is akin to serum-globulin in plasma. Paramyosinogen in muscle is characterized by the low temperature at which it coagulates (+47°). Cell- globulin is also found in the animal cell. The globulins of vegetable cells are interesting as having been obtained in well-defined crystalline form and in great purity of composition. 1 These are not generally coagulable by heat, and indeed vegetable proteids show many points of divergence from those of the animal. Osborne 2 finds that solutions of pure crystalline edestine obtained from plants take up hydrochloric acid inexact chemical relations, forming the hydrochlorato or bihydrochlorate of edestine. The simplest formula for edestine ( containing two atoms of sulphur) which can be calculated gives a molecular weight of 7,138, twice which is 14,276. This latter molec- ular weight exactly unites with one molecule of hydrochloric acid to form edestine hydrochlorate. Osborne regards the many variations in similar L ' native " albumins as being fundamentally caused by the quantity and quality of the acid or alkali with which they unite. Albuminates. — If any of the above native animal proteids or any coagulated proteid be treated with an alkaline solution, alkali albuminate is formed. In this way the alkali of the intestine acts upon proteid. If hydrochloric acid acts on proteid. there is a gclatin- ization and slow conversion into acid albuminate, a process accelerated by the presence of pepsin. This takes place in the stomach. Both alkali and acid albuminates are in- soluble in water, but both are soluble in dilute acid or alkali, without loss of individual identity. Proteoses and Peptones. — These are bodies obtained from the digestion of proteids, through a process of hydrolysis. They are non-coagulable by heat. If a mixture of pro- teoses and peptones be saturated with ammonium sulphate the proteoses are said to be precipitated, while true peptone remains in solution. The chemical identity of this true peptone is still, however, to be established. In the gastric digestion of fibrin, proto- proteose, hetero-proteose, and deutero-proteose B, arise as primary cleavage products. 8 1 Osborne : Journal of American Chemical Society, 1894, vol. xvi., Nos. 9, 10; and other arti- cles in the same journal by the same author. 2 Op. efl.,1899, vol. 21, p. 48(3. 3 Zunz, E. : Zeitschrift fiir physiologische Chemie, 1899, Bd. 28, S. 132. Vol.. I. — 37 578 AN AMERICAN TEXT- HOOK OF PHYSIOLOGY. Fibrin yields a carbohydrate radicle which appears in deutero-proteose B and subse- quently in peptone A. 1 The primary proteoses are believed to break np into secondary proteoses, such as deutero-proteose A and deutero-proteose C. and perhaps others, and these secondary proteoses maybe converted into peptones, although gastric digestion will not convert some deutero-proteoses into peptone. 2 Egg albumin and other proteids yield similar products. The whole process of proteolytic cleavage has been compared with the hydrolytic cleavage of starch into dextrins and sugars. According to Kiihne, proteid consists of a hemi- and an anti- group, which separate into distinct hemi- and anti- bodies in proteolysis. Of the final products, hemi- and anti-peptone, only the former yields leucin and tyrosin in tryptic proteolysis. This is the only radical difference between the two peptones, hence hemi-peptone has never been isolated. Kutscher 3 denies the existence of anti-peptone and shows that prolonged tryptic proteolysis almost completely transforms proteid into amido bodies. Coagulated Proteids. —These are insoluble in water, salt -solutions, alcohol, dilute acids and alkalies, but soluble in strong acids and alkalies, pepsin-hydrochloric acid, and alkaline solutions of trypsin. The chemical or physical change which is effected in coagulation of proteid is unknown. Combined Proteids. — These consist of proteid united to non-proteid bodies such as hgemochromogen, carbohydrates, and nucleic acid. Chromo-proteids. — These are compounds of proteid with an iron- or copper-contain- ing pigment, like haemoglobin, which has already been described. Histohcematins are iron-containing pigments found especially in muscle. That which is found in muscle is called myohsematin, and resembles bsemochromogen somewhat in its spectroscopic appear- ance, and is believed to be present in two forms corresponding to haemoglobin and oxyhaemo- globin. It has been regarded as an oxygen-carrier to the tissues. Among the inverte- brates the blood often contains only white corpuscles with sometimes a colored plasma. Thus the blood-serum of the common earth-worm contains dissolved haemoglobin, that of some other invertebrates a green respiratory pigment, chlorocruorin, whose charac- terizing component seems similar to hsematin ; hcemerythrvn occurs in the pinkish corpus- cles of Sipunculus, while the blood of crabs, snails, and other animals (mollusks and arthropods) is colored blue by a pigment, hcemocyanin, which contains copper instead of iron. Glyco-proteids. — These consist of proteids combined with a carbohydrate. They are insoluble in water, but soluble in very weak alkalies. On boiling with dilute mineral acids they yield a reducing substance. Mucin* are found in mucous glands, goblet cells, in the cement substance of epithelium and in the connective tissues. Of the nearly related mucoids may be named colloid, a sub- stance appearing like a gelatinous glue in certain tumors; pseudo-mucerid, the slimy body which gives its character to the liquid in ovarian cysts; and chondro-mucoid, found as a constituent of cartilage. On boiling chondro-mucoid with dilute sulphuric acid it yields acid-albuminate, a peptone substance, and chondroitic acid. The last is a nitrogenous ethereal sulphuric acid, yielding a carbohydrate on decomposition, and found preformed in every cartilage * and in the amyloid liver. 5 It is. of course, not a proteid. Amyloid is similar to chondro-mucoid, and may be identical with it. Tt is said to consist of chondroitic sulphuric acid in combination with proteid. 6 and yields proteid and phosphoric acid on decomposition. 1 Pick : Zeitsehrifijur •physiologwehe Chemie, 1899, Bd. 28, S. 219. a Folin: Ibid., 1898, Bd. 25, S. 1 52. B Die Endprodukle der Trypsrinverdauung, Strassburt;, 1899. 4 Morner: Zeitschriftfur physiologische Chemie, 1895, Bd. 20, S. 357. b Odili : Archiv fiir exper. Pathologic und Pharmakologie, 189-1, Bd. 33, S. 376. 6 Krawkow : Ibid., 1897, Bd. 40, S. 195. THE CHEMISTRY OF THE ANIMAL BODY. 579 Nucleo-proteids, or Nucleo-albumins ' and Nucleic Acids. — These are compounds of proteid with nuclein, which latter yields phosphoric acid on decomposition. If nucleo- proteid, which is found in every cell, be digested with pepsin-hydrochloric acid, there remains a residue of insoluble nuclein, which is likewise insoluble in water but soluble in alkalies. If this nuclein yields xanthin bases on further decomposition, it is called true nuclein; if it fails to yield these bases, it is called paranuclein or pseudonuclein. Nucleo-proteids yielding proteid and paranuclein on decomposition include the casein of milk, pyin of the pleural cavity, vitellin of the egg, Bunge's iron-containing hsematogen of the egg, as well as nucleo-proteids found in all protoplasm. They all contain iron. Paranuclein is probably absorbable (see p. 514). Casein yields on peptic digestion phosphorized albumoses from which paranuclein is split : this cleavage is followed by the further digestion of the albumose and the gradual solution of the paranuclein.-' Kobrak 3 shows that woman's casein has two-thirds the acidity of cow's casein, but that the former dis- solved and reprecipitated six times has the same properties as the latter. He believes that woman's casein may consist of cow's casein united with another product of more basic properties. A second group of nucleo-proteids yields true nuclein on decomposition. This true nuclein is a modified form of the original nucleo-proteid, and consists of nucleic acid in combination with proteid. On decomposition the nuclein breaks up into its constituent proteid and nucleic acid, which latter always yields one or more of the xanthin bases, which arc. therefore, called nuclein bases. The nucleic acid is similar to that derived from sperm, which is combined with protamin in the sperm nucleus. The nucleic acid of yeast nuclein yields guanin and adenin, that of a bull's testicle adenin, hypoxanthin, and xanthin, that of the thymus adenin and guanin, that of the pancreas guanin alone. The latter has been termed " guanylic acid," and "adenylic" and "xanthylic" acids may also be considered individual nucleic acids. Each one of this family of acids has the power of combining with any soluble proteid to form nucleo-proteid, hence there may exist a large variety of nucleo-proteids. And the variety is further increased by the diversity of other decom- position products yielded by the various nucleic acids. Thus most nucleic acids yield thymic acid, which, however, cannot be found in pancreas nucleo-proteid. A crystalline base called cytosin has been discovered in thymus nucleic acid. Some nucleic acids, like that derived from yeast, readily yield carbohydrates (a hexose and a pentose) : while others, like thymus nucleic acid, show the presence of the carbohydrate group only in the pro- duction of levulic acid after very thorough decomposition ; and still others (salmon sperm) fail to indicate the presence of any carbohydrate radicle. According to Kossel, nuclei may at times contain free nucleic acid. According to Bang, 4 nucleic acid may unite in three ways: with protamin, as in sperm nucleic acid; loosely with proteid, as in most nucleo-proteids; and strongly with proteid, as in pancreas nucleo-proteid. Thelast-nai 1 pancreas nucleic acid yields guanin on decomposition, and has been termed "guanylic arid." Bang gives the following analysis : guanin, 36 percent, (containing nine-tenths of all the nitrogen present); a little ammonia; a pentose, 30 per cent., and I '_(),. I7.»'. per cent. The rest unaccounted for is 17.5 per cent. Phospho-glyco-proteids. — This class is represented by Hammarsten's hdico-proteid, which yields paranuclein. and, unlike other nucleo-proteids of the paranuclein class, it yields a reducing carbohydrate on boiling with acids. The Albuminoids. -These are bodies derived from tine proteid in the body, but nol themselves convertible into proteid. They are resistant to the ordinary proteid solvents, and as a rule exist in the solid state when in the body. 1 These two terms arc used here as synonymous, though Hammarsten would confine the term nucleo-albmnin to those proteids which yield paranuclein. 2 Salkowski: Zeitschrift fur physiologische <'li'ini<\ 189!*, I'll. 27, 8. 297. » I'lirnjrrx Archiv, 1900, P.d. 80, S. 69. * Zeitschrift fiir physiohgisehe Chemie, 1898, Bd. 26, S. 133. >n AN AMERICAN TEXT- HOOK OF PHYSIOLOGY. Collagen. — This is the chief constituent of the fibres of connective tissue, of the organic matter of bone (ossein) and is likewise one of the constituents of cartilage. Col- lagen is insoluble in water, dilute acids and alkalies. On boiling with water it forms gelatin through hydration, which is soluble in hot water, but gelatinizes on cooling (as in bouillon). Dry gelatin .-wells when broughl into cold water. By continuous boiling or by gastric or tryptic digestion further hydration takes place with the formation of soluble gelatin peptone. Gelatin fed will not take the place of proteid, but. like sugar, only more effectively, it may prevent proteid waste by being burned in its stead. 1 Gelatin .yields leucin and glycocoll on decomposition, but no tyrosin. It therefore gives the biuret reaction, but none with Millon's reagent. It contains but little sulphur. It yields about the same ainido- acids as ordinary proteid. Elastin. — This is very insoluble in almost all reagents and in boiling water. On decomposition it yields leucin, tyrosin, glycocoll, and lysatin. It is slowly hydratcd by boiling with dilute acids, and by pepsin hydrochloric acid. It contains very little sulphur, and gives Millon's test. It is found in various connective tissues, and especially in the cervical ligament. Keratin and Neuro-keratin. — These are insoluble in water, dilute acids and alkalies; insoluble in pepsin hydrochloric acid, and alkaline solutions of trypsin. Keratin is found in all horny structures, in epidermis, hair, wool, nails, hoofs, horn, feathers, tortoise-shell, whalebone, etc. Neuro-keratin has been discovered in the brain, and in the medullary sheath of nerve-fibres. 2 On decomposition with hydrochloric acid keratin yields all the products given by simple proteids. It contains more sulphur than simple proteid and yields more tyrosin. Drechsel 3 believes that it is transformed from simple proteid by the substitution of sulphur for some of the oxygen and of tyrosin for leucin or other amido- acid. Part of the sulphur is loosely combined, and a lead comb turns hair black, due to the formation of lead sulphide. There are different keratins, and their sulphur content varies greatly. Histon. — Iliston is a proteid split off from yeast nuclein and the nuclein of the white blood-corpuscles and blood plates. Kossel has suggested that it is a combination of pro- teid and protamin, which the investigations of Bang * tend to confirm. Protamins and Remarks on the Theoretical Composition of the Proteid Molecule. — The protamins have been discovered in fish-sperm united with nucleic acid. According to Kossel, protamins are the simplest proteids. They till give the biuret test. On heating with dilute acid or in tryptic digestion they are converted into protone (protamin peptone), and then they break up into amido acids. Several protamins have been dis- covered. That obtained from sturgeon-sperm is called sturin, from the herring, clupein, from the salmon, salmin, and from the mackerel, scombrin. Sturin, according to Kossel, 5 breaks up as follows ; C 36 H fi9 N 19 7 + 5H 2 = C 6 H 9 N 3 2 + 3C 6 H M N 4 2 + C 6 H 14 N 2 2 sturin. Ilistidin. Axginin. I.ysin. Kossel'- investigations show thai salmin and clupein are identical and yield on decomposition arginin and amido valerianic acid, while scombrin also yields arginin, without any histidin or lvsin. 6 1 Voit : Zeitnehrififui Biolopie, 1872, Bd. 8, S. 297. 1 Kulme and Chittenden: Ibid., 1890, Bd. 26, S. 291. 3 Ladenbuipfs Ilrlnirlt
. -J7-J. 3 Ray, McDermott, and Lusk : Ibid,, 1S99, vol. iii. p, 153. * Deutsche medicinisehe Wochenschrift, 1899, S. 209. 5 Sitzungsberichte der Gesellschaft zur Befordeiimg der gesammten NaturvnssenwhafienjMU Marburg, 1899, S. L02. 6 Bnnge : Physiologische Chemie, 3d ed., 1893, S. 56. 7 Verhandlungen der Berliner physiologischen Gesellseliaft, Archiv fur Physiologic, 1894, S. 383. 582 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. glyoocoll has obtained a body insoluble in water, but swelling in it, forming a gelatinous mass. The substance gives the biuret reaction, is insoluble in alcohol and dilute hydrochloric acid, but dissolves in pepsin-hydrochloric acid. These reactions show its kinship to gelatin. Lilienfeld likewise de- scribes a synthetically formed peptone and a coagulable proteid, 1 the peptone formed principally through condensation of the above-described product with the ethyl-esters of the amido- bodies, leucin and ty rosin, the proteid from the same with addition of formic aldehyde. Grimaux likewise has produced, with other reagents, colloids which resemble proteids. Probably none of these substances are native proteids, but they furnish indications of lines of attack for the future mastery which in time is sure. 1 Verhandlungen der Berliner physiologischen Gesellschaft, Archiv fur Physiologie, 1894, S. 555. INDEX Abdominal muscles, action of, in vomiting, 387 respiratory action of, 407 respiration, definition of, 398 Absorbents, 318 Absorption, effect of alcohol on, 535 in the small intestine, 313 in the stomach, 312 mechanism of, 312 nature of process, 27 of fats, 317 of gases by liquids, 414 of proteids, 316 of sugars, 317 of water and salts, 318 part played by leucocytes in, 48 paths of, 311 spectrum of oxyhemoglobin, 41 Accelerator centre, cardiac, 177 respiratory, 457 nerves of the heart, 167, 168, 169 Accessory articles of the diet, 357 thyroids, 268 Acetic acid, 536 Acetone, relation of, to fat metabolism, 539 Acetonitril, 542 Acetonuria, 537 Acetyl-acetic acid, 537 Acetyl-propionic acid, 538 Achroodextrin. 285, 566 Acid, acetic, 536 acetyl-acetic, 537 acetyl-propionic, 538 amido-acetic, 537 amido-ethyl-sulphonic, 543 a-amido-a-thiopropionic, 546 aspartic, 557 benzoic, 569 butyric, 539 capric, 541 caproic, 540 caprylic, 541 carbamic, 548 carbolic, 569 carbonic, chemical structure of, 545 choleic, 543 cholic, 543 chondroitic, 578 cynurenic, 571 diamido-acetic, 551 o-e-diamido-caproic, 552 diamido- valeric, ~>.->2 dithio-diamido-ethidene lactic, 547 fellic, 543 formic, 534 glutamic, 558 glycerin phosphoric, 559 glycuronic, 567 hippuric, 33ft, 569 homogentisic, 570 hydriodic, 509 hydrobromic, 509 hydrochloric, 507 hydrocumaric, 570 Acid, hydrocyanic, 542 hydrofluoric, 510 iso-butyl amido-acetic, 540 iso-valerianic, 539 lactic, 545 levulic, 538 malic, 558 mercapturic, 547 metapliosphoric, 514 methyl amido-acetic, 538 monobasic fatty, 532 nucleic, 579 oleic, 560 orthophosphoric, 514 oxalic, 557 oxaluric, 555 oxybutyric, 548 oxyphenyl-acetic, 570 oxy phenyl -am ido-propionic, 570 palmitic, 541 parabanic, 555 phenaceturic, 569 phenyl-acetic, 569 propionic, 538 sarco-lactic, 546 silicic, 519 stearic, 541 succinic, 557 sulphuric, 506 sulphurous, 506 thiolactic, 547 thvmic, 579 uric, 322, 338, 554, 557 Acids, effect of, on pancreas, 236 Acinus, definition of, 212 Acromegaly, 273 Adamkiewicz reaction for proteids, 576 Addison's disease, '.'71 Adenin, :i:«», 554 Adipocere, 541, 560 Adrenal bodies, internal secretion of, 27'.' removal of, 271 secretory nerves of. 272 Adrenal extracts, physiological action of. 271 Afferent respiratory nerves, 460 Age, influence of. on heal production, 182 on pulse rate, 121 on respiration. 125 relation of body temperature to. 469 Air, alveolar, composition of, 113 atmospheric, composition of, 110, 113 complemental, \'~. expired, COmpOSil Ion of. I |0 inspired, composil ion of, l lo in t lie lungs, renewal of, 1 13 passages, obsl i ucl ion of, 152 residual. 127 respiratory changes In, 110 stationary, 127 suction of, into veins, 97 supplemental, 127 tidal, volume of, 126 variations in the composition of, 435 Albuminates, 577 583 584 INDEX. Albuminoids, digestion of, in the stomach. 297 enumeration of, 577 nutritive value of, "-'77, 349 properties of, 579 protection of proteids by, '■'>l'.< tryptic digestion of, 304 Albuminous glands, 216 Albumins, properties of, 577 Albumose injections, effect of, on blood, coagu- lation, 62 Alcaptonuria, 570 Alcohol, absorption of, in the stomach, 313 amy I. 539 cerotyl, 540 cetyl, 540 ethyl. 535 melicyl, 540 nutritive value of, 358 physiological action of, 357, 535 propyl. 536, 538 toxic effects of, 359 Alcoholic fermentation, 535 Alcohols, monatomic, 531 Aldehydes, general properties of, 534 Aldoso. 561 Alimentary canal, movements of, 369 principles, 276 Allantoic, 555 Alloxunc bases, 338, 339, 552 Altitude, effect of, on the number of red cor- puscles, 46 Alveolar air, composition of, 413 capacity, 427 tension of carbon-dioxide, 413 of oxygen, 413 Alveolus, glandular, definition of, 212 Amido-acetic acid, 537 Amido-acids, properties of, 538 Amines, definition of, 541 Ammonia, inhalation of, 440 occurrence of, 511 origin of, in the body, 511 properties of, 511 Ammoniacal fermentation of urine, 512 Ammonium carbamate, 548 carbonate, 523 cyanate, 542 magnesium phosphate, 527 Amniotic fluid, inhibitory eflect of, on respira- tion, 464 Amoeboid movement of leucocytes, 48 Ampho-peptone, definition of, 293 Ainygdalin, fermentative decomposition of, 542 Amy] alcohol, 539 Amylodezl rin, 566 Amyloid, 578 Amylolytic enzyme of gastric juice in the dog, 296 of succns entei icns, 308 of the liver, 330 enzymes, definition of, 280 action of. in I lie bod v, 2*5 Amylopsin, 232, 280 action of, on starch. 566 digestive action of, 305 ■ mi in rence of, 304 properties of, 305 Anabolism, definition of, 19 A usesthetics, effect of, on body-temperature, 472 Animal foods, composition of, 278 heat, 167 source of, 17 1 Annulus Vieussens, L59 Antalbumid, 293 Antilytic secretion, 230 Antimony poisoning, 5] I Anti-peptone, definition <>f, 293 Anti-peptone, nature of, 302 Antiperistalsis, intestinal, 383 of the stomach, 379 Antrum pylori, 377 Apex beat, 117 preparation of the frog's heart, 188 ventricular, rhythmicity of, 151 Apncea, definition of, 440 foetal, 164 phenomena of, 441 relation of vagi to, 442 Apomorphia, action of, 389 Arabinose, 562 Arginin, 552 Argon of the blood, 417 Aromatic compounds m urine, 572 metabolism of, 568, 569 Arsenic poisoning, 514 Arterial blood-pressure, explanation of, 92 pulse, cause of, 93 definition, 139 extinction of, 94 Arteries, coronary, 179 elongation of, 14(1 rate of flow in, 101 Artificial respiration, circulatory effects of, 453 methods of maintaining, 446 Asparagin, 558 Aspartic acid, 557 Asphyxia, 441 circulatory changes in, 445 efl'ects of, on the blood-vessels, 202 on the respiratory rhythm, 425 stages of, 445 Aspiration of the thorax, influence of, on the circulation, 77, 95 on the lymph-flow, 147 on venous circulation, 77, 95 Assimilation, general characteristics of, 19 Associated respiratory movements, 408 Asymmetrical carbon atom, definition of, 545 Atelectasis, 396 Atmospheric air, composition of, 410, 413 Atrophv of the heart after section of the vagi, 167 Atropin, action of, on salivary glands, 222, 229 on sweat glands, 260 eflect of, on body-temperature, 472 Augmentor centre of the heart, 177 nerves of the heart, 161, lt>7 Auricles, connection of, 135 degree of emptying, in systole, 138 functions of, 135 influence of, on venous blood-flow, 136 negative pressure in the, 137, 138 systolic changes in the, 115 Auricular pressure, 135, 137 systole, duration of, 124, 136 eflect of, on venous blood-flow, 138 on ventricular tilling, 137 Auriculo-ventricular valves, 108 Auscultation, 118 Axilla, temperature in the, 468 Bacterial decomposition in the intestines, 309 Banting diet. :i.">:: Barometric pressures, effect of, on respiration, 434 Bartholin, duct of, '.'17 Basophiles, 47 Baths, influence of, on body-temperature, 471 Beckmann's apparatus, 68 Beef-tea, physiological action of, 359 I leer. 535 Beeswax, 540 Benzoic acid. 340, 569 INDEX. 585 Benzol, molecular constitution of, 568 Beuzopyrol, 571 Bidder's ganglion, 148 Bile, amount secreted, 246, 321 antiseptic property of, 326 composition of, 245, 321 discharge of, from the gall-bladder, 248, 249 fatty acids of the, 541 influence of, on ein unification of fats, 307 mineral, constituents of, 530 pigments of, 245, 322 physiological value of, 325 relation of, to fat absorption, 325 secretion of, 246 sulphur of, 507 Bile-acids. 245 detection of, 324 Neukomm's test for, 545 occurrence of, 323 origin of, 324 Pettenkofer's test for, 324, 544 relation of, to fat absorption, 326 Bile-capillaries, 244 Bile-ducts, occlusion of, 249 Bile-pigments, 322 chemical properties of, 574 Gmelin's test for, 322, 574 origin of, 45, 530 Bile-salts, 245 chemistry of, 543 circulation of, 544 Bile-secretion, normal mechanism of, 248 relation of, to blood-flow in the liver, 247 Bile-vessels, motor nerves of, 248 Biliary fistula;, 321 Bilievanin, 574 Bilirubin, 245, 574 Biliverdin, 245, 574 Bilixanthin, 574 Biuret, 549 Bladder, urinary, movements of, 369, 390 vaso-motor nerves of, 209 Blood, 33 chemical composition of, 50 circulation of, 76 coagulation of, 54 defibrinated, 34 distribution of, in tbe body, 63 foreign, action of, on tbe heart, 192 gaseous exchanges of the, 411 general function of the, 33 histological structure of, 33 identification of, 573 oxidations in the, 423 reaction of tbe, 34, 290 regeneration of, after hemorrhage, 63 specific gravity of, 31 total quantity of, in the body, 63 transfusion, 64 Blood-corpuscles, inorganic salts of, 50, 530 varieties of, 33 Blood-gases, analyses of, 411 extraction of, 420 tension of, 415 Blood-leucocytes, 47 Blood-plasma, color of, 33 composition of, 51 inorganic salts of, 50 Blood-plates, 49 Blood -pressure, aortic, 91 capillary, 84, 93 effect of the accelerator nerves on, 170 effect of the depressor nerve on, 173 effect of, on renal secret ion, 253, 256 mean, definition of, 90 methods of measuring, 84, 85 origin of the, 91,92 Blood-pressure, pulmonary, 91 respiratory changes in, 147 venous, 91, 94 Blood-serum, composition of, 51 definition, 34 mineral constituents of, 530 osmotic pressure of, 68 Bodily metabolism, estimation of, 343 movements, effect of, on lymph-flow, 147 temperature, effect of, on respiratory ex- changes, 432 Body-weight, influence of, on heat-production, 482 loss of, from starvation, 362 Border-cells of the gastric glands, 237, 238 Brain, vaso-motor nerves of the, 203 Bromelin, 280 Bromine, 508 Bronchial capacity, 427 Broncho-constrictor nerves, 465 Broncho-dilator nerves, 465 Brunner's glands, 243 Butfy coat, 55 Butyric acid, 539 Cadaverin. 543 Caffein, 553 action of, on the kidneys, 254 on body-temperature, 472 Calcium, absorption of, 525 excretion of, 526 physiological value of, 524 relation of, to heart muscle, 151 carbonates, 524 chloride, 523 fluoride, 510, 523 phosphates, 523 ■ salts, action of, on the heart, 190 amount of, in fibrin, 58 excretion of, 356 nutritive value of, 356 relation of, to blood-coagulation, 57, 524 sulphate, 523 Calorie, definition of. 504 Calorimetric equivalent, 478 Calorimetry, direct and indirect, 365, 475, 478 Cane sugar, injection of, 317 inversion of, 565 Capacity of the heart -ventricles, 105 Capillaries, biliary, 244 blood, length of, 79 permeability of, TO pressure in the. - 1 rate of flow in. 101 resistance in the, SI structure of. B0 time, spent by the blood in, 103 secretion of the fundic viands, 238 Capillary circulation, microscopic characters of, *80 pressure, origin of, 93 relation of, to lymph formation, 72, 75 Capric acid. "> 1 1 Caproic acid, 540 ( 'aprylic acid, 511 Capsules, suprarenal, extirpation of, '.'71 < larbamic acid. 5 18 i elal ion of, to u rea formal ion, 336 ( larbamide, 5 18 Carbo-bsamoglobin, nature of, 39 Carbohydrates, absorption of, 317 affinity of ceil substance for, 568 chemist ry of, 561 combu6< ion equivalent of, 365 ill tin it ion of, "'lil digestion of, in the stomach, 296 586 IXDEX. Carbohydrates, dynamic value of, 475 fermentation of, in the intestines, 310 molecular constitution of, 561 nutritive value of, 277, 353 origin of fat from, 35:2 proteid-protection by, 568 synthesis of, 26 Carbon, metabolism of, 518 occurrence of, 516 properties of, 516 Carbon -dioxide, action of, on the heart, 191 dyspnoea, 444 elimination, conditions affecting, 429 cutaneous, 422 estimation of, 428 inhalation, effects of, 440 occurrence of, 517 of the blood, extraction of, 517 properties of, 518 tension of, in the alveoli, 413 in the blood, 416 Carbon equilibrium, definition of, 345 Carbonic acid, chemical constitution of, 545 Carbon monoxide, absorption spectrum of, 44 composition of, 38 properties of, 517 Carbon-monoxide lnemoglobiu, 517 inhalation, 440 Carburetted hydrogen inhalation, 440 Cardiac centre, augmentor, 177 inhibitory, 176 cycle, analysis of, 122 definition of, 104 duration of, 123 dyspnoea, 444 excitation, propagation of,-during vagus stim- ulation, 163 impulse, 117 nerves, anatomy of, 159 classification of, 171 extrinsic, 159 of liogs, 160 of mammals, 160 Cardio inhibitory centre, respiratory variations in, 451 Cardio pneumatic movements, 412 Cardiogram, 117 Cardiometer, 106 Cam in, 554 Casein, "Jfil composition of, 579 curd ling of, by acids, 296 by rennin, 295 Catalysis, 282, 503 Cell-differentiation, 22 Cell-division, 20 Cell-granules of glandular epithelium, 216 Cellulose, 565 Centre, augmentor of the heart, 177 cardio- inhibitory, 176 defecation, 387 d( glutition, 377 expiratory, l.">7 inspiratory, 157 micturition, 391, 393 pei ipberal reflex, 178 respiratoi y, 455 salivary secretory, 230 sweat, '-'(in thermogenic, 491 vaso-motor, 198 vomiting, 389 < en tri petal nerves of the heart, 171 ( lentrosome, 22 Cerebral circulation, 203 crossed, 443 Cerebral cortex, relation of, to the vaso-motor centre,- 202 Cerebri n, 559 Cerotyl alcohol, 540 Cerumen, L'57 Cervical sympathetic, vaso-motor function of, 193 Cetyl alcohol, 540 Chest, effects of opening the, 115 Cheyne-Stokes respiration, 424 ( Ihief cells of the gastric glands, 237 ( Ihinese wax, 540 Chinolin, 571 Chloral, effect of, on the respiratory rhythm, 425 hydrate, 536 Chlorine, inhalation of, 440 occurrence of, 507 Chlorocruorin, 578 Chloroform, fate of, in the body, 533 Chocolate, nutritive value of, 357 Cholagogues, 246 Cholesterin, 575 amount of, in the blood, 51 distribution of, 325 excretion of, 325 of the bile, 245 of milk, 261 of sebaceous secretion, 257 Choletelin, 574 Cholin, 541, 543 ChoJo-haematin, 323 Chondroitic acid, 578 Chondro-mucoid, 578 Chorda tympani nerve, vaso-dilator function of, i nervous regulation of, 376 Demilune.-, 219 Depressor nerve, 17.', 203 Deutero-proteose, definition of, 293 Dextrose, action of, on the heart, 191 amount of, in the blood, 51, 317 origin of, 563 oxidation of, in the tissues, 317 storage of, 563 Diabetes mellitus, dextrose excreted in, 354, 563 fatty acids in, 536 on proteid diet, 329 phosphorus excretion in, 515 relation of the pancreas to, 266 Dialysis, definition of, 65 of soluble substances, 69 Diaphoretics, effect of, on heat dissipation, 489 Diaphragm, movements of, 398 Diastase, 280 Diastatic enzymes, 280, 566 Dicrotic pulse, 144 wave of the pulse-curve, 143 Diet, accessory articles of, 357 average, for man, 366 Dietetics, 366 Differential manometer, 131 Diffusion, definition of, 65 of proteids, 70 through membranes, 66 Digastric muscle, 372 Digestion, action of alcohol on, 535 gastric, 287 in the large intestine, 309 influence of, on respiratory exchanges, 431 intestinal, 299 of fats, 305 of proteids, 292, 301 of starch, 284 pancreatic, 301, 308 purpose of, 275 salivary, 283 Digitalis, effect of, on the respiratory rhythm. 425 Dioxyacetone, 558 Dioxyphenyl-acetic acid, 570 Disaccharides, 564 digestion of. 308 Disassimilation, definition of, 19 Dissociation of elect inly tes, 67 Diuretics, action of, 25 I Drinking-water, 504 Dropsy, 147 Drowning, phenomena of, 445 resuscitation from, 445 Drugs, action of. on body-temperature, 472 on salivary glands, '-''J','. 229 on sweat-glands, 260 on t hei mogenesis, 184 on thermolysis, i-' 1 Duct of Bartholin, 217 of Ki vinos, -.'17 of S ten son, 217 of Wharton, 217 of Wirsung, 231 Dyslysin, 54 l Dyspepsia, cause of. 309 Dyspnoea, definil ion of. 1 1 1 effect of, on intestinal movements, 386 phenomena of. 1 1 1 variel ies of, 1 13, 1 1 1 Eck fistula. :;::ii Edestine, .".77 Efferent respiratory nerves, 463 588 INDEX. Egg albumin, absorption of, 315 Elastin, 580 Ele< trical changes in active glands, 231 in the beating heart, 152, 153 in the lnart, during vagus stimulation, 164 Electrolytes, definition of, 67 Emigration of leucocytes, 83 Emphysema, influence of, on tlie respiratory rhythm, 424 Emulsification of fats, 306 influence of the bile on, 307 Emulsions, preparation of, 307, 559 Endocardiac pressure (see Intracardiac press- ure). Eocmata, nutritive, 315 Energy, potential, of foods, 364 Enzyme action, theories of, 282 glycolytic, 354 Enzymes, classification of, 280 composition of, 279 definition of, 279 effect of, on blood coagulation, 63 general properties of, 281 mode of action of, 282 of pancreatic juice, 332, 235, 301 solubility of, 281 Eosinophiles, 47 Epiguanin, 554 Epinephrin, 272, 572 Episarcin, 554 " Erection " of the heart, 114 Erectores spiuae muscles, respiratory action of, 405 Erytbroblasts, 15 Erythrodextrin, 285, 566 Erythrose, 562 Escape of the heart from vagus inhibition, 163 Ether, ethyl. 536 Ethereal sulphates, 506 of the urine, 572 Ethers, properties of, 536 Ethyl alcohol, 535 Ethylamine, 541 Eudiometer, 421 Eupnoea, definition of, 440 Excitation, cardiac, electrical variation in, 153 propagation of, 153, 154 wave, cardiac, 152 Excretiu, occurrence of, in feces, 320 Excretions, definition of, 213 Exercise, effect of on metabolism, 359 on pulserate, 121 Expiration, forced, muscles of, 407 movements of, 106 Expiratory centre, 157 Extirpation of the liver, 336 of the pancreas, 266 of the thyroids, 268 Extractives of the blood, 50, 51 Ext racts, adrenal, 271 ovai ian, '-'7 I testicular. 273 thyroid, 269 Exudations, secretion of, 215 Fat, affinity of cell substance for, 568 nut lit l vi- history of, 559 origin of, from carbohydrates, 352 from pi oteid, 351, 560 Pat-absorption, influence of bile on, 325 mechanism of, 318 Pat-combustion, equivalent of, 365 l'.ii formation in the body.351,560 Fat-metabolism, acetone formation in, 537 Fats, absorption of, in the stomach, 313 action of, on gastric secretion, 241 digest ion of, 305 Fats, dynamic value of, 475 emulsification of, 306 gastric digestion of, 297 nutritive value of, 277, 350 of feces, 319 origin of, in the body, 351, 560 relation of, to glycogen formation, 329 synthesis of, from fatty acids, 558 Fatty acids, monobasic, 532 degeneration in phosphorus poisoning, 514 Feces, composition of, 319 Fellic acid, 543 Fermentation, alcoholic, 535 lactic, 545 Ferments, unorganized, 279 Ferratiu, 528, 529 Ferric phosphates, 528 Ferrosulphide, 528 Fever, body-temperature in, 472 cause of, 473 effect of, on blood coagulation, 55 on the respiratory centre, 458 heat dissipation in, 489 Fibrillar contraction of the heart, 181, 183 Fibrin ferment, 56 absence of, in circulating blood, 61 nature of, 57 origin of, 59 preparation of, 59 mode of deposition of, 54, 55 Fibrin-globulin, 56 Fibrinogen, 53, 54 Fibrinoplastin, 56 Fictitious meal, effect of, on gastric secretion, 239 Filtration processes in secretion, 213, 215 Flavors, nutritive value of, 359 Fluorine, occurrence of, 510 Food, combustion equivalent of, 365 definition of, 275 dynamic value of, 364 effect of, on respiratory activity, 431 energy liberated by, 474 influence of, on thermogeuesis, 484 rate of movement of, in the intestines, 314 Food -stuffs, classification of, 276 composition of, 278 Liebig's classification of, 346 Force of ventricular systole during vagus stimulation, 163 Formic acid, 534 aldehyde, 533 Formose, synthesis of, 533 Frequency of respiration, conditions affecting, 425 relation of, to the pulse-rate, 426 Galactose, 562, 564 Gall bladder, motor nerves of, 248 Galvanic current, effect of, on the heart apex, 150 Ganglion-cells of the heart, 148 Ganglion, submaxillary, 219 Gas analysis, 421 Gas-pump, description of, 420 Gaseous interchanges in the lungs, 410, 417 in the tissues, 419 Gases, absorption of, 414 in tin- large intestine, 320 in the blood, respiratory changes in, 411 of the saliva, 221 law of partial pressure of, 413 poisonous, inhalation of, 440 solutions of, 415 Gastric digestion of proteids, 292 value of, 299 fistulas, 288 glands, histology of, 237 INDEX. 589 Gastric glands, secretory changes in, 242 juice, acidity of, 289 action of, on carbohydrates, 296 on milk, 296 antiseptic property of, 288 artificial, preparation of, 291 composition of, 238, 288 methods of obtaining, 287 mineral constituents of, 530 secretion, inhibition of, 241 nervous regulation of, 239 normal mechanism of, 240 relation of, to the character of the diet, 241 stimulants for, 241 Gelatin, digestion of, in the stomach, 297 nutritive value of, 349 proteid, protecting power of, 567 Gelatoses, 297 Genio-hvoid muscle, function of, in mastication, *372 Gerhardt's reaction, 537 Gland, adrenal, 271 mammary, 262 pancreatic, 231, 266 parathyroid, 268 parotid, 217 sublingual, 217 submaxillary, 217 thyroid, 267 Gland-cells, selective activity of, 27 Glands, albuminous, histology of, 216 Bru nner's, 243 cutaneous, 257 gastric, 237 intestinal, 243 Lieberkiihn's, 243 mucous, histology of, 216 salivary, 215 sebaceous. 257 serous, definition of, 216 structure of, 211 sweat, 259 Glauber's salt, 522 Globin, 37 Globulicidal action of serum, 36 Globulins, 577 Glomeruli, renal, secretory function of, 253 Glossopharyngeal nerves, influence of, on respi- ration, 462 Glottis, respiratory movements of, 408 Glucosamin, 564 Glucoses, 562 synthesis of, 563 Glutamic acid, 558 Glutamin, 558 Glutolin, 53 I Hutoses, 297 Glycerin, 558 aldehyde, 558 phosphoric acid, 559 Glycerose, 558 Glycocoll, 5:57, 543 nutritive history of, 538 Glycogen, 566 amount of, in the liver, 327 demonstration <>f. in the liver, 327 distribution of, 330 effect of exercise oil. 361 of starval ion on, 362 of sugars on, 328 function of, 329 in the muscles, 330 origin of, 326, 327 properties of, 327, 566 Glycogen-elimination of the liver, 265 Glycogen-formation, effect of proteid diet on, 328 Glycogen-formers, 328 Glycogenic theory, 329 Glycolysis, 354 Glycolytic enzyme, 280, 354 origin of, 267 Glyco-proteids, 576, 578 Glycosazones, 562 Glyco-secretory nerves, 248 Glycoses, 562 Glycosuria after pancreas extirpation, 266, 563 Glycu ionic acid, 567 Gmel in's test for bile-pigments, 322, 574 Goblet cells, 216 Goitre, 269 Gout, 557 Grammeter, 477 Gram-molecular solution, 67 Guauin, 339, 554 Guauidin, 550 Giinzburg's reagent, 508 H^matin, 37, 44, 573 Hsematogen, 356 composition of, 579 nutritive value of, 528 Hsematoidin, 44, 323, 574 Hasniatopoiesis. definition of, 45 Haematopoietic tissues, embryonic, 46 Haeniatoporphyrin, 44, 574 Htemerythrin, 578 Haeinin, 44, 573 Hsemochromogen, 37, 44, 573 Haeruocyanin, 578 Haemoglobin, 573 absorption spectra of, 43 action of, on carbonates, 517 affinity of, for CO2, 417 amount of, 38 compounds of, with gases, 38 condition of, in the corpuscles, 35 crystals of, 39 decomposition products of, 37 derivatives of, 4 1 distribution of, in animals, 37 elementary composition of, 37 molecular formula of, 37, 38 nature of, '■'2 conduction of, from auricles to ventricles, 155 effect of blood-supply on, 186 590 INDEX. Beart heat, genesis of, 149, 150 heat produced by, 108 rate of, 121 Heart-pause, 122 position of, 1 17 pumping action of, 7^ refractory period of, 156 Heart-sounds, 118 suction-pump action of, 134 tetanus of, L65 vaso-motor nerves of, 206 work done by the, 1"7 Heat-dissipation, conditions affecting, 485 estimation of, l~ (l Heal dyspnoea, 441, 443 expenditure of, 476 income of, 475 Heat-production, amount of, 364 by the heart, L08 conditions affecting, 482 estimation of, 481 nlation of, to respiratory activity, 483 Heat-regulation, 495 source of, 474 Helico-proteid, composition of, 579 Hemi-peptone, decomposition of, by trypsin, 303 definition of, 293 Hemorrhage, effect of, on heniatopoiesis, 46 fatal limits of, 63 regeneration of the blood after, 63 relation of, to blood-pressure, 91 saline injections after. Hi Hemorrhagic dyspnoea, 444 Hepatin, 528 Heredity, physical basis of, 28 Hezon-bases, origin of, 580 Hexoses, 562 Hibernation, effect of, on the respiratory quotient, 438 Hiccough, 455 Higher brain centres for the heart, 178 Hippuric- acid, nutritive history of, 339 Histidin, 552 II istohsematin, 44, 578 Hist on, 580 effect of, on intravascular clotting, 61 Homogentisic acid. 570 Homothermous animals, 467 Hiifner's method of urea determination, 549 Hydra-mia from saline injections, 69 Hydramic plethora, effect of, on lymph secre- tion, 74 Hydration, nature of the process of, 503 Hydriodic acid, 509 Hydrobilirubin, 320 Hydrobromic a< id, 509 Hydrocarbons, saturated, 531 Hydrochloric acid, occurrence of, 507 of the gastric juice, 238 preparation of, 507 properties of. 50S secretion of, 289 testa for, 508 Hydrocumaric acid. 570 Hydrocyanic- acid, 542 Hydrofluoric acid, circulation of, in tho body, 510 Hydrogen, inhalation of, 440 occurrence of, 499 peroxide, 505 preparation of, 500 properties of, 500 Hydrolysis by enzyme action, 282 definition of, 504 of fats, 305 of proteids. 292 1 1; il i oquinone, 569 Hypertonic solutions, physiological definition of, 69 Hypertonicity, definition of, 37 Hyperpnoea, 1 10 from muscular activity. 442 Hypophysis cerebri, function of, 273 Hypotonicity, definition of, 37 II \ poxanthin, 553 relation of, to uric acid formation, 338 Ice calorimeter, principle of, 504 Icterus. 249, 544 Idio-ventricular rhythm, 152 Imbibition of water, 504 Indol,571 elimination of, 340 occurrence of, in feces, 320 Inferior laryngeal nerve, respiratory function of, iii4 mesenteric ganglion, reflex activity of, 392 Inflammation, emigration of leucocytes in, 83 Iufra-hyoidei muscles, 405 Infundibular body, function of, 272 Inhibition of the heart, reflex, 172 Inhibitory centre, cardiac, localization of, 176 tonus of, 176 centres, respiratory. 1~>7 nerves of the heart, 161 of the intestines, 385 of the pancreas, 233 of the spleen, 333 of the stomach, 382 Innervation of the blood-vessels, 192 of the heart, 148 Inorganic salts of the blood, 50 of urine, 341 relation of, to blood coagulation, 56, 57 to the heart beat, 151, 189 Inosit, 573 Inspiration, enlargement of the thorax in, 398 muscles of, 398, 404 Inspiratory centre, 457 Intercostaies muscles, respiratory action of, 402, 407 Intermittent pulse, 141 Internal secretion, definition of, 265 of the adrenal bodies, 272 of the kidneys, 274 of the liver, 265 of the ovaries, 274 of the pancreas, 266 of the pituitary body, 273 of the testis. 273 of the thyroids, 270 Intestinal contents, reaction of, 310 digestion, 299 juice, 243 movements, 382 385 Intestines, innervation of, 384 intrinsic nervous mechanism of, 384 large, absorption in the, 314 peudular movements of, 384 peristalsis of, 382 putrefactive changes in the, 310 small, absorption in the, 313 vaso-motor nerves of, 206 Intracardiac pressure, H>7, 125, 126 methods of measuring, 129, 130 Intrapulmonary pressure, 408 Intrathoracic pressure, 397, 409 Intravascular clotl Ing, 60, 61 Intrinsic nerves of the heart, 148 Invertase, occurrence of, 308 Invertinc, definition of, 280 Iodine, 509 todothyrin, properties of, 270 Ionic theory of solutions, 67 INDEX. 591 Iron, amount of, in haemoglobin, 39 excretion of, 530 inorganic, absorption of, 529 nutritive history of, 528 occurrence of, 528 synthesis of, into haemoglobin, 529 salts, excretion of, 356 nutritive value of, 356 Irradiation of medullary centres, 201 Irrigating fluids for the isolated heart, 189, 191 Irritability of living matter, 18 Ischaeniia of heart muscle, 181 Iso-butyl alcohol, 539 Iso-butyric acid, 539 Iso-dynamic equivalence of foods, 365 Isolated apex of frog's heart, 188 Isolation of the heart, 148, 191 I.somaltose, 565 Iso-pentyl alcohol, 539 Isotonic solutions, 36, 69 Isotonicity, 36, 68 Iso-valerianic acid, 539 Jaundice, 249, 544 Jecorin. 564 Karyokinesis, 20 Katabolism, definition of, 19 Keratin, 580 Ketoses, definition of, 561 Kidneys, blood-flow through the, 255 histology of, 249 internal secretion of, 274 nerve-endings in, 251 vaso-motor nerves of, 207, 256 " Klopf-versuch " of Goltz, 175 Kymograph. 89 Lactalbumin, 261 Lacteal vessels, 318 Lacteals, absorption through the, 311 Lactic acid, 545 fermentation, 545 occurrence of, in the stomach, 289 Lacto-globulin, 261 Lactose, 262, 565 Laky blood, 35 Laugerhans, bodies of, 232 Lanolin, 257, 575 Large intestine, digestion in the, 309 Latent heat, definition of, 504 period of cardiac accelerator nerves, 170 of heart muscle, 153 of vagus-stimulation, 162 Latham's hypothesis of the structure of pro- toplasm, 24 Laughing, 454 Lecithin. 559 amount of, in the blood, 51 occurrence of, 325 of bile, 245 of milk. 261 Leech extract, effect of, on blood coagulation, 62 lymphagogic action of, 73 Leucin, chemical properties, 540 formation of. in fcryptic digestion, 303 nutritive history of, 540 occurrence of, 540 Leucocytes, behavior of. in blood capillaries, 82 classification of, 17. 48 emigration of, 83 from the thymus <,dand, composition of. 51 functions of. 18 influence of. on blood-plasma, 49 origin of, 49 Leucocythaemia, fatty acids in, 530 nnrin bases excreted in, 557 Leucouuclein, effect of, on intravascular clot- ting, 61 Levatores ani muscles, expiratory action of, 407 costarum breves, inspiratory action of, 402 Levulic acid, 538 Levulose, oil.' fate of, in pancreatic diabetes, 267 occurrence of, 564 oxidation of, in diabetes, 564 Lieberkuhn's crypts, histology of, 243 Liebitr's method of urea determination, 549 Life, general hypothesis of, 25 Ligatures of Staunius, 178 Limbs, vaso-motor nerves of, 209 Lipase, 305 Lipochromes, 574 Liqueurs, 535 Living matter, elementary constituents of, 499 general properties of. 18 m molecular structure of, 23 Liver, defensive action of, against intravascular clotting, 61 extirpation of the, 336 functions of, 320 histology of, 244, 321 internal secretion of, 265 lymph formation in, 73 nerve-endings in, 245 secretory function of, 244 nerves of, 247 urea formation in, 331 vaso-motor nerves of, 206 Loew's hypothesis of the structure of pro- toplasm, 23 Loop of Heule, 250 Lungs, capacity of, 427 nerve-supply of, 465 structure of, 396 vaso-motor nerves of. 205 Lunulas of the semilunar valves, 111 Lutein, 574 Luxus consumption, 348 Lymph, 33 amount of, 146 definition of. 70 formation of, 71 gases of, 419 mechanical theory of the origin of the, 75 movement of, 71, 146 pressure of. 1 hi secretion of, 214 Lymphagogues, action of, 73, 74 Lymphatics of the heart. 186 Lymphatic system, nature of, 145 Lymph glands. 1 16 Lymphocytes, 18 Lysatin. 551 Lysatinin, relation of, to urea formation, 337, 551 Lysin, 552 Magnesium carbonate, 527 nutritive history of, 527 occurrence of. 527 phosphates, 527 Malic acid. 558 Malpighian corpuscle of fche kidnev, structure of. 249 Maltase, 280, 565 in starch digestion, 285 occurrence of. 308 Mammary glands, histological changes in. 262 normal secret ion of, 264 secretory nerves of, 263 structure of. '-'61 Manuose. 562 592 INDEX. Manometer, differential, 131 elastic, 127 maximum, 107 mercurial, 87 Marsh gas, 532 Masseter muscle, 372 Mastication, 372 " Mastzellen," relation of, to colostrum corpus- cies, -'<;:; Meal extracts, physiological action of, 359 Meals, composition of, 278 Meconium, biliary salts in, 544 Melanins, 574 M< licyl alcohol, 540 Mercapturic acids, 547 Mercury manometer, description of, 87 Metabolism, conditions influencing, 359 definition of, 20 during sleep, 361 during starvation, 362 effect of temperature on, 362 influence of the cell-nucleus on, 22 methods of estimating, 343 Metaphosphoric acid, 514 Methane, origin of, 532 Met haemoglobin, 44, 57.'! Methods, physiological. .'!1 Methyl amido-acetic acid, 538 Methylamine, 541 Methyl mercaptan, 534 selenide, 534 telluride, 534 violet, in testing for mineral acids, 289 Micellae, definition of, 25 Micturition, 389 centre for, 391. 393 nervous mechanism of, 392 Milk, composition of, 261 mineral constituents of, 530 normal secretion of, 264 Milk-sugar, 565 Millon's reaction for proteids, 576 nature of, 569 with phenol, 569 Mineral acids, tests for, 289 constituents, amount of, in the tissues, 530 Mitosis, •-'ii Molecules, physical and physiological, 25 Mononuclear leucocyte-. I- Morphin, effeel of, on body-temperature, 472 Mouth, temperature in the, 469 Mucin of bile, 325 of gastric .juice. 288 of saliva, 2H.'{ physiological value of, 221 properties of. 578 secretion of. 217 Mucous glands, histology of, 216 Mailer's experiment, 152 Mu n\ icl. 555 Muscarin, 543 act ion of. on the heart, 150 Muscle, digastric. 372 genio-hyoid, 372 glycogenic function of, 330 involuntary, properties of, 370 masseter, 372 mineral constituents of, 530 mylo-hyoid. 372 obliquus externus, 407 interniis, 11)7 pterygoid, external, 372 internal, 372 pyramidalis, 407 temporalis, :'>72 transversalis abdominis, 407 trapezius, 105 Muscles, abdomiuales, action of, in vomiting, 387 respiratory function of, 407 erectores spina 1 , 405 expiratory, 407 glycogen of the, 330 infrahyoidei, 405 inspiratory, 399, 405 intercostal. 402, 407 levatores ani, 407 costarum, 402 of mastication, 372 pectorales, 405 quadrati lumhorum, 399 rhomboidei, 405 scalei, 401 serrati postici, 399, 402 st e in o-cle id 0- mastoid, 404 thermogenic function of, 490 triangulares stern i, 407 vaso-motor nerves of, 210 Muscular exercise, effect of, on metabolism, 359 on the pulse rate, 121 on the rate of respiration, 426 on the respiratory exchanges, 433 on the respiratory quotient. 438 on the sweat glands, 260 on the venous circulation, 95 Mycoderma aceti. 537 Mylo-hyoid muscle, 372 Myogonic theory of the causation of the heart- beat, 150 Myohsematin, 578 Myosin, absorption of, 315 Myxcedema, 269 Native albumins. 577 Negative pressure in the auricles, 137 in the heart, 98 in the thorax, 95 in the veins, 94 variation of the beating heart, 153 Nerve, auriculotemporal, 218 chorda tympani, 194, 219 coronary, of the tortoise, 164 depressor, 172, 203 facial, secretory fibres of, 219 glossopharyngeal, secretory fibres of. 218 Jacobson's, 218 lingual, secretory fibres of, 219 small superficial petrosal. 218 vagus, cardiac branches of, 159 gastric branches of, 381 intestinal branches of, 385 pulmonary branches of, 465 respiratory functions of. 459 secretory fibres of, 232, 239 trophic influence of, on the heart, 166 Nerve-endings in the liver, 245 in the salivary glands. 220 Nerves, augmentor, of the heart, 167 cardiac, 1 I s cervical sympathetic. 193 depressor, of the heart. 172 of the bile vessels, 248 phrenic, 163 septal, of the frog's heart, 166 splanchnic, 17.'! trigeminal, 463 N'ervi erigentes, intestinal branches of, 385 Neukomiu's test for bile acids, 545 Neuridin, 543 Neu rin, 543 Neurogenic theory of the causation of the heart- beat. 149 Neuro-keratin, 580 Neutral salt-, effect of, on blood coagulation, 62 INDEX. 593 Neutrophils, 47 Nicotin. action of, on intestinal movements, 384 on secretory nerves, 229 Nitric oxide, 512 haemoglobin, 39, 512 Nitrogen equilibrium, definition of, 344, 512 history of, in the body, 512 inhalation, 440 occurrence of, 510 of the feces, 320 preparation of, 510 tension of the blood, 417 Nitrogenous equilibrium, definition of, 344, 512 excreta of milk, 262 of sweat, 259 extractives of the spleen, 333 metabolism, estimation of, 343 Nitrous oxide, inhalation of, 440 properties of, 512 Nceud vital, 456 Nucleic acid, 579 Nuclein bases, 552 composition, 556, 579 Nucleo-histon of the blood-plates, 49 relation of, to intravascular clotting, 61 Nucleo-proteids, classification of, 577 properties of, 579 Nucleus, functions of, 22 relation of, to oxidation, 503 Nutrition of living matter, 18 Nutritive value of albuminoids, 349 of carbohydrates, 353 of fats, 350 of proteids, 276, 345 of salts, 354 of water, 354 Obliquus extern us, respiratory action of, 407 internus, respiratory action of, 407 Occlusion of the bile-duct, effect of, 249 (Edema, 148 (Esophagus, deglutition in the, 374 Oils, effect of, on gastric secretion, 241 on pancreatic secretion, 236 Olefines, 542 Oleic acid, 541-560 Oncometer, 255 Oophorin tablets, action of, 274 Opening of the chest, effect of, on heart, 115 Opium, effect of, on respiratory rhythm, 425 " Organeiweiss," 346 Ornithiu, 552 Orthophosphoric acid, 514 Osazones of glycoses, 562 Osmosis, definition of, 65 relation of, to secretion, 213 Osmotic pressure, definition of, 65 method of determining, 67, 68 relation of, to concentration, 66 Osones. preparation of, 562 Osteomalacia, 524, ■".•.'.". ovariotomy in, 271 ( Osteoporosis, 525 Ovariotomy, effects of, 274 Ovaries, internal secretion of, 274 Oxalate solutions, effect of, on blood coagula tion, 63 < Oxalic acid, 557 < Oxaluric acid, 555 Oxidases, 281 Oxidation, 501 physiological, Hoppe-Seyler'a theory of. 505 Traube's theory of, 502 Oxidizing enzymes, 2S0 < )xybutyric acid. 5 Id Oxycholin, 543 Oxygen, alveolar tension of, 413 38 Oxygen, occurrence of, 500 preparat ion of, 501 proper) ies of, 501 tension in the blood, 415 respiratory effects of, varying, 440 Oxygen-absorption, coefficient of, 415 conditions affecting, 429 cutaneous, 122 estimation of, 428 ( Oxygen-dyspnoea, 444 Oxyhemoglobin, composition of, 38 dissociation of, 415, 501 Oxyntic cells of gastric glands, 237 Oxyphenyl-acetic acid, 570 Oxyphenyl-amido-propionic acid, 570 Oxyphiles, 47 Ozone inhalation, 440 preparation of, 502 properties of, 502 Palmitic acid, 541 Pancreas, anatomy of, 231 extirpation of, 266 grafting of, 267 histology of, 231 innervation of, 232 internal secretion of, 266 mineral constituents of, 530 secretory changes in, 233 vaso-motor nerves of, 207 Pancreatic diabetes, 267, 353, 563 fistulas, preparation of, 300 juice, amylolytic action of, 305 artificial, 301 collection of, 300 composition of, 232, 299 fat-splitting power of, 305 secretion, composition of, 232, 299 histological changes during, 233 nervous mechanism of, 232 normal mechanism of, 235 reflex character of, 236 relation of, to the character of the food, 237 Papain, 280 Papillary muscles, 110 Parabamic acid, 555 Paracasein, 296 Paraffins, 531 Paraformic aldehyde, 533 Paraglobulin, amount of, in the blood, 53 composition of, 53 functions of, 53 origin of, 53 properties of, 53 Paralytic secretion, 229 Parapeptone, definition of, 292 Paranuclein, 579 Parathyroids, anatomy of, 268 function of, 269 Parotid gland, anatomy of, 217 innervat ion of, 218 I'ate de I'oie gras, 560 Pause, compensatory, of the heart, 156 Pauses, respiratory, 124 Pectoral muscles, respiratory action of, 105 Pendular movements of the intestines, 38 1 Pcntamel hylene-diamin, 543 Pentoses. 562 Pepsin, 237, 238 effect of, oil blood coagulation, 63 preparation of, 291 proper! Les of, 290 Pepsin-hydrochloric acid, action of, 292 Pepsinogen granules, 2 12 Peptic digestion, 292, 294 Pepton-injection, effect of, on lvmph formation, 73 594 IXDEX. Pepton-injection, toxicity of, 316 Peptones, absorption of, in the stomach, 313 ,1. ■Unit ion of, 292, 295 effecl of, on blood coagulation, 62 proper! ies of, 294, 577 Perfusion cannula. 187 Peripheral reflex centres, 178 Peristalsis, definition of, 372 intestinal, 382 of the stomach, :;7!> of the ureters. 389 Permeability of the capillary walls, 70 Peroxide of hydrogen, 505 Pettenkot'er's reaction for hile acids, 324, 544 Pexinogen granules, 242 Ptlimer's hypothesis of the structure of proto- plasm, '.'•'> Phagocytosis, 48 Pharynx, deglutition in the, 373 Phenaceturic acid, 569 Phenol, 569 elimination of, 340 Phenyl-acetic acid. 569 Phloridzin diabetes, 563 Phosphates, 51 1 Phosphoric acid, salts of, 514 Phosphorus, nutritive history of, 515 occurrence of, 513 peroxide, 514 poisoning, 513 preparation of, 513 properties of, 513 Phrenic nerves, 463 Physical molecules, definition of, 25 Physiological division of labor, 22 molecules, 25 salt solution in transfusions, 64 Physiology, definition of, 17 human, definition of, 30 methods employed in, 30 subdivisions of, 17, 29 Pigments, biliary, 45, 245. 322, 530, 574 blood-, 37, 44, 573 Pilocarpin, action of, on salivary glands, 229 on sweat-glands, 260 Pilomotor mechanism, relation of, to thermo- lysis, 494 Pituitary body, anatomy of, 272 functions of, 273 internal secretion of, 273 extracts, action of, 272 Plain muscle, histology of, 369 physiology of, 370 tune of, 371 Plant-cells, assimilation in, 18 1'lasnia of blood. :;:;, .">() oxygen absorption-coefficient of, 416 Plastic food-stuffs, definition of, 346 Plethysmograph, 196 Pneumatic cabinet, 453 Pneumogastric nerve (see Vagus). pulmonary branches of, 465 respiratory function of, 459, 460 Pneumograph, 123 Poikilothermous animals, 467 I'olynueleatcd leucocytes. IS Polypncea, 441 Portal vein, vaso-motor nerves of, 209 Positive variation of the heart during vagus stimulation, 164 Post-mortem rise of temperature, 497 Potassium carbonates, nutritive history of, 520 chlorides, nutritive history of, 519 cyanide, 5 12 occurrence of, 519 phosphates, nutritive history of, 520 illation of. to heart muscle, 151 Potassium salts, toxicity of, 520 sulphocyanide, detection of, 284 occurrence of, 283, 542 of the urine, 507 thiocyanide, 512 Potential energy of food, 364 Pressor nerves, 202 Pressure, intracardiac, 107 intrathoracic, 396, 409 intraventricular, 125 of the lymph, 146 Propeptones, definition of, 292 Propionic acid, 538 Propyl alcohol, 536, 538 Protagon, 559 Protamine, nature and origin of, 24 Protamins, properties of, 580 Proteid, affinity of cell substance for, 568 circulating, definition of, 346 metabolism during starvation, 363 effect of muscular work on, 360 end-products of, 337 Proteid-absorption, mechanism of, 316 Proteids, absorption of, 315 classification of, 576 color reactions of, 576 combined, classification of, 579 combustion equivalent of, 365 diffusion of, 70 dynamic value of, 475 effect of, on glycogen formation, 328 gastric digestion of, 292 general reactions of, 575 general significance of, 24 living, theoretical structure of, 23, 24 molecular structure of, 581 nutritive value of, 276, 345 of milk, 261 of the blood, 49, 50 origin of fat from, 351 osmotic pressure of, 69 putrefaction of, in the intestines, 310 rapidity of oxidation of, 347 simple, classification of, 576 substitutes for, in the diet, 348 synthesis of, 518, 582 tryptic digestion of, 303 vegetable, 577 Proteose injection, effects of, 316 Proteoses, definition of, 292 properties of, 577 Proteolysis, 293 tryptic, 303 value of, 315 Proteolytic enzymes, definition of, 280 Protoplasm, 17, 499 Prothrombin, 58 Pseudo-mucoid, 578 Pterygoid muscles, 372 Ptomaines, chemical structure of, 542 Ptyalin, 221, 280 action of. 284, 2-6, 566 occurrence of. 28 1 Pulmonary circulation, 78, 103 innervation of, 205 ventilation, forces concerned in, 413 Pulse, arterial, cause of, 93 celerity of, 142 definition of, 139 dicrotic wave of, 143 extinction of, 94 frequency of, 121, 141 regularity of, 111 respiratory variations in the rate of, 451 size of, 111 tension of, 141 transmission of, 140 INDEX. 595 Pulse, relation of, to body-temperature, 171 respiratory, 96 Pulse-curve, 142 Pulse-rate, diurnal variations of, 121 Pulse-volume of the heart, definition of, 105 Purin. 553 bases, 552 in leucocythtemia, 557 Putrefaction, intestinal, products of, 310 Putrescin, 543 1'yin, 579 Pyramidalis muscle, expiratory action of, 407 Pyridin, 571 Pyrocatechin, 569 QUADRATI lumborum, respiratory action of, 399 Quinine hydrochlorate, action of, on salivary glands, 222 Rarefied air, respiration of, 452 Eate of conduction in heart muscle, 154 of heart-beat, variations of, 121 of progress of the food in the intestines, 314 of respiratory movements, 425 of transmission of the pulse, 140 Reaction, influence of, on action of ptyalin, 286 of bile, 322 of blood, 34 of gastric juice, 288 of intestinal contents, 310 of pancreatic juice, 232, 300 of succus entericus, 308 of sweat, 342 of urine, 250, 334 Rectus abdominis, expiratory action of, 407 Red corpuscles, behavior of, in the capillaries, 81 color of, 35 composition of, 51 disintegration of, 45 form of, 35 function of, 35 number of, 35 origin of, 45, 46, 333 size of, 35 structure of, 35 variations in the number of, 46 Reduction, 502 processes in the animal body, 536 Reflex acceleration of the heart, 177 coughs, 455 discharge of bile, 248 inhibition of the heart, 172 secretion of gastric juice, 239 of pancreatic juice, 236 of saliva, 230 viiso-motor changes, 202 Reflexes through sympathetic ganglia, vaso- motor, 200 Refractory period of the heart, 156, 158 Regeneration of blood after hemorrhage, 63 Rennin, 238 action of, on milk, 296 occurrence of, in gastric juice, 295 of the kidneys, 274 preparation of, 295 Reproduction of living matter, 18, 20 Reproductive organs, vaso-motor nerves of, 208 Residual air, definition of, 427 Respiration, artificial, 446 associated movements of, 408 cutaneous, 122 definition of, 395 heat dissipated in, 488 intensity of, 129 internal, 422 nervous mechanism of, 455 rhythm of, 423 Respiratory activity, conditions affecting, 429 centres, 455 afferent nerves to, 459 conditions influencing the, 458 foetal, Ml rhythinicity of, 458 food-stuffs, definition of, 346 movements, circulatory effects of, 447 duration of, 424 effect of, on blood-pressure, 448 on venous circulation, 95, 96 frequency of, 425 special, 453 nerves, afferent, 460 efferent. 463 pauses, 424 pressure, 408 quotient, 410 during hibernation, 434 relation of, to the diet, 353 variations of, 437 sounds, 409 Resuscitation from drowning, 445 Rete mirabile of the Malpighian corpuscles, 249 Rh am nose, 562 Rheometer, 99 Rhomboideus muscles, respiratory action of, 405 Rhythm of the respiratory movements, 423 Rhythmic activity of the vaso-coustrictor cen- tre, 201 Rhythinicity of the heart, abnormal, 152 cause of, 148 Ribs, respiratory movements of, 400 Rickets. 351!, 525 Right lymphatic duct, 145 Ringer's solution for the heart, 190 Riviuus, ducts of, 217 Roy's tonometer, 188 Saccharose, 564 Saliva, composition of, 220, 283 mineral constituents of, 530 properties of, 220, 283 uses of, 286 Salivary corpuscles, 283 glands, 215 anatomy of, 217 histology of, 219 histological changes in, 226 nerves of, 218, 221 vaso-motor nerves of, 222 secretion, action of drugs on, 229 normal mechanism of, 230 Salkowski's reaction for cholesterin, 575 Sahnin, 580 Salt-licks, 355 Salt solution, physiological, injection of, 64 Salts, absorption of. 318 lympbagogic act ion of, 73 nutritive value of, 27l>. 354 Saponification of fats, 306, 558 Saprin, 543 Sarcin, 553 Sarco-lactic acid, 546 Sarcosin, 538 Scaleni muscles, inspiratory action of. 401 Scombrin, ">^'> Sebaceous glands, structure <<(, 257 secretion, composition of, 342 function of, 258 physiological value of, 312 Sebum, composil ion of, 257 Secreting glands, electrical changes in, 231 histological changes in, 226 Secret ion, anl ilytic, 230 biliary, 248 capillaries of the gastric glands, 238 596 INDEX. Secretion, definition of. 211 gastric, 240 histological changes during, 226 internal, definition of, 211 intestinal, 243 mammary, 264 mechanism of, 213 panel eal ic, 235 paralytic, 229 psychical, of gastric juice, 239 relation of, to intensity of stimulus, 223 salivary. 230 sebaceous, 257, 342 sweat, 259 urinary, 251 Secretions, general characteristics of, 213 Secretogogues for the gastric glands, 359 Secretory centre, salivary, 230 fibres proper, definition of, 224 nerves, evidence for, 222 mode of action of, 225 of the adrenal bodies, 272 of the kidneys. 251 of the liver, 247 of the mammary glands, 263 of the pancreas, 232 of the stomach, 239 of tli<' swear glands, 259 salivary, endings of, 220 significance of, 214 stimulation of, 222 Semilunar valves. 110 Sensory nerves, influence of, on respiration. 463 of the heart, 172 relation of, to the respiratory centre, 459 reflex influence of, on the pulse-rate, 175 Septal nerves of the frog's heart, 166 Serous cavities, 146 Serrati postici inferiores, respiratory function of, :>w superiores, inspiratory action of, 402 Serum, bactericidal action of, 36 glohulicidal action of, 36 osmotic pressure of. 68 toxicity of, 36 Serum-albumin, action of, on carbonates, 517 amount of, in the hlood, 52 composition of, 52 functions of. 52 properties of, 52 Sex, influence of, on heat production, 482 on pulse-rate, 121 on respiration, 430 relation of body-temperature to, 470 Shivering. 362, KM Silicic acid, properties of, r>l!) Silicon, 519 Simple proteids, 576 Sinuses of Valsalva, 1 1 1 Size, influence of, mi pulse-rate, 121 Skatol, 572 elimination of. 340 occurrence of, in feces, 320 Skin, functions of. 341 glands of, '.'57 Sleep, etlect of. on metabolism, 361 on the respiratory quotient, 438 on respiration, 124 Smegma prseputii, 257 Sneezing, 154 Snoring, 455 Sobbing, 454 Sodium ammonium phosphate, 523 carbonates, 522, 523 chloride, nutritive history of, 521 phosphates, 522 sulphate, 522 Special respiratory movements, 453 Specialization of function, 21 Specific gravity of blood, 34 of blood-corpuscles, 34, 35 of urine, 251 heat, definition of, 477 of the human body, 504 Spectroscope, 40 Spectrum, definition of, 40 of CO-hsemoglobin, 44 of haemoglobin, 42 of oxyhemoglobin, 41 solar, 41 Spermaceti, 540 Spermin, physiological action of, 273 Sphincter antri pylorici, 377 pylori, 377, 381 ' urethrse, 390 vesicae internus, 390 Sphincters ani, 386 Sphygmograur, 143 Sphygmograph, 142 Sphygmomanometer, 141 Sphygmometer, 141 Spinal centres for vaso-motor nerves, 199 Spirometer, 427 Splanchnic nerves, gastric fibres of, 382 influence of, on blood-pressure, 173 on respiration, 403 intestinal fibres of, 385 stimulation of, 173 Spleen, composition of, 333 function of, 322 innervation of, 333 movements of, 322 vasomotor nerves of, 207 Stannius's ligatures, 178 Starch, 566 digestion of, 2^4, 305 hydrolysis of, by acids, 286 by amylolytic ferments, 285 Starvation, etlect of. on metabolism, 362 glycogen disappearance during, 331 nutrition during, 350 phosphorus excretion in, 516 potassium excretion in, 520 Steapsin, 232, 280 den stration of, 306 occurrence of, 305 Stearic acid, 541 Stenson's duct, 217 Stereo rin, 575 Sterno-cleido-mastoid muscles, respiratory ac- tion of, 404 Sternum, respiratory movements of, 401 Stethograph, 423 Stimulants of the sweat glands, 260 physiological action of, 357 Stimuli, artificial, effect of, on I lie heart, 156 Stokes's reagent, composition of, 43 Stomach, absorption in, 312 extirpation of, 299 glands of, 237 immunity of, to its own secretion, 2i)7 innervation of, 381 movements of. 377. 378 musculature of, 377 Strom uhr of Ludwig, 99 St rontium, 526 Strychnine, etlect of, on body-temperature, 472 Sturin, 580 Sublingual gland, anatomy of, 217 Submaxillary gland, anatomy of, 217 Succinic acid, 557 SUCCUS entencus, 243 :n lion of, on carbohydrates. 309 collection of. 308 INDEX. 597 Succus entericus, digestive action of, 308 ferments of, 308 Suction action of the heart, 134 Sudorific drugs, 2(50 Suffocation (see Asphyxia). Sugar injections, lymphagogic action of, 73 Sugars, absorption of, 313, 317 consumption of, by the tissues, 353 effect of, on glycogen formation, 328 synthesis of, 533 Sulphates of the urine, estimation of, 506 origin of, 506 Sulph-hsemoglobin, 506 Sulphur, elimination of, 340 metabolism of, 507 neutral, 506 occurrence of, 505 Sulphuretted hydrogen, inhalation of, 440 properties of, 506 Sulphuric acid, 506 Sulphurous acid, 506 Superior laryngeal nerves, influence of, on res- piration, 459, 462 Supplemental air, definition of, 427 Suprarenal capsules, extirpation of, 271 Swallowing, 375 Sweat, amount of, 258, 342 composition of, 259, 342 nitrogenous constituents of, 512 Sweat-centres, spinal, 261 Sweat-glands, secretory nerves of, 259 stimulation of, 260 structure of, 258 Sweat-nerves, 259 Sweat-secretion, action of drugs on, 260 Sympathetic nerves, cardiac, 168, 171 pulmonary, 466 reflex influence of, on the pulse-rate, 175 secretory fibres to the pancreas, 232 to the salivary glands, 218, 222 vaso-motor centres, 200 Synthesis of proteids, 518, 582 of sugars, 563 Synthetic processes of plants, 518 Syntonin, absorption of, 315 occurrence of, in peptic digestion, 292 Systole, auricular, 124, 136 ventricular, 123 Tartar, 524 Taurin, 507, 543 Tea, nutritive value of, 357 Temperature, axillary, 468 body-, effect of, on respiratory activity, 432 influence of drags on, 472 lowering of, 472 variations of, 469 effect of, on enzymes, 281 on beat dissipation, 487 on metabolism, 362 on sweat glands, 260 on tin- respiratory quotient, 438 on tryptic digest ion, 301 external, effect of, on respiration, 426 on respiratory exchanges, 432 on thermotaxis, 196 influence of, on beat production, 483 on ptyalin, 286 of annuals, 167 of respired air, I in post-mortem rise of, 497 regulat ion of, 473 topography of. 468 Temporal muscle, :'>7'.' Tension of the blood-gases, 415 Testicular extracts, action of, 273 Testis, internal secretion of, 273 Tetanus of the heart, 165 Tetramethylene-diamin, 543 Theobromin, 553 Theophyllin, 553 Thermo-accelerator centres, 492 Thermogeuesis, 477 mechanism of, 489 Thermogenic centres, 491 nerves, 190 tissues, 490 Therino-inhibitory centres, 492 Thermolysis, 485 mechanism of, 494 Thermotaxis, 489, 495, 496 Thiolactic acid, 547 Thiry-Vella fistula, 308 Thoracic duct, 145 Thorax, effects of opening the, 115 movements of, in respiration, 397 negative pressure in the, 396 Thrombin, 58, 280 Thrombus, 60 Thymic acid, 579 Thyroglobuliu, 509 Thyroidectomy, 269 Tbyroid extract, injection of, 269, 270 Thyroids, anatomy of, 267 extirpation of, 268 functions of, 268 grafting of, 269 internal secretion of, 270 Thyroiodine, 50!) Tidal air, volume of, 426 Time of a complete circulation, 79 Tinctures, definition of, 535 Tissue-proteid, definition of, 346 Tissue-respiration, 422 Tongue, vaso-motor nerves of, 204 Tonicity of involuntary muscle, 371 of vaso-constrictor centre. 199 Tonograph, definition of, 127 Tonometer, 188 Tonus, ventricular, during vagus stimulation, 163 Transfusion of blood, 61 Transversalis abdominis muscle, respiratory action of, |i>7 Trapezius muscle, respiratory action of, 405 Traube-Hering waves, 201 Triangulares sterni muscles, expiratory action of, 407 Trigeminal nerves, inlluence of, on respiration, 463 Trimethylamine, 511 Trioses, 559 Trommel's test for carbohydrates, 562 Tropseolin 00 test for mineral acid, 289 Trophic inlluence of the vagi on the heart, 167 nerves of tin- salivary glands, 224 pulmonary, 166 Trypsin, 232 effect of. on blood coagulation, 63 exl racts, preparal ion of, 301 properl ies of, 301 Trypsinogen, 235 granules, 235 Tryptic digestion, products of, 302 value of. 304 Tryptophan, 57 1 Tubules, ii mi iferous, 250 Tunicin, 566 Ty rosin, 570 formation of, in tryptic digestion. 303 I 'nits, calorimel ric, 177 Unorganized ferments, definition of, 279 I na. amount of, in sweat, 335 598 INDEX. Urea, amount of, in the blood, 51 in the urine, 335 antecedents of, '■>"■'■> elimination of, 252 estimation of, .~>4!l formation of, after removal of the liver, 337 in the liver, 331 origin of, in the body, 550 in the liver, 266 preparation of, 5 18 from proteid, '-V.'u presence of, in sweat, 342 properties of, ~>1!' Ureters, movements of, 371, 389 Uric acid, formation of, 338 in the liver, 322 in the spleen, 333 molecular structure of, 554 occurrence of, 338 origin <>t', in birds, 557 in mammals, 338, 556" preparation of, 555 properties of, 555 Urinary bladder, innervation of, 392 movements of, 390 pigments, origin of, from haemoglobin, 45 secretion, normal stimulus for, 255 relation of, to the blood-flow through the kidney, 253 Urine, acidity of, after meals, 290 composition of, 250, 334 ethereal sulphates of, 572 secretion of, 251 Uriniferons tubules, secretory function of, 252 structure of, 250 Urobilin, 574 VAGUS, anabolic action of, on the heart, 166 anatomy of, in the dog, 159 cardiac branches of, 159 effect on the heart, nature of, 166 gastric branches of, 381 inhibition, dependence of, on the character of the stimulus, 165 intestinal branches of, 385 nerves, pulmonary branches of, 465 relation of, to apnoea, 442 respiratory function of, 459 pneumonia. 4 secretory fibres of, to the pancreas, 232 to the stomach, 239 stimulation, auricular effects of, 164 effect of, on the heart, 152, 163 on the ventricle, 162 latent period of, 162 Valsalva's experiment, 452 sinuses, 111 Valves, auriculo-ventricular, 108 of lymphatic vessels, 146 semilunar, 110 Valvules conniventes, value of, in absorption, 314 Vaseline, 531 Vasoconstrictor centre, rhythmical activity of, 201, 151 nerves, discovery of, 193 Vaso dilator nerves, discovery of, 194 Vaso-motor centre, medullary, 198 cent res. spinal. 199 sympathetic, 200 nerves, anatomy of, 198 methods of investigating, 195 of the brain, 203 of the generative organs, 208 of the head. 204 of Che heart. 206 of the intestines, 206 Vaso-motor nerves of the kidney, 207, 256 of the limbs, 209 of the liver, 206 of the lungs, 205, 466 of the muscles, 210 of the pancreas, 207 of the portal system, 209 of the salivary glands, 222 of the spleen, 2<>7 of the tongue. 205 of the veins, 195 special properties of, 197 reflexes, 201 through the vagi, 172 Vegetable foods, composition of, 278 proteids, 577 Veins, effeel of compression of, on lymph forma- tion. 72 entrance of air into, 97 rate of How in, 101 vaso-motor nerves of, 209 Velocity of blood-flow, 99, 100, 101 Vense Thebesii, 1S4 Veno-motor nerves of the limbs, 209 Venous blood-How. effect of the auricles on, 137 circulation, 95, 96 pressure, 91 , 94 pulse, respiratory, 96 Ventilation, principles of, 439 Ventricles, independent rhvtbm of, 152 work done by, 106, 107 Ventricular cycle, analysis of, 133 diastole, duration of, 123 pressure-curves, analysis of, 128 pressures, 125 systole, duration of, 123 Vernix caseosa, 258 Vessels of Thebesius, 186 Villus, intestinal, structure of, 318 Viscero-motor nerves to the intestines, 385 Viscosity of irrigating media for the heart, 191 Visual purple, 575 Vital capacity of the lungs, 427 force, definition of, 25 Vitellin, composition of, 579 Voluntary control of the heart, 178 Vomiting. 387 causes of, 388 centre for, 389 nervous mechanism of, 388 Wandering cells, definition of, 48 Water, absorption of, 313, 318 amount lost through the lungs, 410 distribution of, 503 effect of, on pancreatic secretion, 236 elimination of, 340 imbibition of, 504 latent beat of, 504 nutritive value of, 276, 354 properties of, 503 Wharton's duct, 217 William's frog-heart apparatus,188 valve, 187 Wines, 535 Wirsung's duct, 231 Work done by the heart ventricles, 106, 107 Xanthin, 553 physiological significance of, 339 Xantho-protcid reaction, 576 Xylose, 562 Yawning, 454 Zymogen granules, definition of, 228 of the pancreas, 235 Catalogue SL Medical Publications W. 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So necessary is this book in the study of Internal Medicine that it comes largely to this country in the original German. In view of these facts, Messrs. W. B. Saunders & Com- pany have arranged with the publishers to issue at once an authorized edition of this great encyclopedia of medicine in English. For the present a set of some ten or twelve volumes, representing the most practical part of this encyclopedia, and selected with especial thought of the needs of the practical physician, will be published. The volumes will contain the real essence of the entire work, and the purchaser will therefore obtain at less than half the cost the cream of the original. Later the special and more strictly scientific volumes will be offered from time to time. The work will be translated by men possessing thorough knowledge of both English and German, and each volume will be edited by a prominent specialist on the subject to which it is devoted. It will thus be brought thoroughly up to date, and the American edition will be more than a mere translation of the Ger- man ; for, in addition to the matter contained in the original, it will represent the very latest views of the leading American specialists in the various departments of Internal Medicine. The whole System will be under the editorial super- vision of Dr. Alfred Stengel, who will select the subjects for the American edition, and will choose the editors of the different volumes. Unlike most encyclopedias, the publication of this work will not be extended over a number of years, but five or six volumes will be issued during the coming year, and the remainder of the series at the same rate. Moreover, each volume will be revised to the date of its publicatfon by the American editor. This will obviate the objection that has heretofore existed to systems published in a number of volumes, since the subscriber will receive the completed work while the earlier volumes are still fresh. The usual method of publishers, when issuing a work of this kind, has been to compel physicians to take the entire System. This seems to us in many cases to be undesirable. Therefore, in purchasing this encyclopedia, physicians will be given the opportunity of subscribing for the entire System at one time ; but any single volume or any number of volumes may be obtained by those who do not desire the complete series. This latter method, while not so profitable to the pub- lisher, offers to the purchaser many advantages which will be appreciated by those who do not care to subscribe for the entire work at one time. This American edition of Nothnagel's Encyclopedia will, without question, form the greatest System of Medicine ever produced, and the publishers feel con- tinent that it will meet with general favor in tin- medical profession. 18 NOTHNAGEL'S ENCYCLOPEDIA VOLUMES JUST ISSUED AND IN PRESS VOLUME I Editor, William Osier, M. D., F. R. C. P. Professor of Medicine in Johns J /op kins University CONTENTS Typhoid Fever. By Dr. H. Curschmann, of Leipsic. Typhus Fever. By Dr. H. Curschmann, of Leipsic. Handsome octavo volume of about 600 pages. Just Issued VOLUME II Editor, Sir J. W. Moore, B. A., M.D., F.R.C.P.I., of Dublin Professor of Practice of Medicine, Royal College of Surgeons in Ireland CONTENTS Erysipelas and Erysipeloid. By Dr. H.Len- hartz, of Hamburg. Cholera Asiatica and Cholera Nostras. By Dr. K. von Lieber- meister, of Tubingen. Whoooing Cough and Hay Fever. By Dr. G. Sticker, of Giessen. Varicella. By Dr. Th. von Jor- gensen, of Tubingen. Variola (including Vaccination). By Dr. H. Immermann, of Basle. Handsome octavo volume of over 700 pages. Just Issued VOLUME vn Editor, John H. Musser, M. D. Professor of Clinical Medicine, University of Pennsylvania CONTENTS Diseases of the Bronchi. By Dr. F. A. H«»ff- M INN, of Leipsic. Diseases of the Pleura. By Dr. Rosenkach, of Berlin. Pneumonia. By Dr. E. Aufrecht, of Magdeburg. VOLUME m Editor, William P. Northrup, M. D. Professor of Pediatrics, University and Bellevue Medical College CONTENTS Measles. By Dr. Th. von JOrgensen, of Tubingen. Scarlet Fever. By the same author. Rofheln. By the same author. VOLUME VIII Editor, Charles G. Stockton, M. D. Professor of Medicine, University of Buffalo CONTENTS Diseases of the Stomach. By Dr. F. Riegel, of Giessen. VOLUME DC Editor, Frederick A. Packard, M. D. I'/iysicia>. to the Pennsylvania Hospital and to the Oiildren's Hospital, Philadelphia CONTENTS Diseasesof the Liver. By 1 >RS. II. Quincke and G HoPPE-SEYLER, of Kiel. VOLUME VI Editor, Alfred Stengel, M.D. Professor of Clinical Medicine, University of Pennsylvania CONTENTS Anemia. By Dr. P. EHRLICH, of Frankfort- on-the-Main, and Dr. A. Lazarus, of Char- lottenburg. Chlorosis. By Dr. K. von Noorden, of Frankfort-on-the-Main. Dis- eases of the Spleen and Hemorrhagic Diathesis. By Dr. M. LlTTEN, ol Berlin. VOLUME X Editor, Reginald H. Fitz, A.M., M. D. Herse- Professor of the Theory and Practice cf Physic, Harvard t University CONTENTS Diseasesof the Pancreas. By Dr. L. Oser, Diseases of the Suprarenals. if Vi'iina. By Di. E Nm -m r, ol \ ienna. VOLUMES IV, V, and XI Editors announced later "ol. IV — Influenza and Dengue. By Dr. < >. I.kk 1 1 1 n-ti rn, of Cologne. MalarialDis- eases By Dr. I. Mannaberg, ol Vienna. <>1. \ Tuberculosis and Acute General Milhry Tuberculosis. By Dr.G.Corni 1, of 1 rlin. 'ol. II. — Diseases of the Litestines and Pertoneum. By Dr. H. NOTHNAGKL, of T ienna. 19 CLASSIFIED LIST OF THE MEDICAL PUBLICATIONS or W. B. SAUNDERS & COMPANY ANATOMY, EMBRYOLOGY, HISTOLOGY. Bbhm, Davidoff, andHuber — Histology, . Clarkson A Text-Book of Histology, . . Haynes— A Manual of Anatomj Heisler — A Text-Book of Embryology, . . Leroy -Essentials of Histology McClellan— Art Anatomy McClellan — Regional Anatomy Nancrede — Essen tiats of Anatomy Nancrede — Essentials of Anatomy and Manual of Practical Dissection BACTERIOLOGY. Ball — Essentials of Bacteriology Frothingham — Laboratory Guide, I . . . Gorham — Laboratory Bacteriology, . . . Lehmann and Neumann — Atlas of Bacte- riology Levy and Klemperer's Clinical Bacteri- ology Mallory and Wright— Pathological U nique, McFarland — Pathogenic Bacteria, CHARTS, DIET-LISTS, EtTC. Griffith— Infant's Weight Chart, . Hart — Diet in Sickness and in Healtji Keen— Operation Blank Laine — Temperature Chart, . . . 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M. and Therapeutics, 15 Saunders' Pocket Medical Formulary, . . 12 Sayre — Essentials of Pharmacy 15 Sollmann— Text- Book of Pharmacology, . 12 3 ! Stevens — Manual of Therapeutics, ... 13 3 I Stoney — Materia Medica for Nurses, . . 13 to I Thornton — Prescription-Writing 14 20 MEDICAL PUBLICATIONS OF IV. B. SAUNDERS 6- CO. 21 MEDICAL JURISPRUDENCE AND TOXICOLOGY. Chapman — Medical Jurisprudence and Toxicology 5 Golebiewski and Bailey— Atlas of Dis- eases Caused by Accidents 17 Hofmann and Peterson— Atlas of Legal Medicine 16 NERVOUS AND MENTAL DISEASES, ETC. Brower — Manual of Insanity 22 Chapin — Compendium of Insanity, ... 5 Church and Peterson — Nervous and Men- tal Diseases 5 Jakob & Fisher — Atlas of Nervous System, 17 Shaw — Essentials of Nervous Diseases and Insanity 15 NURSING. Davis — Obstetric and Gvnecologic Nursing, 5 Griffith— The Care of the Baby 7 Hart — Diet in Sickness and in Health, . . 7 Meigs— Feeding in Early Infancy, . . 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An American Text-Book of Physiology, 2 Budgett— Essentials of Physiology, ... 22 Raymond — Human Physiology n Stewart— Manual of Physiology, .... 13 PRACTICE OF MEDICINE. An American Year-Book of Medicine and Surgery 3 Anders — Practice of Medicine 4 Eichhorst — Practice of Medicine 6 Lockwood — Manual of the Practice of Medicine 9 Morris — Ess. of Practice of Medicine, . . 15 Salinger and Kalteyer — Modern Medi- cine 11 Stevens — Manual of Practice of Medicine, 13 SKIN AND VENEREAL. An American Text-Book of Genito- urinary and Skin Diseases 2 Hyde and Montgomery— Syphilis and the Venereal Diseases, 8 Martin — Essentials of Minor Surgery, Bandaging, and Venereal Diseases, . . 15 Mracek and Stelwagon— Atlas of Diseases of the Skin 16 Stelwagon — Essentials of Diseases of the Skin 15 SURGERY. An American Text-Book of Surgery, . . 2 An American Year-Book of Medicine and Surgery, 3 Beck — Fractures, 4 Beck — Manual of Surgical Asepsis, ... 4 Da Costa — Manual of Surgery, 5 International Text-Book of Surgery, . . 8 Keen— Operation Blank 8 Keen — The Surgical Complications and Sequels of Typhoid Fever 8 Macdonald — Surgical Diagnosis and Treat- ment 9 Martin — Essentials of Minor Surgery, Bandaging, and Venereal Diseases, . . 15 Martin— Essentials of Surgery 15 Moore — Orthopedic Surgery 10 Nancrede — Principles of Surgery 10 Pye — Bandaging and Surgical Dressing, . 11 Scudder — Treatment of Fractures, ... 12 Senn — Genito-Urinary Tuberculosis, ... 12 Senn — Practical Surgery 12 Senn— Syllabus of Surgery 12 Senn — Pathology and Surgical Treatment of Tumors 12 Warren — Surgical Pathology and Thera- peutics 14 Zuckerkandl and Da Costa — Atlas of Operative Surgery, 16 URINE AND URINARY DISEASES. Ogden — Clinical Examination of the Urine, n Saundby — Renal and Urinary Diseases, . 11 Wolf — Handbook of Urine-Examina- tion 14 Wolff — Essentials of Examination of Urine, 15 MISCELLANEOUS. Bastin — Laboratory Exercises in Botany, . 4 Golebiewski and Bailey— Atlas of Dis- eases Caused by Accidents 17 Gould and Pyle — Anomalies and Curiosi- ties of Medicine 7 Grafstrom — Massage 7 Keating — How to Examine for Life Insur- ance 8 Saunders' Medical Hand-Atlases, . . 16,17 Saunders' Pocket Medical Formulary, . . 12 Saunders' Question-Compends, , , , 14,15 Stewart and Lawrance — Essentials of Medical Electricity 15 Thornton — Dose-Book and Manual of Prescription-Writing 13 Warwick and Tunstall— First Aid to the Injured and Sick 1^ Books in Preparation. Jelliffe arid Diekman's Chemistry. A Text-Book of Chemistry. By Smith Ely Jelliffe, M. D., Ph.D., Professor of Pharmacology, College of Pharmacy, New York; and George C. Diekman, Ph. G., M. D., Professor of Theoretical and Applied Pharmacy, College of Pharmacy, New York. Octavo, 550 pages, illustrated. Brower's Manual of Insanity. A Practical Manual of Insanity. By Daniel R. Brower, M. D., Pro- fessor of Nervous and Mental Diseases, Rush Medical College, Chicago. 121110 volume of 425 pages, illustrated. Kalteyer's Pathology. Essentials of Pathology. By F. J. Kalteyer, M. D., Assistant Demon- strator of Clinical Medicine, Jefferson Medical College ; Pathologist to the Lying-in Charity Hospital ; Assistant Pathologist to the Philadel- phia Hospital. A New Volume in Saunders' Question- Compend Series. Gradle on the Nose, Throat, arid Ear. Diseases of the Nose, Throat, and Ear. By Henry Gradle, M. D., Professor of Ophthalmology and Otology, Northwestern University Medical School, Chicago. Octavo, 800 pages, illustrated. Budgett's Physiology. Essentials of Physiology. By Sidney P. Budgett, M. D., Professor of Physiology, Washington University, St. Louis, Mo. A New Volume in Saunders 1 Question- Compend Series. Griffith's Diseases of Children. A Text-Book of the Diseases of Children. By J. P. Crozer Griffith, Clinical Professor of Diseases of Children, University of Pennsylvania. Galbraith on the Four Epochs of Woman's Life. The Four Epochs of Woman's Life: A Study in Hygiene. By Anna M. Galbraith, M. D., Fellow New York Academy of Medicine; At- tending Physician Neurologic Department New York Orthopedic Hos- pital and Dispensary, etc. With an Introduction by John H. Musser, M. D., Professor of Clinical Medicine, University of Pennsylvania. 121110 volume of about 200 pages. Date Due PRINTED IN U.S.* CAT NO. 24 161 DW D ooo 224 607 7 m €/? U SO 12 S 0T i( H85?a 1900 v. 1 Howell, William H An American text-book of physiology MEDICAL SCIENCES LIBRARY UNIVERSITY OF CALIFORNIA, IRVINE IRVINE, CALIFORNIA 92664