key: cord-0690060-rc85u30z authors: Ashour, Hend; Elsayed, Mohamed H.; Elmorsy, Soha; Harb, Inas A. title: Hypothesis: The Potential Therapeutic Role of Nicorandil in COVID‐19 date: 2020-08-09 journal: Clin Exp Pharmacol Physiol DOI: 10.1111/1440-1681.13395 sha: dc39757bb6aaa7f026acfe98a5b2e9aae211c113 doc_id: 690060 cord_uid: rc85u30z At present,there is yet no specific antiviral treatment or immunization against the newly identifiedhuman severe acute respiratory syndrome virus (SARS‐CoV2) that results in a rapidly progressive pandemic coronavirus disease 2019 (COVID‐19). We believein a crucial need for a clinical strategy to counteract this viral pandemic based on the known pathogenesis throughout the disease course. Evidence suggests thatexaggerated patient’s inflammatory response and oxidative stressarelikelyto aggravate the disease pathology. The resulting endothelial dysfunction further induces fibrosis and coagulopathy.These disturbancescan generatesevere respiratory distress syndrome (ARDS) that canprogress into respiratory and circulatory failure. Nicorandil is an anti‐anginal vasodilator drug acts by increasing nitric oxidebioavailabilityand opening ofK(ATP) channel. Recently, nicorandil is recognized to possess multiple protective effects against tissue injury. Here, we address apossible modulatoryrole of nicorandil against COVID‐19 pathogenesis. We hypothesise nicorandil would be an effective form of adjuvant therapy against COVID‐19. The angiotensin-converting enzyme 2 (ACE2), is a cell surface enzymepresent in almost all organs. ACE2 is widely expressed in the lower respiratory tract cells besidesits cardiac, renal, and intestinal expression 4 . ACE2is believed to be the SARS-CoV2 receptor. It facilitates cellular invasion, replication, and viral pathogenicity 5 . This could explain its ability to affectvarious organs,especially the gastrointestinal tract, the heart andthe kidneys. Aprecise antiviral or a specific immunization hasn't been identified yet,raising a need for adjuvant pharmacologic therapy. We believe thattargeted therapiesbased on the known COVID-19 pathogenesisshould be considered. Nicorandil (N-[2-hydroxyethyl]-nicotinamide nitrate) is a therapeutic agent used clinicallyfor the treatment of angina. Nicorandil is believed to act by increasing nitric oxide availability and by opening ATP-sensitive K channels (K + ATP ) 6 .Several studies have alsoshownthe involvement of nicorandil in inflammatory process and oxidative stress regulation. In this context, we hypothesise apotential benefit of nicorandil administration as an adjuvant drug therapy in COVID-19 management, based on the currently addressed pathogenesis. Following SARS-CoV2 lung invasion, the primed dendritic cells and epithelial cells initiate vast amounts of pro-inflammatory cytokines, including interleukins (IL-1β, IL-2, IL-6, IL-8), tumour necrosis factor (TNF),and C motif chemokines (CCL) 2, 3, and 5. This augmented inflammatory response would promote cellular injury and apoptosis 7 . Such inflammatory response is promoted by the expression of adhesion molecules 8 . The intense inflammatory response may activate a "cytokine storm"and hence, marked cell death 9, 10 .The inflammatory mediators released from dying cells would further promote This article is protected by copyright. All rights reserved inflammation and pulmonary cellular injury 11 ,initiating a vicious circle of intensified inflammatory and immune responses that may end in critical outcomes. The extent of pulmonary inflammation in COVID-19 ranges from patchy inflammatory cellular infiltration to bilateral diffuse infiltrates and pneumocytes desquamation with hyaline membrane degeneration 12 . In a study by Solaimanzade, COVID-19 radiologic findings of pulmonary ground-glass opacification and patchy infiltrates characterized up to 86% of patients. The impaired oxygenation initiates hypoxia and tachypnea 13 . In ARDS patients, hypoxemia and mechanical ventilation with high oxygen pressure generateextensive reactive oxygen and nitrogen species 14 . The liberated oxidants target and destruct cellular proteins, lipids, carbohydrates, and DNA and exacerbate tissue inflammation and injury 15 . Combating acute lung injury by nicorandil may be possible viamultiple mechanisms. In fact, the anti-inflammatory and anti-oxidative properties of nicorandil have been previously shown in several studies. Nicorandil has an ability to attenuate lipopolysaccharide-induced human pulmonary artery endothelial cells (HPAEs) injury. It can also abort the inflammatory process by suppressing monocyte-endothelial adhesion, the key step in the inflammation pathogenesis. In a study by He et al., nicorandil abolished HPAECs nuclear factor (NF-κB) and mitogen-activated protein kinase (MAPK) and hence, aborted inflammatory cytokine formation and suppressed apoptosis 16 .Nicorandil protected the HPAECs against hypoxia-induced injury. It restored the diminished HPAEs endothelial nitric oxide synthase (eNOS) production and the activation of mitoK ATP channels 17 . Nicorandil exhibits anti-free-radical characteristics since itcould scavenge hydroxyl radicals through itsnicotinamide moiety. Nicorandilefficiently inhibits superoxide anion production by the activated neutrophils 18 . In addition, nicorandil can correct the lipoperoxidation and free radical injuryinduced by diabetes mellitus in ratkidneys, cardiac muscle and liver tissues 19 . In a rat model of silica-induced lung injury,nicorandil effectively downregulated the elevated inflammatory markers NF-κB, TNF-α,and MPO in the lung tissues. Moreover, nicorandil restored This article is protected by copyright. All rights reserved the oxidant/antioxidant balance through inhibiting iNOS and up regulated GSH, SOD, Nrf-2 and HO-1 20 . Pre-treatment with nicorandil (100 µg/kg·h) protected non-ventilated lung collapse and re-expansion in one-lung ventilation rabbit model 21 . Nicorandil's effect was mediated through the notable oxidation/inflammation suppression. The expression levels of MDA, TNF-α, and the NF-κB were significantly reduced. Meanwhile, phosphatidylinositol-3-kinase (PI3K), hypoxiainducible factor (HIF-1α), and SOD were upregulated in the injured lungs treated with nicorandil. The immunomodulatory effect of nicorandil and lung tissue protection against apoptosiswas reflected on improved arterial oxygen saturation and oxygen partial pressure. Recently, Abe and co-workers documented an effective rat lung protection from ischemic injury when preconditioned with nicorandil. The drug decreased the extent of pulmonary microvascular permeability at 60 mints following reperfusion. Nicorandil's effect on the permeability was evidenced by a prominent reduction in the filtration coefficient and the wet-to-dry lung weight ratio 22 A bronchodilator effect of nicorandil has also been shown when a dose of 6 mg/hr infused intravenously prevented thiamylal-fentanyl-induced bronchoconstrictionin humans 23 . Theairway smooth muscle relaxing action of nicorandil presumably was established through NO donation 24, 25 and the K + ATP opening activity 26 . About one-third of the Middle East Respiratory Syndrome-related coronavirus (MERS-CoV) and the old SARS-COV cases have been associated with radiological findings of lung fibrosis 27, 28 . Likewise,SARS-CoV2 infection hasa high tendency for pulmonary parenchymal and interstitial fibrosis 29, 30 especially encountered in the advanced-phases 31 . The risk of such changes is higher in the older age groupowing to an observed more intense lung pathology in the acute phase of the disease in this group of patients 11 . The prevention of pulmonary fibrosis in patients infected withSARS-CoV2 is an issue that urgently needs to be addressed. This article is protected by copyright. All rights reserved Experimentally, nicorandil has been shown to produce improvement in a number of lung fibrosis models. Nicorandil improved the lung tissue histological picture ofa rat model of cyclophosphamide-induced lung fibrosis 32 ,silica-induced lung inflammation and fibrosis 20 , and bleomycin-induced lung fibrosis 33 and in more recently published study of Kseibati and coworkers 34 .The fibrosis-ameliorating effect of nicorandil was attributed to its ability torelieve pulmonary oxidative stress. Its beneficial actions were signaled by a reduction in the inflammatory markers present inthe bronchoalveolar lavage fluid and adecrease in the profibrotic marker, transforming growth factor-β (TGF-β) and the indicator of pulmonary collagen deposition (hydroxyproline content). These studies support the nicorandilanti-fibrotic potential. The antifibrotic potential of nicorandil was further documented in acute myocardial infarction patients subjected to coronary angioplasty. Acute intravenous nicorandil followed by 6 months of treatment decreased the patient's plasma level of procollagen type III amino-terminal peptide (PIIINP) and ameliorated left ventricular remodelling and improved function 35 Coagulopathy is becoming an increasingly recognized feature of cases severe COVID-19. This article is protected by copyright. All rights reserved SARS-CoV2 infection induces not only pulmonary vascular endothelial injury 41 but it also targets vascular endothelial cells all overthe body and markedly affects patients with cardiometabolic comorbidities as well as hypertensive patients as SARS-CoV2 has been shown to inhibits eNOS activity and decreases NO bioavailability 42 The intact vascular endothelium resists spontaneous platelets activation and consequently abortsthe coagulation cascade,and so can prevent pathologic thrombus formation. Physiologically producedNOprotects the endothelium and preventstissue factor secretion upon activation byseveral proinflammatory cytokines 41 This article is protected by copyright. All rights reserved membrane glycoproteins GP-VI, CD42b, PAC-1, and CD63. These glycoproteins were found to be significantly reduced in the nicorandil-treated group compared to controls 49 Another study carried out by Lu and co-workers indicatedthat adjuvant nicorandil therapy in patients with unstable angina alleviated the inflammation-mediated thrombus formation. Nicorandil prevented the peripheral blood platelet activation as indicated by reduced CD63, CD42b, PAC-1 and GP-VI fluorescence intensity 50 It is of great importance to highlight the acute myocardial injury manifestations inCOVID- infected female patients.The myocardial dysfunction was described without evidenceof obstructive coronary disease, and even without interstitial pneumonia manifestations 52 .Moreover, acute cardiac injury was reported in the severe cases admitted to theICU.Myocardial injury was confirmed by the elevation of high-sensitivity troponin I (hs-cTnI) biomarker,particularly in patientshaving higher plasma inflammatory cytokines and higher blood pressure measurements as compared to the non-ICU patients 53 . The anti-inflammatory anti-oxidant property of nicorandil protected the coronary endothelial cell injury in patients undergoing percutaneous coronary intervention 54 and reduced the incidence of death following acute myocardial infarction 55 .In a direct cardiac tissue effect, nicorandil protected the heart against doxorubicin-induced cardiotoxicity. Nicorandil fixed the doxorubicin-impaired NO bioavailability and NF-kB activation and the resulted apoptosis and consequently improved cardiac functions and the myocardial histological picture 56 .In another study, nicorandil counteracted cardiac fibrous tissue formation through inhibiting cultured rat cardiac fibroblasts proliferation 57 . This article is protected by copyright. All rights reserved In patients undergoing percutaneous coronary intervention, intravenous nicorandil administration just before reperfusion significantly improved the epicardial flow and tissue perfusion that was reflected on the ST-segment resolution 58 . The vasodilatory effect of nicorandil refers to its nitrate-like characteristics as well as the K + ATP channel openingactivity, resultingin vascular smoothmuscle cells relaxation and consequentlyboth venous and arterial blood vessels vasodilation 59 . Intravenous bolus administration of nicorandil in congestive heart failure patients significantly reducedthe pulmonary capillary wedge pressure accompanied by an increased cardiac index.This was accompanied by a decrease in arterial blood pressure only with doses of nicorandil exceeding 398 µg/kg 60 Inacute heart failure (AHF) admitted to the ICU admitted, 100µg/kg nicorandil bolus injection followed by 5 days 60-100µg/kg/h, significantly diminished the myocardial stress markersand gave better echocardiographic findingsand that was reflected on the patients' clinical picture.Furthermore, nicorandil improved the hemodynamics in the patients expressed high baseline systolic arterial blood pressure (SBP)(>140mmHg), and in cases with low SBP (<140mmHg) the drug was shown to be safe without producing marked hypotension 63 . Nicorandil also improved patients' hemodynamics regardless of their baseline systolic arterial blood pressure 63 . These clinical studies demonstrate thatnicorandil is a safe and effective medication for the treatment of acute heart failure emergencies. A more recent study by Mehra et al., looks into the relationship between cardiovascular disease, drug therapy, and mortality in COVID-19 hospitalised patients.Mehra and co-workers found that the increased risk of mortalitywasassociated with older age groups(>65 years), coronary artery disease, heart failure, cardiac arrhythmias, chronic obstructive pulmonary disease, and current smokers. No increased risk of in-hospital death was found to be associated This article is protected by copyright. All rights reserved with the use of vasodilator drugs like angiotensin-converting enzyme inhibitors or the use of angiotensin receptor blockers 64 . Denoting vasodilator safety in COVID-19 treatment. Furthermore, the European Society of Cardiology guidelines indicate the efficacy of intravenous vasodilators at an early stage for AHF patients without excessively low blood pressure (SBP >90 mmHg) 65 Since ACE2 is recognized as a functioning SARS-CoV2 receptor, and since it has amarkedrenal Nicorandil treatment of cultured podocytes could increase the antioxidant mitochondrial manganese superoxide dismutase content and suppress macrophages xanthine oxidase expression 68 .Nicorandil supported renal functions in salt-sensitive hypertensive rats. Significant glomerular upregulation of endothelial nitric oxide synthase (eNOS) expression was verified 69 . The nephroprotectiveeffects of nicorandil have been assessed in several clinical studies. The acute renal hemodynamic effects of nicorandil were compared to those of nitroglycerin in patients with stable coronary artery disease and normal renal functions. The coloredDoppler ultrasound revealed increased renal artery peak-systolic, end-diastolic, and mean blood flow velocities in the nicorandil-treated group compared to the pre-treatment values andcompared to those of the nitroglycerin-treated group 70 This article is protected by copyright. All rights reserved A retrospective chart review on patients with coronary vascular disorders receiving hemodialysis for end-stage renal disease suggested avaluable role of the nicorandil treatment in improving patient clinical outcomes and increased the patient's survival 71 . In this review, we have tried to shed light on the possible benefits of nicorandil therapy in the COVID-19 management. Nicorandil possesses multiple potential modulatory properties on the currently known pathogenesis of the disease. 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All rights reserved Doppler ultrasound Efficacy of oral nicorandil in patients with end-stage renal disease: A retrospective chart review after coronary angioplasty in japanese patients receiving hemodialysis The authors declare that there are no conflicts of interest This article is protected by copyright. All rights reserved