GIFT OF iOdU 5553 UNIVERSITY OF CALIFORNIA PUBLICATIONS IN PHYSIOLOGY Vol. 4, No. 19, pp. 201-206, plate 1 Issued September 10, 1914 THE BLOOD-PRESSURE EFFECTS OF THE APPLICATION OF CREATIN TO THE CEREBRAL CORTEX BY ROBERT STANTON SHERMAN UNIVERSITY OP CALIFORNIA PUBLICATIONS Note. The University of California Publications are offered in exchange for the publi- cations of learned societies and institutions, universities and libraries. Complete lists of all the publications of the University will be sent upon request. For sample copies, lists of publications and other information, address the Manager of the University Press, Berkeley, California, U. S. A. All matter sent in exchange should be addressed to The Exchange Department, University Library, Berkeley, California, U. S. A. PHYSIOLOGY S. S. Maxwell, Editor. Price per volume $2. Cited as Univ. Calif. Publ. Physiol. VoLl. 1. On Method by which the Eggs of a Sea-urchin (Strmngylocentrotug purpuratus) can be Fertilized with the Sperm of a Starfish (Astcriat ochracea), by Jacques Loeb. Pp. 1-8, April, 1903 05 S. On the Mechanism of the Action of Saline Purgatives, and the Counteraction of their Effect by Calcium, by John Bruce Mac- Callum. Pp. 5-6. May, 1903 _. T .. .05 S. Artificial Parthenogenesis in Molluscs, by Jacques Loeb. Pp. 7- August, 1903 , 05 4. The Relations of Biology and the Neighboring Sciences, by Wilhelm Ostwald. Pp. 11-31. October, 1903 _ _.. .25 5. The Limitations of Biological Research, by Jacques Loeb. Pp. 33-37. October, 1903 _ 05 6. The Fertilization of the Egg of the Sea-urchin by the Sperm of the Starfish, by Jacques Lceb. Pp. 39-53. November, 1903 15 7. On the Relative Toxicity of Distilled Water, Sugar Solutions and Solutions of the various Constituents of the Sea-water for Marine Animals, by Jacques Loeb. Pp. 55-69. November, 1903. 8. On the Segmental Character of the Respiratory Center in the Medulla Oblongata of Mammals, by Jacques Loeb. Pp. 71-75. November, 1903. Nos. 7 and 8 in one cover .25 9. On the Production and Suppression of Glycosuria in Rabbits through Electrolytes (a preliminary communication), by Martin H. Fischer. Pp. 77-79. December, 1903 ... .05 10. On the Influence of Calcium and Barium on the Flow of Urine (a preliminary communication), by John Bruce MacCallum. Pp. 81-82. January, 1904 , 05 11. Further Experiments on the Fertilization of the Egg of the Sea-urchin with Sperm of various species of Starfish and a Hclothurian, by Jacques Loeb. Pp. 83-85. February, 1904 ,.. .05 12. On the Production and Suppression of Glycosuria in Rabbits through Electrolytes (second communication), by Martin H. Fischer. Pp. 87-113. February, 1904 30 13. The Influence of Saline Purgatives on Loops of Intestine Removed from the Body, by John Bruce MacCallum. Pp. 115-123. March, 1904. 14. The Secretion of Sugar into the Intestine Caused by Intravenous Saline Infusions, by John Bruca MacCallum. Pp. 125-137. March, 1904. Nos. 13 and 14 in one cover .. .25 15. On the Influence of the Reaction of the Sea-water on the Regeneration and Growth of Tub'ilyxianj, by Jacques Loeb. Pp. 139-147. April, 1904 10 18. The Possible Vjcf.iiPit^e of the Amphotoric Reaction of Certain Colloids upon the Sign of their Hloctii'-al Uharge in the Presence of Acid and Alkalis, by Jacques Loeb. Pp. 149-150. May, 1904. 17. Concerning Dynamic Conditions which contribute toward the Deter- mination of the Morphological Polarity of Organisms (first com- munication), by Jacques Loeb. Pp. 151-161. 7 text figures. May, 1904. Nos. 16 and 17 in one cover 15 18. The Action of Cascara Sagrada (& preliminary communication), by John Bruce MacCallum. Pp. 163-164. May, 1904 05 19. Artificial Parthenogenesis and Regular Segmentation in an Annelid (Ophelia), by G, Bullot. 13 text figures. Pp. 165-174. June, 1S04 10 20. On the Action of Saline Purgatives in Rabbits and the Counteraction of their Effect by Calcium (second communication), by John Bruce MacCallum. Pp. 175-185. July, 1904. 21. On the Local Application of Solutions of Saline Purgatives to the Peritoneal Surfaces of the Intestines, by John Bruce MacCallum. Pp. 187-197. July, 1904. Nos. 20 and 21 in one cover -... .25 22. On the Toxicity of Distilled Water for the Fresh-water Gammarns. Suppression of this Toxicity by the Addition of small quantities of Sodium Chloride, by G. Bullot. Pp. 199-217. July, 1904 .20 Vol. 4, No. 19, pp. 201-206, plate 1 Issued September 10, 1914 THE BLOOD-PRESSURE EFFECTS OF THE APPLICATION OF CREATIN TO THE CEREBRAL CORTEX BY KOBEET STANTON SHERMAN (From the Rudolph Spreckels Physiological Laboratory of the University of California) The first observations on the chemical stimulation of the cerebral cortex were made by Landois. 1 He described the occur- rence of epileptiform seizures, beginning some minutes after the application of creatin to the brain surface, and recurring at intervals with increasing severity. He noted that in connection with the seizures there was evidence of increased blood pressure as shown by marked pulsation and bulging of the brain substance in the trephine hole. These evidences of increased blood pres- sure have probably been noticed by all who have repeated the experiment. My attention was called to this particular phase of the creatin effects by Professor S. S. Maxwell, who asked me to determine the exact relations existing between the blood pressure and the oncoming and continuance of the seizures. It is well known that muscular exertion can produce a rise of blood pressure. This has been shown, among others, by the observations of Lowsley. 2 He concluded from his experiments that muscular exercise causes an immediate rise in systolic, diastolic and pulse pressures, and that cessation of exercise is followed by a rather rapid return to normal. It is also well 1 Deutsch. Mecl. Woch., vol. 13, p. 685, 1887. 2 American Journal of Physiology, vol. 27, p. 447, 1911. 202 University of California, Publications in Physiology [VOL. 4 known that certain psychic states markedly increase the blood pressure. It is conceivable that creatin could act either directly, by some "specific effect upon the brain, or indirectly, through bringing about the muscular contractions. There is also a practical side to this question in that, in cer- tain diseases, the raising of the blood pressure would be danger- ous. It is conceivable that to patients in such conditions it might be harmful to feed soups or other extracts of meat in which creatin is present in large amounts. The animals experimented upon were rabbits lightly nar- cotized with morphine. The blood pressure was recorded by means of a membrane manometer, the cannula being inserted into the carotid artery. Two signal magnets were used, one con- nected with a laboratory clock to record time and the other to mark the time of occurrence of various incidents of the experi- ment. In order to compare the time of the rise in blood pressure with the onset and duration of each epileptiform seizure, a thread was attached to the vibrissae, the so-called whiskers, of the rabbit. The thread was passed over a pulley and connected to a writing point, which worked in a vertical direc- tion, and in this way the muscular contractions were recorded. This mode of attachment to the recording apparatus was used because in the rabbit the earliest sign of a seizure is usually a twitching of the muscles of the face and neck. In every case simultaneous ordinates were made. The order of procedure was as follows : The brain was care- fully exposed by a trephine opening over the hemisphere just posterior to the coronal suture. The membrane manometer was then connected with the carotid artery. After connecting t<he vibrissae to the thread for recording muscular movements, the dura was carefully removed and creatin applied to the motor area of the cortex. That there is a rise in blood pressure coincident with the epileptiform attacks produced by the application of creatin to the brain, is shown by the following typical experiment. ' Babbit, lightly narcotized with morphine. Left motor area exposed and determined by electrical stimulation, creatin applied to the surface of the brain. Ten minutes later epileptiform attacks were noted. They began by chewing movements and slight movements of the right fore-leg, during 1914] Sherman: Cerebral Cortex 203 which there was a small rise in blood pressure, which lasted about one minute. Next the right hind foot moved and then a general paroxysm ensued, during which the blood pressure rose to a height of 35 mm. of mercury above normal. This lasted for about two and one-fourth minutes. The blood pressure did not fall to normal until a minute after the general paroxysm had ceased. Tracing shown in plate 1. In general it was observed that the more severe the paroxysm the higher was the blood pressure. It is well known that there are three mechanical factors that bring about alterations in blood pressure: (1) Rate of Heart, (2) Force of Heart, (3) Peripheral Resistance. Lowsley 3 in experimenting upon the effects of various forms of exercise showed definitely that the rise in blood pressure was brought about by an increase in rate and force of the heart. My observa- tions on the rise in blood pressure produced by the application of creatin to the brain are in accordance with Lowsley 's state- ment so far as the rate and the force of the heart-beat is con- cerned. In my experiments (see tracing) the rate of heart-beat during the paroxysm was markedly increased. It is also to be seen that there is a marked increase in pulse pressure coincident with the paroxysm, thereby indicating an increase in force of each heart beat. The question now arises as to the exciting cause of this change in the blood pressure. Since we may suppose that stimulation of the cerebral cortex might bring about some condition analogous to that of an emotional state, and it has been shown by Cannon and De la Paz 4 that emotional excitement can markedly increase the adrenal secretion, it seems possible that the rise of blood pressure was brought about by a reflex increase of the production of adrenalin. This idea was tested in the following way: Both adrenals were tied off, and creatin was applied to the brain in the manner described above. During each of the epileptiform paroxysms which ensued there was a rise in blood pressure which was in no way different from that obtained when the adrenals were left intact. This shows that the rise in blood pres- sure is not due to an excessive production of adrenalin. s American Journal of Physiology, vol. 27, p. 446, 1911. 4 American Journal of Physiology, vol. 28, p. 64, 1911. 204 University of California Publications in Physiology [VOL. 4 If the rise in the blood pressure were due to psychic causes, one might expect it to begin before the paroxysm of muscular contractions, and it might even occur without the incidence of muscular contractions. The tracings obtained in my experiments show uniformly that the increase in blood pressure does not precede the muscular contractions, but keeps pace in time and magnitude with the violence of the convulsions. That the rise in blood pressure does not occur until after the actual muscular contractions have begun is shown in all my tracings. It will be noticed also, that while the rise of blood pressure is nearly synchronous with the muscular paroxysm, the pressure does not again return to normal for a little time after cessation of muscu- lar contraction. The results just stated seem to indicate a close relation, pos- sibly a causal relation, between the muscular contractions and the rise in blood pressure, although a common cause for both is not excluded. The latter possibility was put to the test in the following way: The rabbit was prepared as in the previous experiment, and after the production of the epileptiform attacks through the action of creatin upon the cortex had begun, and the manometer had been arranged to record the blood pressure, artificial respira- tion was provided for by the method of Meltzer and Auer, 5 and curare was administered. It should be mentioned here that, in accordance with the experience of Meltzer and Auer, it was nec- essary to use an intravenous injection of atropin in order to insure success with the artificial respiration. The atropin had no noticeable effect upon the progress of the convulsions and did not prevent the characteristic rise of the blood pressure. Curare was then administered by injection into the marginal vein of the ear. When through the effect of the curare the muscular contrac- tions had ceased, the periodic changes in the blood pressure also disappeared. This would tend to show that the rise of blood pressure was not directly caused by the cerebral excitation, but was an indirect result of the muscular contractions. B Zentralblatt fur Physiologie, vol. 23, p. 210, 1909. 1914 1 Sherman: Cerebral Cortex 205 A comparison of the results of these different experiments would seem to lead to the conclusion that the chief cause of the elevation in blood pressure, in connection with the epileptiform seizures induced by creatin, is to be found in the action of the metabolic products of the muscular contractions. SUMMARY 1. When epileptiform convulsions are produced in the rabbit by the application of creatin to the brain, characteristic eleva- tions of blood pressure occur. 2. The rise of blood pressure follows, but does not precede the muscular paroxysm. 3. The rise of blood pressure is not due to excessive produc- tion of adrenal secretion, for it occurs after ligation of the adrenal vessels. 4. The characteristic changes of the blood pressure are totally prevented by the action of curare. Transmitted April 9, 1914. EXPLANATION OF PLATE 1 Tracing showing blood pressure and muscular paroxysms in rabbit after application of creatin to the motor areas. The two parts of the figure are separated by a time interval of forty minutes. A. Eecord of writing point connected wtih vibrissae and indicating mus- cular paroxysms. B. Time in minutes. C. Blood pressure. D. Atmospheric pressure. QI 0,, 2 2 , 3 3 simultaneous ordinates. [206] UNIVERSITY OF CALIFORNIA PUBLICATIONS ^Continued) Vol.2. 1. The Control of Heliotropic Reactions in Fresh-water Crustaceans by Chemicals, especially CO, (a preliminary communication), by Jacques Loeb. Pp. 1-3. November, 1904 05 2. Further Experiments on Heterogeneous Hybridization in Echinodenns, by Jacques Loeb. Pp. 5-30. December, 1904 8. Influence of Calcium and Barium on the Secretory Activity of the Kidneys (second communication), by John Bruce MacGallum. Pp. 31-42. December, 1904. 4. Note on the Galvanotropic Reactions of the Medusa Polyorchit penicillata A. Agassiz, by Frank W. Bancroft. Pp. 43-46. Decem- ber, 1904. Nos. 2, 3 and 4 in one cover .45 6. The Action on the Intestines of Solutions containing two Salts, by John Bruce MacCallum. Pp. 47-64. January, 1905. 6. The Action of Purgatives in a Crustacean (Sida cry&tallina), by John Bruce MacCallum. Pp. 65-70. January, 1905. Nos. 5 and 6 in one cover - .25 7. On the Validity of Pfiuger's Law for the Galvanic Action of Para- mecium (preliminary communication), by Frank W. Bancroft. P. 71. February, 1905. 8. On Fertilization, Artificial Parthenogenesis and Cytolysis of the Sea-urchin Egg, by Jacques Loeb. Pp. 73-81. February, 1905. Nos. 7 and 8 in one cover .16 9. On an Improved Method of Artificial Parthenogenesis, by Jacques Loeb. Pp. 83-86. February, 1905 - .05 10. On the Diuretic Action of Certain Haemolytics, and the Action of Calcium in Suppressing Haemoglobinuria (preliminary communica- tion), by John Bruce MacCallum. Pp. 87-88. March, 1905. 11. On an Improved Method of Artificial Parthenogenesis (second com- munication), by Jacques Loeb. Pp. 89-92. March, 1905. Nos. 10 and 11 in one cover .05 12. The Diuretic Action of Certain Haemolytics and the Influence of Calcium and Magnesium in Suppressing the Haemolysis (second communication), by John Bruce MacCallum. Pp. 93-103. May, 1905. 18. The Action of Pilocarpine and Atropin on the Flow of Urina, by John Bruce MacCallum. Pp. 105-112. May, 1905. Nos. 12 and 13 in one cover 25 14. On an Improved Method of Artificial Parthenogenesis (third com- munication), by Jacques Loeb. Pp. 113-123. May, 1905 15 15. On the Influence of Temperature upon Cardiac Contractions and its Relation to Influence of Temperature upon Chemical Reaction Velocity, by Charles D. Snyder. Pp. 125-146. September, 1905 25 16. Artificial Membrane Formation and Chemical Fertilization in a Star- fish (Asterina), by Jacques Loeb. Pp. 147-158. September, 1905 .15 17. On the Influence of Electrolytes upon the Toxicity of Alkaloids (pre- liminary communication), by T. Brailsford Robertson. Pp. 159-162. October, 1905 05 18. Studies on the Toxicity of Sea-water for Fresh-water Animals (Gammarus pulex De Geer), by C. H. Wolfgang Ostwald. Pp. 163-191; plates 1-6. November, 1905 85 19. On the Validity of Pfluger's Law for the Galvanotropic Reactions of Paramecium, by Frank W. Bancroft. Pp. 193-215; 8 text figures. November, 1905 _ ~ .20 Vol.3. 1. On Chemical Methods by which the Eggs of a Mollusc (Lottia Gigantea) can be caused to become Mature, by Jacques Loeb. Pp. 1-8. November, 1905 .05 2. On the Changes in the Nerve and Muscle which seem to Underlie the Electrotonic Effect of the Galvanic Current, by Jacques Loeb. Pp. 9-15. December, 1905 05 8. Can the Cerebral Cortex be Stimulated Chemically? (Preliminary communication), by S. S. Maxwell. Pp. 17-19. February, 1906 .05 4. The Control of Galvanotropism in Paramecium by Chemical Sub- stances, by Frank W. Bancroft. Pp. 21-23. March, 1906 10 6. The Toricity of Atmospheric Oxygen for the Eggs of the Sea-urchin (Strongylocentrotus purpuratus) after the Process of Membrane Formation, by Jacques Loeb. Pp. 33-37. March. 1906. 6. On the Necessity of the Presence of Free Oxygen in the Hypertonic Sea-water for the Production of Artificial Parthenogenesis, by Jacques Loeb. Pp. 39-47. March, 1906. Nos. 5 and 6 in one cover 15 7. On the Counteraction of the Toxic Effect of Hypertonic Solutions upon the Fertilized and Unfertilized Egg of the Sea-urchin by Lack of Oxygen; by Jacques Loeb. Pp. 49-56. April, 1906 ~ .05 UNIVERSITY OF CALIFORNIA PUBLICATIONS (Continued) 8. On the Production of a Fertilization Membrane in the Egg of the Sea-urchin with the Blood of Certain Gephyrean Worms (a pre- liminary note), by Jacques Loeb. Pp. 57-58. March, 1907 .05 9. Note on the Synthesis of a Protein through the Action of Pepsin (preliminary communication), by T. Brailsford Robertson. Pp. 59-60. April, 1907 05 10. The Chemical Character of the Process of Fertilization, and its Bear- ing upon the Theory of Life-Phenomena, by Jacques Loeb. Pp. 61-80. September, 1907 , 25 11. A New Proof of the Permeability of Cells for Salts or Ions (a pre- liminary communication), by Jacques Loeb. Pp. 81-86. January, 1908 ~. .06 12. The Origin of two new Retrogressive Varieties by one Mutation m Mice, by Arend L. Hagedocrn. Pp. 87-90. September, 1908 .05 13. On Synthesis of Paranuclein through the Agency of Pepsin and Chemi- cal Mechanics of Hydrolysis and Synthesis of Proteins through the Agency of Enzymes, by T. B. Robertson. Pp. 91-94. December, 1908 05 14. The Inheritance of Yellow Color in Rodents, by Arend L. Hagedoorn. Pp. 95-99. March, 1909 05 15. Table of H* and OH~ Concentrations corresponding to Electromotive Forces determined in Gas-chain measurements, by C. L. A. Schmidt. Pp. 101-113. September, 1909 10 16. The Proteins, by T. Brailsford Robertson. Pp. 115-194. October, 1910 $1.00 17. Further Proof of the Identity of Heliotropisra in Animals and Plants, by Jacques Loeb and S. S. Maxwell. Pp. 195-197. January, 1910 .05 Vol.4. 1. Experiments on the Function of the Internal Ear, by S. S. Maxwell. Pp. 1-4. September, 1910 05 2. On the Rise of Temperature in Rabbits, Caused by the Injection of Salt Solutions, by Theo. C. Burnett. Pp. 5-7. September, 1910 05 8. A Biochemical Conception of Dominance, by A. R. Moore. Pp. 9-15. September, 1910 .05 4. Galvanotropic Orientation in Gonium pectorale, by A. R. Moore and T. H. Goodspeed. Pp. 17-23. May, 1911 ... 05 5. On a Possible Source of the Biological Individuality of the Tissues and Tissue-fluids of Animal Species, by T. Brailsford Robertson. Pp. 25-30. May, 1911 _...-.' 05 6. Some Factors Influencing the Quantitative Determination of Gliadin, by J. E. Greaves. Pp. 31-74. August, 1911 40 7. Errors of Refraction Occurring in the Students of the University of California, by Theo. C. Burnett. Pp. 75-77. August, 1911 05 8. On the Cytolytic Action of Ox-Blood Serum upon Sea-Urchin Eggs, and Its Inhibition by Proteins (Preliminary communication), by T. Brailsfcrd Robertson, Pp. 79-88. February, 1912 10 9. On the Nature of the Cortical Layer in Sea Urchin Eggs, by A. R. Moore. Pp. 89-90. March, 1912. 10. On the Nature of the Sensitization of Sea Urchin Eggs by Strontium Chloride, by A. R. Moore. Pp. 91-93. March, 1912. Nos. 9 and 10 in one cover 05 11. On the Isolation of Oocytase, the Fertilizing and Cytolyzing Substance in Mammalian Blood Sera, by T. Brailsford Robertson. Pp. 95-102. March, 1912. 12. On the Extraction of a Substance from the Sperm of a Sea Urchin (Strongylocentrotus purpuratus) which will Fertilize the Eggs of that Species, by T. Brailsford Robertson. Pp. 103-105. March, 1912. IS. The Demonstration of "Masked" Iron in Blood, by C. B. Bennett. Pp. 107-108. March, 1912. Nos. 11, 12 and 13 in one cover 10 14. A New Method of Heterogeneous Hybridization in Echinoderms, by A. R. Moore. Pp. 109-110. March, 1912. 15. Can the Presence of Acid Account for the Oedema of Living Muscle, by A. R. Moore. Pp. 111-114. April, 1912. Nos. 14 and 15 in one cover 05 16. On the Oxydations and Cleavages of Glucose. Yeast Glucase, a New Glucolytic Ferment, by Victor Birckner. Pp. 115-183. September, 1912 .75 17. Negative Phototropism in Diaptomus by Means of Strychnine, by A. R. Moore. Pp. 185-186. November, 1912 ------ -05 18. On the Volume Changes of the Arm During Muscular Exercise, by Esther V. Starkweather. Pp. 187-200. October, 1913 .15 19 The Blood-Pressure Effects of the Application of Creatin to the Cerebral Cortex, by Robert Stanton Sherman. Pp. 201-206, plate 1. Septem- ber, 1914 5 Other series: American Archaeology and Ethnology, Botany, Classical Philology, Eco- nomics, Engineering, Entomology, Geology, History, Lick Observatory Bulletins, Lie*. Ob- servatory Publications, Mathematics, Modern Philology, Pathology, Philosophy, Psychology, Publications of the Academy of Pacific Coast History, and Zoology. NON-CIRCULATING BOOK UNIVERSITY OF CALIFORNIA LIBRARY U. C. BERKELEY LIBRARIES