Use of Nicorandil in Cardiovascular Disease and Its Optimization

Nicorandil, a unique dual pharmacological mechanism anti-anginal agent with adenosine triphosphate sensitive potassium (KATP) channel agonist and nitrate-like properties, provides cardiologists with a means of managing angina pectoris patients effectively and provides long-term cardioprotection. The aim of this review is to provide an update on the efficacy of treatment with nicorandil, which counteracts cardiac damage in patients with acute or chronic ischaemic heart disease, congestive heart failure and arrhythmia, with particular emphasis on that induced by ischaemic preconditioning (in which strong protection against ischaemia-reperfusion injury is afforded by a brief preliminary ischaemic period). First, the rationale for nicorandil treatment and its pharmacological effects on the vasculature and cardiomyocytes are reviewed. The mechanisms underlying ischaemic preconditioning, with a focus on those that involve the KATP channel pathway, such as mitochondrial permeability transition pores, sub-lethal reactive oxygen species generation and nitric oxide production are then discussed. Next, clinical practice related to ischaemic preconditioning and pharmacological preconditioning with nicorandil as well as other favourable mechanisms of improvement of prognosis, in which it plays a role in improving endothelial function, modulating autonomic nervous system activity and stabilizing plaque are summarized. Finally, the tolerability of nicorandil is discussed.

[1]  J. Tijssen,et al.  Efficacy of nicorandil versus propranolol in mild stable angina pectoris of effort: a long-term, double-blind, randomized study. , 1992, Journal of cardiovascular pharmacology.

[2]  J. Sasaki,et al.  A multicenter comparison of nicorandil and diltiazem on serum lipid, apolipoprotein, and lipoprotein levels in patients with ischemic heart disease , 1992, Cardiovascular Drugs and Therapy.

[3]  A. Fitton,et al.  Nicorandil. A review of its pharmacology and therapeutic efficacy in angina pectoris. , 1992, Drugs.

[4]  N. Taira,et al.  Nicorandil as a hybrid between nitrates and potassium channel activators. , 1989, The American journal of cardiology.

[5]  R. Mann,et al.  Safety profile of nicorandil—prescription‐event monitoring (PEM) study , 1999, Pharmacoepidemiology and drug safety.

[6]  E. Roland Safety profile of an anti-anginal agent with potassium channel opening activity: an overview. , 1993, European heart journal.

[7]  A. Camm,et al.  Exercise capacity after single and twice-daily doses of nicorandil in chronic stable angina pectoris. , 1989, The American journal of cardiology.

[8]  M. Kinoshita,et al.  Absence of hemodynamic tolerance to nicorandil in patients with severe congestive heart failure. , 1994, American heart journal.

[9]  K. Shirato,et al.  Vasodilatory effect of nicorandil on coronary arterial microvessels: its dependency on vessel size and the involvement of the ATP-sensitive potassium channels. , 1995, Journal of cardiovascular pharmacology.

[10]  R M Rapoport,et al.  Endothelium-dependent and nitrovasodilator-induced relaxation of vascular smooth muscle: role of cyclic GMP. , 1983, Journal of cyclic nucleotide and protein phosphorylation research.

[11]  P. Quandalle,et al.  Potassium channel activators in vasospastic angina. , 1993, European heart journal.

[12]  J. Downey,et al.  Nicorandil opens mitochondrial KATP channels not only directly but also through a NO-PKG-dependent pathway , 2006, Basic Research in Cardiology.

[13]  Guidelines on the management of stable angina pectoris: executive summary: the task force on the management of stable angina pectoris of the European society of cardiology. , 2006 .

[14]  D. Fukai,et al.  Comparison of hemodynamic effects and plasma cyclic guanosine monophosphate of nicorandil and nitroglycerin in patients with congestive heart failure. , 1995, The American journal of cardiology.

[15]  M. Egred Nicorandil-associated ulcerations , 2007, European Journal of Gastroenterology and Hepathology.

[16]  N. Chang,et al.  Effect of ATP-sensitive potassium channel agonists on sympathetic hyperinnervation in postinfarcted rat hearts. , 2009, American journal of physiology. Heart and circulatory physiology.

[17]  R. Luke Chronic renal failure--a vasculopathic state. , 1998, The New England journal of medicine.

[18]  Katherine C. Wu,et al.  Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. , 1998, Circulation.

[19]  充男 三田,et al.  安定狭心症に対するニコランジルの短期的有効性・安全性に関するシステマティック・レビュー:β遮断薬・持続性亜硝酸薬・Ca拮抗薬との比較 , 2010 .

[20]  R. Bolli The Late Phase of Preconditioning , 2000, Circulation research.

[21]  J. Camm,et al.  Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. , 2006, European heart journal.

[22]  I. West,et al.  The Mechanism by Which the Mitochondrial ATP-sensitive K+ Channel Opening and H2O2 Inhibit the Mitochondrial Permeability Transition* , 2006, Journal of Biological Chemistry.

[23]  B. Gersh Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials , 2008 .

[24]  A. Barbaud,et al.  Major aphthous stomatitis induced by nicorandil , 2000 .

[25]  J. Camm,et al.  [Guidelines on the management of stable angina pectoris: executive summary]. , 2006, Giornale italiano di cardiologia.

[26]  M. Zeier,et al.  Increased Infarct Size in Uremic Rats: Reduced Ischemia Tolerance? Materials and Methods , 2022 .

[27]  A. Halestrap What is the mitochondrial permeability transition pore? , 2009, Journal of molecular and cellular cardiology.

[28]  P. Blin,et al.  A double-blind comparison of the long-term efficacy of a potassium channel opener and a calcium antagonist in stable angina pectoris. , 1993, European heart journal.

[29]  S. Holzmann Cyclic GMP as Possible Mediator of Coronary Arterial Relaxation by Nicorandil (SG‐75) , 1983, Journal of cardiovascular pharmacology.

[30]  Y. Hiraoka,et al.  Continuous administration of nicorandil decreases QT dispersion during the chronic phase of acute myocardial infarction. , 2006, International heart journal.

[31]  H. Yagi,et al.  Nicorandil Protects Against Lethal Ischemic Ventricular Arrhythmias and Up-regulates Endothelial Nitric Oxide Synthase Expression and Sulfonylurea Receptor 2 mRNA in Conscious Rats with Acute Myocardial Infarction , 2004, Cardiovascular Drugs and Therapy.

[32]  P. Bernardi,et al.  Opening of the Mitochondrial Permeability Transition Pore Causes Depletion of Mitochondrial and Cytosolic NAD+and Is a Causative Event in the Death of Myocytes in Postischemic Reperfusion of the Heart* , 2001, The Journal of Biological Chemistry.

[33]  N. Tamura,et al.  Nicorandil Attenuates FeCl3-Induced Thrombus Formation Through the Inhibition of Reactive Oxygen Species Production , 2009 .

[34]  F. Boccara Coronary intervention for persistent occlusion after myocardial infarction. , 2007 .

[35]  E. Cantor,et al.  Comparison of nicorandil-induced relaxation, elevations of cyclic guanosine monophosphate and stimulation of guanylate cyclase with organic nitrate esters. , 1991, The Journal of pharmacology and experimental therapeutics.

[36]  W. Laskey,et al.  Adaptation to ischemia during percutaneous transluminal coronary angioplasty. Clinical, hemodynamic, and metabolic features. , 1990, Circulation.

[37]  Y. Ladilov,et al.  Preconditioning with diazoxide prevents reoxygenation-induced rigor-type hypercontracture. , 2010, Journal of molecular and cellular cardiology.

[38]  E. Antman,et al.  Prospective temporal analysis of the onset of preinfarction angina versus outcome: an ancillary study in TIMI-9B. , 1998, Circulation.

[39]  H. Kishida,et al.  Effect of a new coronary vasodilator, nicorandil, on variant angina pectoris , 1987, Clinical pharmacology and therapeutics.

[40]  G. Pöch,et al.  Pharmacological interaction experiments differentiate between glibenclamide-sensitive K+ channels and cyclic GMP as components of vasodilation by nicorandil. , 1992, European journal of pharmacology.

[41]  K. Fox,et al.  Cardioprotection by opening of the KATPchannel in unstable anginaIs this a clinical manifestation of myocardial preconditioning? Results of a randomized study with nicorandil , 1999 .

[42]  R. Foley,et al.  Outcome and risk factors of ischemic heart disease in chronic uremia. , 1996, Kidney international.

[43]  F. Hofmann,et al.  Cyclic GMP-dependent protein kinase stimulates the plasmalemmal Ca2+ pump of smooth muscle via phosphorylation of phosphatidylinositol. , 1988, The Biochemical journal.

[44]  T. Yanagisawa,et al.  Effect of 2-nicotinamidethyl nitrate (SG-75) on membrane potentials of canine Purkinje fibers. , 1981, Japanese journal of pharmacology.

[45]  M. Isobe,et al.  Opening of KATP channel attenuates the increase in QT dispersion produced by the first balloon inflation during coronary angioplasty , 2002 .

[46]  M. Shigekawa,et al.  Maxi K+ channels are stimulated by cyclic guanosine monophosphate-dependent protein kinase in canine coronary artery smooth muscle cells , 1993, Pflügers Archiv.

[47]  M. Sekiguchi,et al.  Coronary microvascular response to intracoronary administration of nicorandil. , 1995, The American journal of cardiology.

[48]  M. Sekiya,et al.  Effects of the Long-Term Administration of Nicorandil on Vascular Endothelial Function and the Progression of Arteriosclerosis , 2005, Journal of cardiovascular pharmacology.

[49]  T. Katagiri,et al.  Acute effects of intravenous nicorandil on hemodynamics in patients hospitalized with acute decompensated heart failure. , 2010, Journal of cardiology.

[50]  M. Kurabayashi,et al.  Comparative effects of nicorandil with isosorbide mononitrate on cardiac sympathetic nerve activity and left ventricular function in patients with ischemic cardiomyopathy. , 2005, American heart journal.

[51]  S. Duty,et al.  The potassium channel openers: a new class of vasorelaxants. , 1990, Blood vessels.

[52]  O. Divitiis,et al.  A double-blind comparison of nicorandil and metoprolol in stable effort angina pectoris , 1993, Cardiovascular Drugs and Therapy.

[53]  E. Raftery,et al.  Comparison of nicorandil and atenolol in stable angina pectoris. , 1990, The American journal of cardiology.

[54]  M. Kinoshita,et al.  Mechanism of the vasodilatory action of nicorandil on coronary circulation in dogs , 1994, Cardiovascular Drugs and Therapy.

[55]  J. Downey,et al.  Oxygen radicals released during ischemic preconditioning contribute to cardioprotection in the rabbit myocardium. , 1997, Journal of molecular and cellular cardiology.

[56]  H. Yagi,et al.  Effects of nicorandil on cardiovascular events in patients with coronary artery disease in the Japanese Coronary Artery Disease (JCAD) study. , 2010, Circulation journal : official journal of the Japanese Circulation Society.

[57]  Y. Taniyama,et al.  Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction. , 1999, Journal of the American College of Cardiology.

[58]  Maria Mori Brooks,et al.  A randomized trial of therapies for type 2 diabetes and coronary artery disease. , 2009, The New England journal of medicine.

[59]  A. Terzic,et al.  Effective Pharmacotherapy Against Oxidative Injury: Alternative Utility of an ATP-Sensitive Potassium Channel Opener , 2007, Journal of cardiovascular pharmacology.

[60]  David A Harris,et al.  Biochemical dysfunction in heart mitochondria exposed to ischaemia and reperfusion. , 2005, The Biochemical journal.

[61]  Sequelae of acute myocardial infarction regarding cardiac structure and function and their prognostic significance as assessed by magnetic resonance imaging. , 2005 .

[62]  W. Hillis,et al.  Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial , 2002, The Lancet.

[63]  G. Pöch,et al.  Molecular Mechanism of Action of Nicorandil , 1992, Journal of cardiovascular pharmacology.

[64]  Hakuo Takahashi,et al.  Oral nicorandil to reduce cardiac death after coronary revascularization in hemodialysis patients: a randomized trial. , 2009, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[65]  A. Collins,et al.  Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. , 1998, The New England journal of medicine.

[66]  S. Pocock,et al.  Seven-year outcome in the RITA-2 trial: coronary angioplasty versus medical therapy. , 2003, Journal of the American College of Cardiology.

[67]  H. Yagi,et al.  Nicorandil but not ISDN Upregulates Endothelial Nitric Oxide Synthase Expression, Preventing Left Ventricular Remodeling and Degradation of Cardiac Function in Dahl Salt-sensitive Hypertensive Rats With Congestive Heart Failure , 2006, Journal of cardiovascular pharmacology.

[68]  T. Murohara,et al.  Impact of a Single Intravenous Administration of Nicorandil Before Reperfusion in Patients With ST-Segment–Elevation Myocardial Infarction , 2005, Circulation.

[69]  L. Toquero,et al.  Anal ulceration associated with Nicorandil: case series and review of the literature , 2006, Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland.

[70]  C. Scully,et al.  Nicorandil-induced severe oral ulceration: a newly recognized drug reaction. , 1999, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[71]  K. Fox,et al.  Cardioprotection by opening of the K(ATP) channel in unstable angina. Is this a clinical manifestation of myocardial preconditioning? Results of a randomized study with nicorandil. CESAR 2 investigation. Clinical European studies in angina and revascularization. , 1999, European heart journal.

[72]  K. Kato Haemodynamic and clinical effects of an intravenous potassium channel opener--a review. , 1993, European heart journal.

[73]  M. Kurabayashi,et al.  Long-Term Nicorandil Therapy Improves Cardiac Sympathetic Nerve Activity After Reperfusion Therapy in Patients with First Acute Myocardial Infarction , 2007, Journal of Nuclear Medicine.

[74]  L. Kevin,et al.  Ischemic preconditioning alters real-time measure of O2 radicals in intact hearts with ischemia and reperfusion. , 2003, American journal of physiology. Heart and circulatory physiology.

[75]  S. Witchitz,et al.  Nicorandil safety in the long-term treatment of coronary heart disease , 1995, Cardiovascular Drugs and Therapy.

[76]  P. Joly,et al.  Association of major aphthous ulcers and nicorandil , 1998, The Lancet.

[77]  K. Wellington,et al.  Nicorandil , 2012, Drugs.

[78]  D. Escande,et al.  K+ channel openers and 'natural' cardioprotection. , 1992, Trends in pharmacological sciences.

[79]  M. Hori,et al.  Opening of the adenosine triphosphate-sensitive potassium channel attenuates cardiac remodeling induced by long-term inhibition of nitric oxide synthesis: role of 70-kDa S6 kinase and extracellular signal-regulated kinase. , 2002, Journal of the American College of Cardiology.

[80]  D. Hausenloy Signalling pathways in ischaemic postconditioning , 2009, Thrombosis and Haemostasis.

[81]  M. Ishihara,et al.  Implications of prodromal angina pectoris in anterior wall acute myocardial infarction: acute angiographic findings and long-term prognosis. , 1997, Journal of the American College of Cardiology.

[82]  Hakuo Takahashi,et al.  Clinical Potential of Nicorandil to Inhibit Major Cardiac Events in Hemodialysis Patients with Suspected Myocardial Ischemia , 2009, Nephron Clinical Practice.

[83]  R. Jennings,et al.  Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. , 1986, Circulation.

[84]  A. Halestrap Calcium, mitochondria and reperfusion injury: a pore way to die. , 2006, Biochemical Society transactions.

[85]  S. Hishinuma,et al.  [Systematic review on the short-term efficacy and safety of nicorandil for stable angina pectoris in comparison with those of β-blockers, nitrates and calcium antagonists]. , 2010, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan.

[86]  M. Loudon,et al.  Nicorandil associated anal ulceration , 2004, Age and ageing.

[87]  C Antzelevitch,et al.  Cellular basis for QT dispersion. , 1998, Journal of electrocardiology.

[88]  Takashi Sugamori,et al.  Effects of Long-term Nicorandil Administration on Endothelial Function, Inflammation, and Oxidative Stress in Patients Without Coronary Artery Disease , 2008, Journal of cardiovascular pharmacology.

[89]  G. Pöch,et al.  Dual Mechanism of the Relaxing Effect of Nicorandil by Stimulation of Cyclic GMP Formation and by Hyperpolarization , 1991, Journal of cardiovascular pharmacology.

[90]  H. Yagi,et al.  [Suppressive effect of nicorandil in ventricular arrhythmias after reperfusion therapy in patients with acute myocardial infarction]. , 2007, Journal of cardiology.

[91]  C. Bauters,et al.  Prevention of Coronary Spasm by Nicorandil: Comparison with Nifedipine , 1992, Journal of cardiovascular pharmacology.

[92]  T. Ohe,et al.  Intravenous administration of nicorandil immediately before percutaneous coronary intervention can prevent slow coronary flow phenomenon. , 2008, European heart journal.

[93]  Ernesto Carafoli,et al.  Calcium pump of the plasma membrane , 1991 .

[94]  M. Kojima,et al.  Nicorandil shortens action potential duration and antagonises the reduction of Vmax by lidocaine but not by disopyramide in guinea-pig papillary muscles , 1988, Naunyn-Schmiedeberg's Archives of Pharmacology.

[95]  T. Yamamoto,et al.  Rho‐associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. , 1996, The EMBO journal.

[96]  S. Silberberg,et al.  ATP inhibits smooth muscle Ca2+-activated K+ channels , 1990, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[97]  Zhan-quan Li,et al.  Double-blind, multicenter, active-controlled, randomized clinical trial to assess the safety and efficacy of orally administered nicorandil in patients with stable angina pectoris in China. , 2007, Circulation journal : official journal of the Japanese Circulation Society.

[98]  I. R. Manousos,et al.  Clinical trials update: The Heart Protection Study, IONA, CARISA, ENRICHD, ACUTE, ALIVE, MADIT II and REMATCH , 2002, European journal of heart failure.

[99]  N. Hagiwara,et al.  Acute Efficacy and Safety of Intravenous Administration of Nicorandil in Patients With Acute Heart Failure Syndromes: Usefulness of Noninvasive Echocardiographic Hemodynamic Evaluation , 2009, Journal of cardiovascular pharmacology.

[100]  T. Kato,et al.  Nicorandil, a potent cardioprotective agent, reduces QT dispersion during coronary angioplasty. , 2001, American heart journal.

[101]  Y. Izumiya,et al.  Long-term use of oral nicorandil stabilizes coronary plaque in patients with stable angina pectoris. , 2011, Atherosclerosis.

[102]  D. Levine,et al.  Clinical Trials Update , 2013 .

[103]  A. Terzic,et al.  Cellular remodeling in heart failure disrupts KATP channel‐dependent stress tolerance , 2003, The EMBO journal.

[104]  I. Ford,et al.  Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial , 2002 .

[105]  D. Berman,et al.  Optimal medical therapy with or without PCI for stable coronary disease. , 2007, The New England journal of medicine.

[106]  W. Howard,et al.  Optimal Medical Therapy with or without PCI for Stable Coronary Disease , 2008 .

[107]  松原 徹夫 Three minute,but not one minute,ischemia and nicorandil have a preconditioning effect in patients with coronary artery disease , 2000 .

[108]  Current status of the background of patients with coronary artery disease in Japan. , 2006, Circulation journal : official journal of the Japanese Circulation Society.

[109]  H M Piper,et al.  A fresh look at reperfusion injury. , 1998, Cardiovascular research.

[110]  R. Cannon,et al.  Cardiovascular complications in renal failure. , 1991, Journal of the American Society of Nephrology : JASN.

[111]  N. Tsujino,et al.  Mechanisms of preventive effect of nicorandil on ischaemia-induced ventricular tachyarrhythmia in isolated arterially perfused canine left ventricular wedges. , 2008, Basic & clinical pharmacology & toxicology.

[112]  Hiroshi Takahashi,et al.  Efficacy of oral nicorandil in patients with end-stage renal disease: a retrospective chart review after coronary angioplasty in Japanese patients receiving hemodialysis. , 2007, Clinical therapeutics.

[113]  G. Döring Antianginal and Anti‐Ischemic Efficacy of Nicorandil in Comparison with Isosorbide‐5‐Mononitrate and Isosorbide Dinitrate: Results from Two Multicenter, Double‐Blind, Randomized Studies with Stable Coronary Heart Disease Patients , 1992, Journal of cardiovascular pharmacology.

[114]  2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina , 2007 .

[115]  M. Chiariello,et al.  Oxygen radicals can induce preconditioning in rabbit hearts. , 1997, Circulation research.

[116]  G. Ulvenstam,et al.  Antianginal and Anti‐Ischemic Efficacy of Nicorandil Compared with Nifedipine in Patients with Angina Pectoris and Coronary Heart Disease: A Double‐Blind, Randomized, Multicenter Study , 1992, Journal of cardiovascular pharmacology.

[117]  E. Marbán,et al.  Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATP-dependent potassium channels. , 2000, Journal of the American College of Cardiology.

[118]  K. Dickstein,et al.  Comparison of the degree of hemodynamic tolerance during intravenous infusion of nitroglycerin versus nicorandil in patients with congestive heart failure. , 1997, American heart journal.

[119]  M. Shibuya,et al.  Nicorandil treatment in patients with acute myocardial infarction: a meta-analysis. , 2009, Circulation journal : official journal of the Japanese Circulation Society.