To study the effect of nicorandil pretreatment on ketone body metabolism and Acetyl-CoA acetyltransferase (ACAT1) activity in hypoxia/reoxygenation (H/R)-induced cardiomyocytes. In our study, we applied H9c2 cardiomyocytes cell line to evaluate the cardioprotective effects of nicorandil. We detected mitochondrial viability, cellular apoptosis, reactive oxygen species (ROS) production and calcium overloading in H9c2 cells that exposed to H/R-induced cytotoxicity. Then we evaluated whether nicorandil possibly regulated ketone body, mainly β-hydroxybutyrate (BHB) and acetoacetate (ACAC), metabolism by regulating ACAT1 and Succinyl-CoA:3-keto-acid coenzyme A transferase 1 (OXCT1) protein and gene expressions. Nicorandil protected H9c2 cardiomyocytes against H/R-induced cytotoxicity dose-dependently by mitochondria-mediated anti-apoptosis pathway. Nicorandil significantly decreased cellular apoptotic rate and enhanced the ratio of Bcl-2/Bax expressions. Further, nicorandil decreased the production of ROS and alleviated calcium overloading in H/R-induced H9c2 cells. In crucial, nicorandil upregulated ACAT1 and OXCT1 protein expressions and either of their gene expressions, contributing to increased production of cellular BHB and ACAC. Nicorandil alleviated cardiomyocytes H/R-induced cytotoxicity through upregulating ACAT1/OXCT1 activity and ketone body metabolism, which might be a potential mechanism for emerging study of nicorandil and other K(ATP) channel openers.
Acetyl-CoA C-Acetyltransferase ; Apoptosis ; Calcium ; Cell Line ; Coenzyme A ; Gene Expression ; Metabolism* ; Myocytes, Cardiac ; Nicorandil* ; Reactive Oxygen Species ; Transferases

BACKGROUND: Ischemic heart disease is the most common type of heart disease and an important cause of death in Korea. Among marketed anti-anginal medications, molsidomine, nicorandil, and trimetazidine are approved in Korea with unique mechanism of actions. As these drugs are not approved by the US Food and Drug Administration, the access to the up-to-dated and comprehensive safety-related information has been less than optimal from drug information resources used by Korean pharmacists. METHODS: A systematic review was conducted using Embase and Korean manuscripts to compile safety updates for these medications. Out of 418 articles from keyword searches, 52 studies were reviewed in full to compare adverse effects (AEs) with the approved package inserts (PI). RESULTS: Molsidomine related adverse effects were mostly mild or moderate, but anxiety, palpitation, epigastric pain, and sexual potency reduction were additional AEs found from the review not listed in PI. Although PI has included ulceration in oral cavity and gastrointestinal tracts including anus by nicorandil, the Korea FDA recently recommended adding corneal, genital, and skin ulcers to the approved PI. Trimetazidine induced Parkinsonism, worsening of the symptoms for patients diagnosed with Parkinson's disease, gastrointestinal burning, and muscle cramps were additionally identified AEs not listed in PI for trimetazidine. CONCLUSION: Continuous evaluations of the safety profile of these agents are needed to balance the risks and benefits to provide evidence-based safety counseling to the patients. In addition, more focused efforts on spontaneous reporting are warranted by healthcare professionals to safeguard patients against AEs.
Anal Canal ; Anxiety ; Burns ; Cause of Death ; Counseling ; Delivery of Health Care ; Gastrointestinal Tract ; Heart Diseases ; Humans ; Korea ; Molsidomine* ; Mouth ; Muscle Cramp ; Myocardial Ischemia ; Nicorandil* ; Parkinson Disease ; Parkinsonian Disorders ; Pharmacists ; Product Labeling ; Risk Assessment ; Skin Ulcer ; Trimetazidine* ; Ulcer ; United States Food and Drug Administration

Potassium channels and transporters maintain potassium homeostasis and play significant roles in several different biological actions via potassium ion regulation. In previous decades, the key revelations that potassium channels and transporters are involved in the production of gastric acid and the regulation of secretion in the stomach have been recognized. Drugs used to treat peptic ulceration are often potassium transporter inhibitors. It has also been reported that potassium channels are involved in ulcerative colitis. Direct toxicity to the intestines from nonsteroidal anti-inflammatory drugs has been associated with altered potassium channel activities. Several reports have indicated that the long-term use of the antianginal drug Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, increases the chances of ulceration and perforation from the oral to anal regions throughout the gastrointestinal (GI) tract. Several of these drug features provide further insights into the role of potassium channels in the occurrence of ulceration in the GI tract. The purpose of this review is to investigate whether potassium channelopathies are involved in the mechanisms responsible for ulceration that occurs throughout the GI tract.
Adenosine ; Channelopathies* ; Colitis, Ulcerative ; Gastric Acid ; Gastrointestinal Tract ; Homeostasis ; Intestines ; Nicorandil ; Peptic Ulcer ; Potassium Channels ; Potassium* ; Stomach ; Ulcer*

Potassium channels and transporters maintain potassium homeostasis and play significant roles in several different biological actions via potassium ion regulation. In previous decades, the key revelations that potassium channels and transporters are involved in the production of gastric acid and the regulation of secretion in the stomach have been recognized. Drugs used to treat peptic ulceration are often potassium transporter inhibitors. It has also been reported that potassium channels are involved in ulcerative colitis. Direct toxicity to the intestines from nonsteroidal anti-inflammatory drugs has been associated with altered potassium channel activities. Several reports have indicated that the long-term use of the antianginal drug Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, increases the chances of ulceration and perforation from the oral to anal regions throughout the gastrointestinal (GI) tract. Several of these drug features provide further insights into the role of potassium channels in the occurrence of ulceration in the GI tract. The purpose of this review is to investigate whether potassium channelopathies are involved in the mechanisms responsible for ulceration that occurs throughout the GI tract.
Adenosine ; Channelopathies* ; Colitis, Ulcerative ; Gastric Acid ; Gastrointestinal Tract ; Homeostasis ; Intestines ; Nicorandil ; Peptic Ulcer ; Potassium Channels ; Potassium* ; Stomach ; Ulcer*

PURPOSE: To investigate the effect of pretreatment with intravenous nicorandil on the incidence of contrast-induced nephropathy (CIN) in patients with renal dysfunction undergoing coronary angiography. MATERIALS AND METHODS: This randomized controlled multicenter study enrolled a total of 166 patients (nicorandil n=81; control n=85) with an estimated glomerular filtration rate <60 mL/min. Nicorandil 12 mg dissolved in 100 mL of 0.9% saline was administered intravenously for 30 minutes just prior to coronary angiography in the nicorandil group. The same volume of only saline was given to the control group. The primary end-point was the incidence of CIN, defined as >0.5 mg/dL increase or >25% rise in serum creatinine (SCr) concentration within 48 hours of contrast exposure compared to baseline. RESULTS: The final analysis included 149 patients (nicorandil n=73; control n=76). The baseline characteristics and the total volume of the used contrast (Iodixanol, 125.6+/-69.1 mL vs. 126.9+/-74.6 mL, p=0.916) were similar between the two groups. The incidence of CIN also did not differ between the nicorandil and control groups (6.8% vs. 6.6%, p=0.794). There was no difference between the two groups in the relative change in SCr from baseline to peak level within 48 hours after coronary angiography (-1.58+/-24.07% vs. 0.96+/-17.49%, p=0.464), although the nicorandil group showed less absolute change in SCr than the control group (-0.01+/-0.43 mg/mL vs. 0.02+/-0.31 mg/mL, p=0.005). CONCLUSION: Prophylactic intravenous infusion of nicorandil did not decrease the incidence of CIN in patients with renal dysfunction undergoing coronary angiography.
Administration, Intravenous ; Aged ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects/methods ; Creatinine/blood ; Female ; Glomerular Filtration Rate ; Humans ; Incidence ; Kidney Diseases/*chemically induced/epidemiology/physiopathology/*prevention & control ; Male ; Middle Aged ; Nicorandil/*administration & dosage/therapeutic use

Drug-eluting balloon (DEB) with angioplasty a paclitaxel-coated balloon catheter is an effective treatment option in patients with in-stent restenosis (ISR) after a drug-eluting stent (DES). We describe a case in which 'no-reflow' phenomenon developed after DEB angioplasty of a DES ISR lesion. Coronary flow was restored after intracoronary administration of nicorandil.
Angioplasty ; Catheters ; Coronary Restenosis ; Drug-Eluting Stents ; Humans ; Nicorandil ; No-Reflow Phenomenon

A 70-year-old male came to the emergency room of the authors' hospital because of sudden cardiac arrest due to inferior wall ST elevation myocardial infarction. His coronary angiography revealed multiple severe coronary spasms in his very long left anterior descending artery. After an injection of intracoronary nitroglycerine, his stenosis improved. The cardiac arrest relapsed, however, accompanied by ST elevation of the inferior leads, while the patient was on diltiazem and nitrate medication to prevent coronary spasm. Recovery was not achieved even with cardiac massage, intravenous injection of epinephrine and atropine, and intravenous infusion of nitroglycerine. The patient eventually recovered through high-dose nicorandil intravenous infusion without ST elevation of his inferior leads. Therefore, intravenous infusion of a high dose of nicorandil must be considered a treatment option for cardiac arrest caused by refractory coronary vasospasm.
Arteries ; Atropine ; Cardiopulmonary Resuscitation ; Constriction, Pathologic ; Coronary Angiography ; Coronary Vasospasm ; Death, Sudden, Cardiac ; Diltiazem ; Emergencies ; Epinephrine ; Heart Arrest ; Heart Massage ; Hemodynamics ; Humans ; Infusions, Intravenous ; Injections, Intravenous ; Male ; Myocardial Infarction ; Nicorandil ; Nitroglycerin ; Porphyrins ; Spasm

BACKGROUND: Arginine vasopressin has been used by prophylactic treatment of vasodilatory shock during coronary artery bypass graft (CABG). Vasopressin may be a cause of spasm in graft artery during CABG. We evaluated the effect of propofol on vasopressin-induced contraction in human gastroepiploic artery (GEA). METHODS: Human GEA were obtained from 35 patients (43-74 yr), undergoing subtotal gastrectomy. Vasopressin-induced a concentration contractions (10(-9) to 10(-6) M) were measured after exposed to without propofol, propofol 10(-5), 10(-4), 10(-3) M. After endothelium denuding vasopressin-induced a concentration contractions were measured with or without propofol 10(-3) M in calcium free solution. In the denuded vascular rings, with or without pretreatment of glibenclamide (10(-5) M), nicorandil (10(-5) M), or diltiazem (10(-5) M) were exposed to with or without propofol 10(-3) M, and vasopressin-induced concentration contractions were measured. RESULTS: Vasopressin-induced concentration contraction on human GEA was independent of functional endothelium. Propofol (10(-4), 10(-3) M) attenuated the vasopressin-induced contraction in the human GEA. Diltiazem attenuated the vasopressin-induced contraction in the human GEA. ATP-sensitive potassium channel does not affect the inhibition effect of propofol on vasopressin-induced contraction CONCLUSIONS: Usual anesthetic dose of propofol does not inhibit vasopressin-induced contraction on human GEA. High dose (>10(-4) M) propofol attenuated vasopresssi-induced contraction on GEA.
Arginine ; Arginine Vasopressin ; Arteries ; Calcium ; Contracts ; Coronary Artery Bypass ; Diltiazem ; Endothelium ; Gastrectomy ; Gastroepiploic Artery ; Glyburide ; Humans ; Nicorandil ; Potassium Channels ; Propofol ; Shock ; Spasm ; Transplants ; Vasopressins

BACKGROUND AND OBJECTIVES: A spasm of the radial artery is one of the most common complications of coronary angiography (CAG) via the transradial approach (TR), and this spasm sometimes disturbs the procedure. Nicorandil has recently shown dose-dependent dilatation of the blood vessels and ischemic preconditioning. This study was designed to evaluate the clinical effects and radial artery vasodilation of high dose nicorandil solution during CAG via the radial artery. SUBJECTS AND METHODS: This study was a prospective, randomized study to compare the effects of 12 mg of nicorandil (the Nicorandil group) and 10 mL of a cocktail solution (nitroglycerine 200 microgram mixed with verapamil 100 microgram) (the Cocktail group) in 146 patients. Vasospasms, which were expressed as the stenosis of the radial artery were examined at 2 parts of the radial artery. RESULTS: There were no significant difference of gender, age and risk factors for the 2 groups of patients. The reductions in the systolic and diastolic blood pressure (BP) 1 minute after drug administration were 33.6+/-11.4/10.4+/-7.7 mmHg in the Nicorandil group and 12.8+/-9.8/3.8+/-5.3 mmHg in the Cocktail group (p<0.001). Both vasodilating agents showed significant radial artery vasodilation after administration of the drugs (p<0.005 for all). The minimal luminal diameter (MLD) after drug administration was more dilated in the Nicorandil group than that in the Cocktail group (0.63+/-0.25 mm vs. 0.48+/-0.19 mm, respectively, p=0.013). CONCLUSION: Nicorandil solution was more effective for inducing vasodilation of the radial artery, but it was not clinical superior to the cocktail solution.
Blood Pressure ; Blood Vessels ; Constriction, Pathologic ; Coronary Angiography ; Dilatation ; Humans ; Ischemic Preconditioning ; Nicorandil ; Phenobarbital ; Prospective Studies ; Radial Artery ; Risk Factors ; Spasm ; Vasodilation ; Vasodilator Agents ; Verapamil

BACKGROUND AND OBJECTIVES: Intravenous nicorandil infusion with percutaneous coronary intervention (PCI) has been reported to reduce reperfusion injury events and to improve cardiac function in patients with an acute myocardial infarction. However, there is limited information on the use of intra-coronary nicorandil. A prospective randomized single center study was designed to evaluate the efficacy of the use of intra-coronary nicorandil. SUBJECTS AND METHODS: Seventy-three patients with an acute ST segment elevation myocardial infarction were randomly assigned to the nicorandil group (n=37) or a control group (n=36); all patients received a PCI. In the nicorandil group of patients, 4 mg of intra-coronary nicorandil was infused directly into the infarct area prior to reperfusion (2 mg before ballooning, 2 mg before stenting). The composite endpoint was the incidence of ventricular arrhythmia, no-reflow and slow flow. We estimated the post thrombolysis in myocardial infarction (TIMI) grade, the myocardial perfusion grade after PCI and the short-term clinical outcome. RESULTS: The baseline characteristics were similar in both groups of patients. A significant difference was observed in the composite endpoint in the nicorandil group of patients as compared to the control group of patients (p=0.037). The achievement rate of post TIMI grade 3 was significantly higher in the nicorandil group of patients (p=0.019). The myocardial perfusion grade 1 was not observed in the nicorandil group of patients; however, it was observed in five patients in the control group (p=0.019). Major adverse cardiac events in hospital and in 30 days were similar between the two groups. CONCLUSION: Intra-coronary nicorandil infusion reduced the occurrence of no-reflow, slow reflow, reperfusion arrhythmia and improved the myocardial perfusion grade and TIMI flow during PCI. The results of this study showed that the use of intracoronary nicorandil improved the clinical outcome in patients with an acute myocardial infarction.
Achievement ; Arrhythmias, Cardiac ; Humans ; Incidence ; Myocardial Infarction ; Nicorandil ; No-Reflow Phenomenon ; Percutaneous Coronary Intervention ; Perfusion ; Prospective Studies ; Reperfusion ; Reperfusion Injury