Nicorandil alleviated cardiac hypoxia/reoxygenation-induced cytotoxicity via upregulating ketone body metabolism and ACAT1 activity

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.

Nuevos enfoques farmacológicos en el manejo de la angina de pecho estable / New pharmacological approaches in the management of stable angina

RESUMEN En años recientes han sido introducidos nuevos antianginosos al mercado con mecanismos de acción novedosos, complementarios a los del arsenal farmacoterapéutico existente. Aunque el tratamiento de primera línea continúan siendo los betabloqueadores, antagonistas de canales de calcio y nitratos, el descubrimientos de nuevos aspectos fisiopatológicos de la enfermedad permitieron el desarrollo de blancos terapéuticos innovadores a nivel celular y molecular. El nicorandil, la trimetazidina, la ivabradina y la ranolazina se consideran nuevos fármacos antianginosos y constituyen la segunda línea de tratamiento de la angina de pecho estable; están indicados en pacientes que persisten sintomáticos a pesar del manejo de primera línea o en aquellos que presentan intolerancia o contraindicación a los betabloqueadores o antagonistas de canales de calcio. La trimetazidina, a través de su mecanismo de acción metabólico, mejora la tolerancia al ejercicio y puede ser útil en pacientes con falla cardíaca y contraindicación al uso de digitales; la ivabradina tiene un efecto cronotrópico negativo sin afectar el inotropismo ni la tensión arterial por lo que se puede usar en pacientes con taquiarritmias o falla cardíaca concomitante; en contraste, la ranolazina no afecta el cronotropismo por lo que se usa en pacientes con bradiarritmias aunque puede generar prolongación del intervalo QTc. La elección de alguno de estos medicamentos antianginosos de primera o segunda línea debe ser individualizado para cada paciente y se basa en las comorbilidades, contraindicaciones y preferencias del paciente. MÉD.UIS. 2016;29(3):79-93.

ABSTRACT In recent years, new antianginal agents with novel mechanisms of action have been launched to the market, as a complement to the existing therapeutic arsenal. Even though the beta-blockers, calcium channel blockers and nitrates continue to be the first line of treatment, recent discoveries of pathophysiological aspects of the disease led to the development of innovative therapeutic targets on both cellular and molecular level. Nicorandil, trimetazidine, ivabradine and ranolazine are novel antianginal drugs and constitute the second line of treatment of stable angina; these drugs are indicated for those patients who persist symptomatic despite treatment with first line agents or in those with contraindication or intolerance to beta-blockers o calcium channel blockers. Trimetazidine, through its metabolic mechanism of action, improves exercise tolerance and might be useful in patients with concomitant heart failure and contraindication to digitalis; ivabradine can be used in patients with concomitant tachyarrhythmias due to its negative chronotropic effect without affecting inotropism or blood pressure; in contrast, ranolazine doesn't affect chronotropism and can be used in patients with bradyarrhythmias, however, it might cause prolongation of the QTc interval. The choice of treatment with either of the first line or second line antianginal agents must be individualized for each patient and based on comorbidities, contraindications and patient's preference. MÉD.UIS. 2016;29(3):79-93.

A Systematic Review on Drug Safety for Molsidomine, Nicorandil and Trimetazidine

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.

Potassium Channelopathies and Gastrointestinal Ulceration

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.

Potassium Channelopathies and Gastrointestinal Ulceration

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.

Intractable hyperkalemia due to nicorandil induced potassium channel syndrome.

Nicorandil is a commonly used antianginal agent, which has both nitrate‑like and ATP‑sensitive potassium (KATP) channel activator properties. Activation of potassium channels by nicorandil causes expulsion of potassium ions into the extracellular space leading to membrane hyperpolarization, closure of voltage‑gated calcium channels and finally vasodilatation. However, on the other hand, being an activator of KATP channel, it can expel K+ ions out of the cells and can cause hyperkalemia. Here, we report a case of nicorandil induced hyperkalemia unresponsive to medical treatment in a patient with diabetic nephropathy.

Preventive Effect of Pretreatment with Intravenous Nicorandil on Contrast-Induced Nephropathy in Patients with Renal Dysfunction Undergoing Coronary Angiography (PRINCIPLE Study)

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 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.

No-Reflow Phenomenon During Treatment of Coronary In-Stent Restenosis With a Paclitaxel-Coated Balloon Catheter

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.

A Case of Successful Recovery from High Dose Intravenous Nicorandil Infusion in Refractory Coronary Vasospasm with Hemodynamic Collapse / 영남의대학술지

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.

The Clinical Effects and Radial Artery Vasodilation After High Dose Nicorandil Solution During Coronary Angiography via the Radial Artery

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.

Effects of Propofol on Arginine Vasopressin-induced Contraction in Isolated Human Gastroepiploic Artery / 대한마취과학회지

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.

The Effect of Intra-coronary Nicorandil Prior to Reperfusion in Acute ST Segment Elevation Myocardial Infarction

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.

Myocardial protective effects of nicorandil and verapamil during ischemia-reperfusion in an isolated perfused rat heart

BACKGROUND: To reduce or prevent myocardial injury during an ischemia-reperfusion episode, some pharmacological interventions, including administering nicorandil or verapamil, have becomepopular in clinical situations. Nicorandil is a N-(2-hydroxyethyl)- nicotinamide nitrate ester, and it's effective mainly by opening the K+ ATP channels in the mitochondrial membrane, and verapamil is useful for reducing the endothelial injury of coronary vessels during ischemia. In this study, we aimed to determine the cardioprotective effect when both drugs are used simultaneously. METHODS: Isolated rat hearts (the Langendorff perfusion model) were perfused with Krebs-Henseleit bicarbonate buffer. After 30 minutes of controlled perfusion, we added nicorandil or verapamil separately and both drugs were administered together in another group (the mixed group) and we then induced ischemia for 30 minutes. We measured the heart rate, the developed ventricularpressure and the dP/dT during the control period during drug infusion and during reperfusion at 15, 30, 45 and 60 minutes. RESULTS: During reperfusion, the mixed group showed more favorable results for the developed left ventricular pressure (LVP), the dP/dT and the rate pressure product (RPP). The heart rate was significantly decreased as reperfusion processed in all the groups. CONCLUSIONS: For myocardial protection during ischemia-reperfusion, a mixed drug regimen is more beneficial than a single drug regimen, and this occurs without inducing a significant decrease of the heart rate.

Prevention of no flow/slow reflow phenomenon in primary PCI by Nicorandil.

AIM: To investigate the efficacy of Nicorandil in preventing no-flow/slow reflow phenomenon in patients with acute myocardial infarction undergoing primary PCI. MATERIALS AND METHODS: From September 2004 to October 2005, 29 patients underwent a primary percutaneous coronary intervention and stenting with nicor-andil as a protocol drug at a dose of 1 mg/hour - this drug was titrated upwards to maximum tolerated dose, with a 2 mg intracoronary bolus given after balloon inflation during PCI. LAD was the infarct related artery in 62% of cases. 72.4% of them had a TIMI thrombus grade of 5. The corrected TIMI frame count following primary percutaneous intervention in the Nicorandil arm was 19.54 + 8.7. None of the patients had a no flow or slow reflow phenomenon with this protocol. One patient developed a subacute stent thrombosis necessitating a revascularization. At a mean follow up of 251 +/- 96.7% days, MACE was not reported in the other patients. Thirty four patients underwent a primary percutaneous coronary intervention and stenting without nicorandil as an adjuvant drug. Some of these patients were retrospectively assessed. They have been followed up for 285.4 +/- 264.6 days. LAD was the infarct related artery in 61.8% of cases while 79.5% of them had a TIMI thrombus grade of 5. The corrected TIMI frame count in this group was 23.9 +/- 17.5 (p <0.56). MACE was reported in 5 of these patients. The mean TIMI frame count for these 5 patients was 40.5 +/- 29.2. Glycoprotein IIb/IIIa receptor inhibitors were given to all patients in both groups. The choice of the agent used was left to the discretion of the operator. CONCLUSION: Nicorandil prevents no-flow/slow reflow phenomenon in patients undergoing primary PCI for acute myocardial infarction. This is shown by a lower corrected TIMI frame count in the nicorandil arm (p < 0.56). Reduction in the incidence of no-flow/slow reflow phenomenon translates into a lower MACE. The drug is safe and does not require intensive monitoring. It must be started early and electively in patients undergoing a primary PCI as a strategy to prevent no-flow rather than to treat this phenomenon.

Curso de Atualização em Cardiologia: aula 2: Angina estável crônica / Actualization in Cargiology: class 2: stable chronic angina

A doença cardiovascular ainda é altamente prevalente no mundo inteiro, e a angina estável é uma de suas apresentações mais comuns. Três controvérsias principais são o manejo dos fatores de risco, o tratamento clínico e a intervenção. Com relação ao tratamento clínico, alé, de aspirina, inibidores da enzina conversora da angiotensina e betabloqueadores. A intervenção coronária percutânea alivia os sintomas sem prolongar a sobrevida além do tratamento clínico. Porém, dados de mortalidade favorecem a cirurgia de revascularização miocárdica em indivíduos com doença bivascular ou trivascular. Novas opções de tratamento sob investigação incluem drogas antianginosas, assim como a terapia celular. Assim, a angina de esforço precisa de uma ampla avaliação, mudanças no estilo de vida e tratamento individualizado para cada paciente.

Influence of Nicorandil on Catecholamine Release in the Perfused Rat Adrenal Medulla

The present study was attempted to investigate the effect of nicorandil, which is an ATP-sensitive potassium (KATP) channel opener, on secretion of catecholamines (CA) evoked by cholinergic stimulation and membrane depolarization from the isolated perfused rat adrenal glands. The perfusion of nicorandil (0.3~3.0 mM) into an adrenal vein for 90 min produced relatively dose-and time-dependent inhibition in CA secretion evoked by ACh (5.32 mM), high K+ (a direct membrane depolarizer, 56 mM), DMPP (a selective neuronal nicotinic receptor agonist, 100micrometer for 2 min), McN-A-343 (a selective muscarinic M1 receptor agonist, 100micrometer for 4 min), Bay-K-8644 (an activator of L-type dihydropyridine Ca2+ channels, 10micrometer for 4 min) and cyclopiazonic acid (an activator of cytoplasmic Ca2+-ATPase, 10micrometer for 4 min). In adrenal glands simultaneously preloaded with nicorandil (1.0 mM) and glibenclamide (a nonspecific KATP-channel blocker, 1.0 mM), the CA secretory responses evoked by ACh, high potassium, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid were recovered to the considerable extent of the control release in comparison with that of nicorandil-treatment only. Taken together, the present study demonstrates that nicorandil inhibits the adrenal CA secretion in response to stimulation of cholinergic (both nicotinic and muscarinic) receptors as well as by membrane depolarization from the isolated perfused rat adrenal glands. It seems that this inhibitory effect of nicorandil may be mediated by inhibiting both Ca2+ influx and the Ca2+ release from intracellular store through activation of KATP channels in the rat adrenomedullary chromaffin cells. These results suggest that nicorandil-sensitive KATP channels may play an inhibitory role in the regulation of the rat adrenomedullary CA secretion.

Effect of temperature on the activation of myocardial KATP channel in guinea pig ventricular myocytes: a pilot study by whole cell patch clamp recording / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The myocardial ATP sensitive potassium channel (K(ATP) channel) has been known for more than two decades, the properties of this channel have been intensively investigated, especially the myocardial protection effect by opening this channel. Numerous studies, including hypothermic, using K(ATP) agonists to achieve a hyperpolarizing cardioplegic arrest, have shown a better myocardial protection than potassium arrest. However, there is no evidence showing that K(ATP) channel could be opened by its agonists under profound hypothermia. We investigated the effect of temperature on activation of myocardial K(ATP) channel by nicorandil.</p><p><b>METHODS</b>Isolated ventricular myocytes were obtained by collagenase digestion of the hearts of guinea pigs and stored in KB solution at 4 degrees C. With a steady ground current, the myocytes were perfused with 1 mmol/L nicorandil until a steady IK(ATP) occurred. Then the cells were perfused with 1 mmol/L nicorandil plus 1 micromol/L glybenclamide. Currents signals were recorded on whole cells using patch clamp technique at several temperatures. The temperature of the bath solution around myocytes was monitored and was controlled at 4 degrees C, 10 degrees C, 20 degrees C, 25 degrees C and 35 degrees C respectively. About 10 cells were tested at each temperature, the cells were considered useful only when the outward current could be induced by nicorandil and blocked by glybenclamide. All data were analyzed using Graphpad PRISM 3.0 (Graphpad, San Diego, CA, USA). Nonlinear curve fitting was done in Clampfit (Axon) or Sigmaplot (SPSS).</p><p><b>RESULTS</b>At 4 degrees C, 10 degrees C, 20 degrees C, 25 degrees C and 35 degrees C, the time needed to open the myocardial K(ATP) channel was (81.0 +/- 0) minutes, (50.5 +/- 11.7) minutes, (28.8 +/- 2.3) minutes, (9.4 +/- 10.2) minutes and (2.3 +/- 1.0) minutes respectively (P = 0.003). The linear relationship between temperature and time needed to open the channel was y (min) = (4348.790 - 124.277x)/60, where y (min) is time needed to open K(ATP) channel, x is temperature, correlation coefficient r = -0.942 (P = 0.00), regression coefficient b = -124.277 (P = 0.00). The current densities among different temperatures were statistically different (P = 0.022), the current density was greater after the activation of K(ATP) channel at higher temperatures. The lower the temperature, the fewer cells in which K(ATP) channels could be opened. At 4 degrees C, only one cell in which the K(ATP) channel could be opened, took a quite long time (81 minutes) and the I-V curve was quite untypical.</p><p><b>CONCLUSIONS</b>K(ATP) channel activated by nicorandil is temperature dependent and the temperature linearly related to time needed to open K(ATP) channel; the lower the temperature, the longer the time needed to open channel and the smaller the current density. At profound hypothermia, it is difficult to activate K(ATP) channels.</p>

Comparison of the Effects of Nicorandil and Cocktail Solution to Prevent Radial Artery Spasm during Coronary Angiography

BACKGROUND AND OBJECTIVES: A radial artery spasm is one of the most common complications of coronary angiography during a transradial, causing considerable patient discomfort, which sometimes disturbs the procedure. This study was designed to evaluate the effects of nicorandil in the prevention of a radial artery spasm during coronary angiography. SUBJECTS AND METHODS: This was a randomized study to compare 4 mg of nicorandil and a 10 mL cocktail solution performed in 100 patients. Vasospasms of the radial artery, which were expressed as stenosis of the vessel diameter with a transradial approach and radial artery patency by pulse oximetry analysis one month later, were examined. RESULTS: Reductions in the systolic and diastolic blood pressures after administration of the spasmolytic agents were 15.8+/-11.8/ 8.4+/-8.0 and 20.5+/-13.6/6.7+/-6.2 in the for nicorandil and cocktail groups, respectively. Nicorandil induced a lesser decrease in the systolic BP than the cocktail, but without statistical significance (p=0.07). Both vasodilating agents showed a significant radial artery vasodilation following their intra-arterial administration (p<0.001 for all). The diameter of the radial artery showed a significant decrease in both groups following catheterization (p<0.05 for all). There were no significant differences between the two groups in terms of radial artery spasms (46 vs. 58% in nicorandil and cocktail groups, respectively, p=0.709). CONCLUSION: Nicorandil, with vasodilatory effects due to a dual mechanism was as effective as the cocktail solution in the vasodilation of the radial artery.

The Effect of Nicorandil on the Pharmacodynamics of Rocuronium / 대한마취과학회지

BACKGROUND: Some investigators have shown that nicorandil, a K(ATP) channel opener, depresses the neuromuscular transmission contraction of the skeletal muscle. However, others have reported that it improves the recovery of vecuronium relaxation and the myotonic activity of muscle. This study investigated the effect of nicorandil on rocuronium relaxation. METHODS: Hemidiaphragm-phrenic nerve preparations were obtained from male Sprague-Dawley rats (150-250 g). The preparations were bathed in Krebs' solution containing in (mM): NaCl 118, KCl 5, CaCl2 2.5, NaHCO3 30, KH2PO4 1, MgCl2 1 and glucose 11. The preparations were, then maintained at 32 degrees C and aerated with a mixture of 95% O2 and 5% CO2. Isometric forces that were generated in response to 0.1 Hz, and, 50 Hz for 1.9 seconds with supramaximal electrical stimulation (0.2 msec, rectangular) to the phrenic nerve were measured using a force transducer. The single twitch tension (ST) and peak tetanic tension (PTT) were calculated as % inhibition of the control, and the tetanic fade (TF), as % increase in the PTT. Each preparation was exposed to one of the 6 nicorandil concentrations (0.0, 0.625, 1.25, 2.5, 5, 10 micrometer), and the adequate volume of the rocuronium solution was cumulatively added to the tissue bath for a desired rocuronium concentration until there was an 80-90% decrease in the ST. The effect of rocuronium at each concentration was allowed to reach a steady state before the tension parameters were measured. The EC5, EC25, EC50, EC75, and EC95 of rocuronium for the ST, PTT and TF were calculated using a probit model. The differences between the EC50 of rocuronium according to the nicorandil concentrations were tested using a t-test and a Bonferroni's correction. RESULTS: 1.25 and 2.5 micrometer nicorandil shifted the cumulative concentration-response curves for the TF of rocuronium to the right. 5 and 10 micrometer nicorandil shifted the cumulative concentration-response curves for the ST of rocuronium to the left. CONCLUSIONS: Lower concentration of nicorandil may help maintain the tetanic contraction during rocuronium relaxation.

Acute hemodynamic effects of nicorandil in patients with primary pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension is managed with vasodilators, and till date no specific drug has been identified with sufficient degree of success. Potassium channels have been implicated in the pathogenesis of primary pulmonary arterial hypertension. We undertook this study to assess the acute effect of oral nicorandil in patients of pulmonary arterial hypertension. METHODS AND RESULTS: We studied acute hemodymanic response of 40 mg oral nicorandil in 10 patients with primary pulmonary arterial hypertension aged between 15 and 39 years (mean age 27.2 +/- 6.7 years). Responders (Group I) were defined as those with > or =20% reduction of pulmonary vascular resistance index and no change or increase in cardiac index; and non-responders (Group II) were those with < 20% reduction of pulmonary vascular resistance index. There were 7 responders (pulmonary vascular resistance index decreased from 22.8 +/- 9.3 to 17.9 +/- 6.5 Wood units) and 2 non-responders (pulmonary vascular resistance index decreased from 26 +/- 3.5 to 25 +/- 1.0 Wood units). The maximum reduction in pulmonary vascular resistance index from baseline was 29.77 +/- 6.53% (23.7-40.5%) in responders and 7.3 +/- 4.2% (4.3-10.3%) in non-responders. The study was halted prematurely in one patient who developed hypotension, requiring intravenous inotropes. CONCLUSIONS: Our results suggest that nicorandil significantly decreases pulmonary artery pressure in primary pulmonary arterial hypertension acutely and can be cautiously tried for the therapeutic use in primary pulmonary arterial hypertension. Further studies are warranted.