Dose Of Nicorandil Research Articles

Dose-dependent prophylactic effect of nicorandil, an ATP-sensitive potassium channel opener, on intra-operative myocardial ischaemia in patients undergoing major abdominal surgery

Nicorandil, a nicotinamide nitrate derivative, relaxes vascular smooth muscle and reduces cardiac muscle contractility by increasing membrane potassium conductance, probably by activating ATP-sensitive potassium channels. In this prospective, randomized, double-blind, placebo-controlled clinical study, we examined the dose-dependent prophylactic effect of nicorandil on intra-operative myocardial ischaemia in 248 patients who had pre-operative risk factors for ischaemic heart disease and were undergoing major abdominal surgery. Patients in group HD (n=81) received a bolus dose of nicorandil 0.08 mg kg(-1) and a continuous infusion of 0.08 mg kg(-1) h(-1). Patients in group LD (n=87) received nicorandil 0.04 mg kg(-1) and 0.04 mg kg(-1) h(-1). Patients in the placebo (P) group (n=80) received the same volumes of saline. The patients were monitored with a three-lead clinical ECG monitor with an ST trending device from arrival in the operating theatre to the end of anaesthesia. Intra-operative myocardial ischaemia occurred significantly less frequently in the HD group (one patient, 1.2%) than in the LD (11 patients, 12.6%) and P groups (21 patients, 26.3%) (P<0.01), and in group LD significantly less than in group P (P<0.05). Administration of nicorandil had little effect on the patients' heart rate or arterial pressure. Three patients in group P and none in either treatment group developed myocardial infarction after surgery.

Mechanisms of the effects of nicorandil in the isolated rat heart during ischemia and reperfusion: a 31P-nuclear magnetic resonance study.

Nicorandil (SG75) is a potent K+-channel activator with an additional nitro moiety. In the present study we investigated the potential mechanisms (K+-channel activation and nitric oxide [NO] release) for the effects of nicorandil on isolated perfused rat hearts during total global ischemia using 31P-nuclear magnetic resonance. After a 10-min control perfusion, hearts were subjected to treatment with nicorandil-containing (100, 300, or 1000 microM) buffer for 10 min, 15 min of total global ischemia, and 30 min of reperfusion. At high dose (10(-3) M), nicorandil reduced ATP depletion during ischemia by 26% compared with untreated hearts. Blockade of K+ channels by glibenclamide prevented this protective effect. At all doses (10(-4) to 10(-3) M), nicorandil reduced the accumulation of protons during ischemia compared with untreated hearts (pH 6.22 +/- 0.03 vs. 6.02 +/- 0.05 in untreated hearts at the end of ischemia). This effect was preserved after blockade of K+ channels by glibenclamide. Hearts treated with nitroglycerine before ischemia also showed reduced proton accumulation. Therefore, NO release accompanied by increased coronary flow before ischemia, which is caused by the nitro moiety of nicorandil and nitroglycerine treatment, results in reduced proton accumulation. During reperfusion, a pro-arrhythmic effect was observed in hearts treated with the nonpharmacologically high dose of nicorandil (1000 microM). Thus, we conclude that the effects of nicorandil are caused by the simultaneous action of both mechanisms K+-channel activation and NO release. The activation of K+ channels prevents deterioration of ATP during ischemia, whereas NO release and increased coronary flow reduce the accumulation of protons--and thus the decrease in pH--during ischemia.

Adenosine triphosphate-sensitive potassium channels are involved in insulin-mediated glucose transport in humans

We investigated the influence of treatment with nicorandil, a K-channel opener currently used for angina, on glucose homeostasis in patients with non-insulin-dependent diabetes mellitus (NIDDM) and coronary artery disease (CAD). Adenosine triphosphate (ATP)-sensitive K (K-ATP) channels are present in various tissues, including pancreatic B cells and skeletal muscle, and are the putative targets of this agent. Nine NIDDM patients with CAD and five healthy subjects participated in the study. Fasting plasma levels (mean ± SEM) of glucose (144 ± 11 to 180 ± 22 mg/dL, P < .05) and insulin (5.8 ± 1.6 to 7.0 ± 1.8 μU/mL, P < .05) and hemoglobin A 1c (7.54 ± 0.47 to 8.11 ± 0.55, P < .01) increased significantly in nine NIDDM patients after treatment with nicorandil at a dose of 5 mg three times daily for 2 to 8 months. Glucose tolerance as examined by an identical meal test deteriorated ( P < .001), but the insulin response did not change significantly. A washout of nicorandil for 1 to 4 months restored glucose tolerance almost to pretreatment levels in four patients. A 5- to 7-day trial of nicorandil (5 mg three times daily) in five healthy subjects resulted in a marginal to twofold increase in fasting plasma insulin, reflecting the progression of insulin resistance. In addition, three healthy subjects showed a substantial reduction in the glucose infusion rate (GIR) required in the euglycemic-hyperinsulinemic clamp study. Since the therapeutic dose of nicorandil did not affect pancreatic B-cell function but caused insulin resistance in both healthy and NIDDM subjects, we conclude that K-ATP channels play a regulatory role in insulin-mediated glucose transport in humans.

Enhancement of the vasorelaxant potency of nicorandil by metabolic inhibition and adenosine in the pig coronary artery.

Nicorandil is used clinically to treat angina and acts in part by opening ATP-sensitive K+ channels whose opening is also enhanced by metabolic compromise. We have therefore investigated whether treatments that mimic conditions in ischaemia can increase the potency of nicorandil to dilate coronary arteries. Ring segments from pig small coronary arteries were mounted on a myograph, contracted with 20 mM K+ Krebs solution containing 200 nM BAYK 6844, and relaxations to cumulative doses of nicorandil were measured. Nicorandil produced a dose-dependent relaxation with a mean pEC50 (-log EC50, M) of 4.76 +/- 0.02. Inhibition of metabolism with carbonyl cyanide m-chlorophenyl hydrazone (CCCP, 100 nM) or by removal of extracellular glucose significantly increased the potency of nicorandil (pEC50s of 5.11 +/- 0.08 and 5.08 +/- 0.06, p < 0.05 in each case). The adenosine analogue 2-chloroadenosine (2-CA, 300 nM) had a similar effect (pEC50 = 5.17 +/- 0.06, p < 0.05). Reducing extracellular pH to 6.8 also significantly increased the potency of nicorandil, but to a smaller extent. Glibenclamide reduced the potency of nicorandil (pEC50 = 3.81 +/- 0.01, n = 7), and abolished its enhancement by CCCP, zero glucose, 2-CA or pH 6.8 solution. 2-CA did not affect the potency of nicorandil in relaxing contractions to 80 mM K+ or the potency of glyceryl trinitrate. We conclude that the potency of nicorandil to cause coronary vasorelaxation is increased under conditions of metabolic inhibition. This effect appears to result from the K+ channel opening action of the drug, and may have significant consequences for its therapeutic effectiveness.

Effects of chronic oral administration of a high dose of nicorandil on in vitro contractility of rat arterial smooth muscle

Nicorandil, which is structurally a nitrate and also a nicotinamide, has a vasodilator action by stimulating guanylate cyclase and ATP-sensitive K + channel. The aim of present study was to examine the effects of chronic oral administration of a high dose of nicorandil on in vitro vascular reactivity. Nicorandil (30 mg/kg), at a dose 6–10-times higher than to decrease blood pressure in rat, was orally administered 2-times daily for 2–4 weeks to the rats. At the end of the administration period, thoracic aorta was isolated for in vitro study. Treatment with nicorandil for 4 weeks markedly reduced the relaxant effect of nicorandil itself and other vasodilators including sodium nitroprusside, nitric oxide, endothelium-derived relaxing factor released by carbachol, 8-Br-cyclic guanosine 3′,5′-monophosphate (cGMP), a K + channel opener, levcromakalim, and forskolin. Increase in cGMP content induced by nicorandil and sodium nitroprusside was less in the aorta from nicorandil-treated rat than in the vehicle-control rat. Chronic administration of nicorandil altered neither the contractile responses to norepinephrine nor the vasodilator effect of verapamil. On the other hand, a 4-week treatment with a dose of nicorandil (2 mg/kg) sufficient to decrease blood pressure in rat showed no change in aortic response. These results suggest that in vivo chronic treatment with a high dose of nicorandil inactivates not only the guanylate cyclase activity but also the mechanism mediated by cGMP; it also attenuates the sensitivity of K + channels to levcromakalim. Prolonged activation of the specific site may desensitize its site of action.

Reply Mechanisms of action of various ATP-sensitive potassium channel openers

Dr. Grover’s very kind and complimentary remarks about the recent review [l] on ATP-sensitive potassium channel openers during ischemia and reperfusion are much appreciated. One point, however, causes Dr. Grover considerable concern-this is the citation of (and by implication a presumed agreement with) the comments in the paper by Richer et al. [2]. This paper was critical of the conclusions of a study [3] by Dr. Grover and colleagues in which the authors compared intravenous versus intracoronary administration of nicorandil versus cromakalim. This reply to Dr. Grover is from the author of the review [ 1 ] and the senior co-author of the contentious paper [2]. Dr. Grover states that “Professor Hearse criticised this study based on the lOO-fold lower dose of nicorandil given into the coronary”. Dr. Grover then goes on to justify the choice of this dose on the basis of the fact that the coronary bed supplies a very small mass of tissue and therefore a much lower absolute dose is required than with intravenous administration. We filly accept this and indeed, neither the review El] nor the Richer article [2] took specific issue with this aspect of Dr. Grover’s protocol design. The criticism that was intended related not to the choice of dose between intravenous and intracoronary studies but to the fact that Grover et al. [3] used a dose of nicorandil that was only 3 times higher than that selected for cromakalim. What Professor Hearse actually stated in his concluding synopsis of the Richer paper was that “they argued that, since nicorandil was ten times less potent than cromakalim, any study designed to compare the two drugs and the two routes of administration should have employed a larger dose of nicorandil.” The choice of intravenous versus intracoronary dose was not actually contested by the author of the review. The point at issue (which has been made on a previous occasion [4] by the co-signatory of this letter) is quite straight forward: namely, that because nicorandil is at least 10 times less potent than

P-1030 - Effects of chronic oral administration of high dose of nicorandil on in vitro contractility of rat aorta.

P-1030 - Effects of chronic oral administration of high dose of nicorandil on in vitro contractility of rat aorta.

Effects of nicorandil and glyceryl trinitrate on infarct size, adenosine release, and neutrophil infiltration in the dog

The major aim of this study was to determine if nicorandil, a potassium channel opener nitrate, produces a reduction in myocardial infarct size at a non-hypotensive dose in dogs and to determine if this effect is the result of an increase in adenosine release or reduction in neutrophil infiltration into the ischaemic area. Glyceryl trinitrate was used for purposes of comparison. Barbitone anaesthetised dogs were subjected to 60 min of left anterior descending coronary artery occlusion followed by 3 h of reperfusion. Nicorandil (100 microgram.kg-1 bolus followed by a 10 microgram.kg-1.min-1 infusion; NC/pre group), glyceryl trinitrate (10 microgram.kg-1 bolus followed by a 1 microgram.kg-1.min-1 infusion; GTN/pre group), or an equivalent volume of saline (control group) were given intravenously 15 min before occlusion and continued to the time of reperfusion. In two other groups, nicorandil (NC/post group) or glyceryl trinitrate (GTN/post group) were given 10 min before reperfusion and continued until the end of the experiment. To measure the release of adenosine from the ischaemic region, coronary venous blood samples were collected before occlusion, during occlusion, and at various times following reperfusion. Myocardial infarct size was determined by triphenyltetrazolium chloride and transmural myocardial blood flow by radioactive microspheres. Transmural myeloperoxidase activity, an index of neutrophil infiltration, was measured in biopsies obtained from the area at risk. Pretreatment with nicorandil and glyceryl trinitrate caused a marked reduction in myocardial infarct size expressed as percent of the area at risk [NC/pre group, 7.8(SEM 1.6)%; GTN/pre group, 11.9(2.3)%; control group, 31.0(5.6)%]. When nicorandil and glyceryl trinitrate were given before reperfusion, both drugs still produced a significant reduction in infarct size [NC/post group, 13.8(2.0)%; GTN/post group, 18.9(4.3)%]. Coronary venous adenosine concentrations during reperfusion were significantly lower in both nicorandil and glyceryl trinitrate pretreated groups, but not in the post-treated groups. Transmural myeloperoxidase activity was significantly lower in both nicorandil treated groups. Pretreatment with a non-hypotensive dose of nicorandil or glyceryl trinitrate markedly reduces myocardial infarct size and adenosine release from the ischaemic-reperfused area. These agents were also effective, but to a lesser degree, when given just before reperfusion. The cardioprotective actions of nicorandil appear to be related not only to its potassium channel opening activity but also in part to its nitrate activity.

Coronary microvascular response to intracoronary administration of nicorandil

Nicorandil is an antianginal drug that causes potent coronary vasodilation of both epicardial and resistance vessels. To measure the dose-response kinetics of bolus injections of intracoronary nicorandil and to compare the vasodilatory response to nicorandil with that of intracoronary papaverine in humans, coronary blood flow velocity was measured in 30 patients using a 3Fr intravascular Doppler catheter. Continuous intravenous nitroglycerin 6 to 8 μg/min was infused to achieve maximal vasodilation of the epicardial vessels. Bolus doses of nicorandil dissolved in warmed saline solution were injected into the left (0.1, 0.2, 0.5, 1.0, 1.5, and 2.0 mg) and right (0.1, 0.2, 0.4, 0.8, 1.0, and 1.5 mg) coronary arteries. Intracoronary nicorandil caused a dose-dependent increase in coronary flow velocity and a decrease in coronary vascular resistance. Maximal vasodilatory effects equivalent to those obtained with 12 ± 2 mg of intracoronary papaverine were induced with nicorandil 1.5 mg in the left coronary artery, and effects similar to those of 10 ± 2 mg of papaverine were produced with nicorandil 1.0 mg in the right coronary artery. The time from injection of nicorandil to the onset of maximal hyperemia and duration of hyperemia were significantly shorter after nicorandil than after papaverine in both coronary arteries. Each dose of nicorandil produced no clinical symptoms and fewer changes in systemic hemodynamics and electrocardiographic QT intervals than did papaverine. These results suggest that a bolus administration of intracoronary nicorandil can safely, quickly, and reliably induce maximal coronary hyperemia comparable to that achieved with intracoronary papaverine in humans.

EFFECT OF NICORANDIL ON POST‐ISCHAEMIC CONTRACTILE DYSFUNCTION IN THE HEART: ROLES OF ITS ATP‐SENSITIVE K’ CHANNEL OPENING PROPERTY AND NITRATE PROPERTY

1. This study aimed to characterize the effect of nicorandil (NC) on myocardial stunning and the role of ATP-sensitive K+ (KATP) channel opening property in its cardioprotective action. 2. In open-chest anaesthetized rabbits, myocardial stunning was induced by 10 min of coronary occlusion followed by 30 min of reperfusion. As an index of regional contractile function, systolic thickening fraction (TF) was measured by an epicardial Doppler sensor. The doses of NC (10 micrograms/kg per min) and nitroglycerin (TNG) (1 micrograms/kg per min) were selected not to lower the systemic blood pressure significantly. 3. In the untreated controls, TF at 30 min after reperfusion was 46.4 +/- 2.9% of the baseline value, indicating myocardial stunning. Both NC and TNG significantly improved post-ischaemic recovery of TF when administered during the pre-ischaemic and post-ischaemic periods (TF = 68.2 +/- 6.4%, 64.7 +/- 2.3%, respectively). However, when their infusion was restricted to a pre-ischaemic 10 min period, TF recovery was improved by NC, but not by TNG (63.4 +/- 7.9%, 40.9 +/- 6.2%, respectively). 4. Pretreatment with glibenclamide (GL; 0.3 mg/kg) did not influence the recovery of TF after the 10 min ischaemia (TF = 52.4 +/- 3.9% at 30 min after reperfusion). However, after the GL injection, a cardioprotective effect from nicorandil pretreatment was not detected (TF = 51.3 +/- 1.7%). 5. These results suggest that nicorandil protects the myocardium against stunning by opening the KATP channel when it is given before ischaemia, and that the nitrate property of nicorandil may also play a role during the reperfusion period in attenuation of post-ischaemic contractile dysfunction.

Protection by nicorandil against the dysfunction of the central vagal baroreflex system following transient global cerebral ischaemia in dogs

1. A possible cerebroprotective effect of nicorandil was investigated in a canine model of 5 min global cerebral ischaemia, and compared with protective effects of nitroglycerin and nicardipine. 2. Cerebral ischaemia was produced by occlusion of the left subclavian and the brachiocephalic arteries with preceding ligation of the intercostal arteries. The decrease in baroreflex sensitivity (BRS), measured by phenylephrine-induced reflex bradycardia, was used to assess the cerebroprotective effect. 3. Nicorandil (10 or 30 micrograms kg-1 min-1, i.v.), nitroglycerin (3 micrograms kg-1 min-1, i.v.) or nicardipine (0.3 micrograms kg-1 min-1, i.v.) were infused for 60 min just before ischaemia. Nitroglycerin and nicardipine decreased mean arterial blood pressure to an extent similar to that induced by the lower dose of nicorandil. Blood flow in the dorsal medulla oblongata was increased by nicorandil and nicardipine, but not by nitroglycerin. 4. Nicorandil at both doses and nitroglycerin prevented the post-ischaemic decrease in BRS. In these cases, bilateral vagotomy during the reperfusion period decreased BRS, indicating that the vagal component of BRS was protected from ischaemia. On the other hand, nicardipine failed to exert a cerebroprotective effect. 5. The present study suggests that nicorandil may possess a direct cerebroprotective effect and that its property as a nitrate might, at least in part, be important for the observed cerebral protection.

Effects of KRN2391, nicorandil and diltiazem on the changes in the electrocardiogram caused by endothelin‐1 in anaesthetized rats

1. The effect of KRN2391, a novel vasodilator, on the changes of electrocardiogram caused by endothelin-1 (ET-1) was studied in anaesthetized rats and compared with the effects of nicorandil and diltiazem. In addition, the effect of KRN2391 on the action potential of guinea-pig papillary muscle was studied. 2. The intracoronary administration (i.c.) of ET-1 (5 micrograms) induced not only ST segment elevation of the electrocardiogram due to contraction of the coronary artery, but also arrhythmias involving atrioventricular block (A-V block), ventricular premature contraction (VPC) and ventricular fibrillation (VF), and resulted in death in most animals. However, the administration of methacholine (3 micrograms, i.c.) produced ST segment elevation alone without developing arrhythmias. 3. Pretreatment with intravenous administration of KRN2391 (30 micrograms kg-1) inhibited the ST segment elevation and the development of arrhythmias induced by ET-1, and decreased the incidence of death. 4. Nicorandil (1000 micrograms kg-1) prevented the ST segment elevation without suppression of the occurrence of VF. Diltiazem (100 micrograms kg-1) suppressed both the ST segment elevation and the occurrence of VF but not other arrhythmias. Nicorandil at 3000 micrograms kg-1 and diltiazem at 300 micrograms kg-1 produced not only a suppression of ST segment elevation and VF incidence but also a decrease in the occurrence of arrhythmias. These doses of nicorandil and diltiazem produced a decrease in death in a dose-dependent manner. 5. KRN2391 (10 and 30 micrograms kg-1), nicorandil (1000 and 3000 micrograms kg-1) and diltiazem (100 and 300 micrograms kg-1) significantly decreased mean blood pressure in a dose-dependent manner. Heart rate was decreased by nicorandil (3000 microg kg-1) and diltiazem (100 and 300 microg kg-1) but was not affected byKRN2391 (10 and 30 microg kg-1).6. KRN2391 (30 microM) significantly shortened the action potential duration of guinea-pig ventricle at 50% and 90% repolarization (APD50 and APD90). The effect of KRN2391 was inhibited by a K+channel blocker, glibenclamide (30 microM).7. These results suggest that the occurrence of ST segment elevation and arrhythmias induced by ET-1 are due to a dual direct action on both coronary vascular smooth muscle and myocardium. Therefore,the protective effects of KRN2391, nicorandil and diltiazem on ET-l-induced heart disorders appear to be due to their direct actions on coronary vascular smooth muscle and the myocardium.

Venodilatory effects of nicorandil in healthy volunteers.

The effects of a single dose of nicorandil (40 mg orally) on human dorsal hand veins in vivo were assessed and compared with the effect of nitroglycerin (0.8 mg sublingually). The hand veins had been preconstricted with norepinephrine to approximately one-third of their initial size. We demonstrated that a venous relaxation occurred after administration of nicorandil and nitroglycerin. In the doses studied, the effect was more pronounced and lasted longer after nicorandil. The pharmacodynamic effects of nicorandil in humans may be explained in part by this venous relaxation.

Usefulness of nicorandil in congestive heart failure

Rest and exercise hemodynamic and hormonal effects of nicorandil, a nicotinamide-nitrate vasodilator, were assessed in 9 patients with New York Heart Association class II or III congestive heart failure (CHF) and left ventricular ejection fraction ≤40%. Single oral doses of placebo and 40 and 60 mg of nicorandil were given in a double-blind, randomized trial. Hemodynamic measurements were assessed at rest, up to 8 hours after dose and at peak exercise performed on an upright cycloergometer 1 hour after the dose. Forearm blood flow and venous capacitance were measured by plethysmography 45 minutes after dose. Plasma noradrenaline and plasma renin activity were assessed 1 hour and 2 hours after dose, respectively. Data were analyzed by analysis of variance. Peak effects were observed between 30 and 60 minutes after dose. Mean blood pressure decreased from 86 ± 7 mm Hg after placebo to 78 ± 7 mm Hg after 40 mg (p < 0.05) and to 78 ± 7 mm Hg after 60 mg (p < 0.05) of nicorandil. Mean pulmonary artery pressure decreased from 24 ± 11 to 15 ± 17 mm Hg (p < 0.05) and to 17 ± 7 mm Hg (p < 0.05) and mean pulmonary wedge pressure decreased from 15 ± 8 to 9 ± 4 mm Hg (p < 0.05) and to 10 ± 5 min Hg (p < 0.05). The changes were significant up to 6 to 8 hours after both doses. Cardiac output increased 2 hours after dose from 4.6 ± 0.7 liters/ mm after placebo to 5.5 ± 0.8 liters/min after 60 mg (p < 0.05). At peak exercise mean pulmonary wedge pressure decreased from 29 ± 8 mm Hg after placebo to 24 ± 7 mm Hg (p < 0.05) and to 27 ± 8 mm Hg (difference not significant) after 40 and 60 mg of nicorandil. Venous capacitance increased from 2.9 ± 1.4 ml after placebo to 3.4 ± 1.3 ml after 40 mg of nicorandil (p = 0.1). Cardiac output 1 hour after the meal was 5.7 ± 1 liters/min after placebo and increased to 6.3 ± 1.5 liters/min (p < 0.05) after 40 mg and to 6.2 ± 1 liters/min (p < 0.05) after 60 mg of nicorandil. Plasma renin activity increased from 18.6 ± 29.3 ng/ml/hour after placebo to 24.3 ± 31.1 (p < 0.05) and 22 ± 31.1 ng/ml/hour (p < 0.05) after 40 and 60 mg of nicorandil. Single oral doses of nicorandil in patients with CHF induce favorable changes on rest and exercise hemodynamics up to 6 to 8 hours. An increase of renin activity is also observed.

Hemodynamic action of nicorandil in chronic congestive heart failure

Nicorandil is a new compound that has shown potent vasodilator activities on venous and arterial beds in experimental pharmacology. This study was designed to evaluate the magnitude and the time course of hemodynamic effects of different doses of nicorandil in congestive heart failure. Eleven patients with severe congestive heart failure (New York Heart Association class III or IV), with a cardiac index < 3 liters/min/m 2 and a pulmonary wedge pressure >15 mm Hg were enrolled in the study. Three patients had ischemic dilated cardiomyopathy and 8 had idiopathic dilated cardiomyopathy. Hemodynamic assessments were performed by right-sided cardiac catheterization (Swan-Ganz catheter) with cardiac output determination (thermodilution) at baseline and from 30 mintues to 12 hours after single oral administration of nicorandil; 3 patients were given 40 mg, 6 patients 60 mg, and 2 patients 80 mg. Maximal hemodynamic changes were observed 30 minutes after dosing and remained statistically significant at 3 hours. Thirty minutes after drug administration, pulmonary wedge pressure decreased 34 ± 6%, cardiac index increased by 55 ± 13% and diastolic and mean arterial pressures decreased by 15 ± 3% and 9 ± 2%, respectively, from baseline values. The decrease in systolic blood pressure was slight (5 ± 2%) and not statistically significant. Calculated systemic vascular resistances decreased by 36 ± 6% and heart rate did not significantly change. Nicorandil was well tolerated. Thus, the results of this first study of nicorandil in congestive heart failure demonstrated the unloading action of this compound on the failing heart, leading to an improvement in cardiac function; further investigation of nicorandil in this therapeutic area is needed.

A controlled single-dose study of the efficacy, dose response and duration of action of nicorandil in angina pectoris

Nicorandil is a vasodilator that acts on the venous and arterial beds of the systemic circulation. It reduces both cardiac preload and afterload, as well as improving coronary blood flow. The present study assessed the efficacy, tolerability, duration of action and optimal single dose of nicorandil in patients with stable angina pectoris. Treadmill exercise tests were undertaken by 8 patients at 2 and 6 hours after single oral doses of 20, 40 and 60 mg of nicorandil, and placebo. Doses were administered at weekly intervals in this double-blind, crossover study. The duration of exercise to onset of angina was increased by 58, 96 and 125 seconds over baseline values (p < 0.01) with the 20-, 40-and 60-mg doses of nicorandil, respectively. Significant improvement in exercise capacity compared with the effects of placebo was maintained at 6 hours after administration. The antianginal activity was accompanied by a marked reduction in blood pressure both at rest and during exercise, which resulted in severe dizziness and fainting in 2 of 6 patients after the 60-mg dose. However, significant reflex tachycardia occurred only at 2 hours after the 60-mg dose. Plasma concentrations of nicorandil correlated with percent reductions in blood pressure at 2 hours after administration (p < 0.001) and with increasing total exercise work load (p < 0.01). The incidence of adverse events appeared to be dose related. Headache and dizziness accounted for most of the reported events. The 20-mg single dose of nicorandil was considered to provide the best combination of antianginal activity and tolerability in this study.

Exercise capacity after single and twice-daily doses of nicorandil in chronic stable angina pectoris

In a double-blind parallel group study, 46 patients with chronic stable angina were randomized, after a 2-week placebo washout period, to 1 of 3 treatment groups for an additional 2 weeks. Groups 1 and 2 received nicorandil (5 mg, n = 5; 10 mg, n = 10) twice daily, respectively, increasing to 10 and 20 mg (n = 20) twice daily after 1 week of treatment; group 3 continued to receive placebo. A symptom-limited Bruce protocol exercise test was performed before and 2 hours after the initial dose and, after 2 weeks of treatment, 2 and 12 hours after administration. The following parameters were measured: resting, peak exercise and recovery blood pressure and heart rate, exercise duration, time to onset of angina and time to 1 mm of ST-segment depression. After initial dosing, there were significant increases in exercise duration (16%—n = 5, n = 10 vs −2% [placebo]) and time to onset of angina (20%, n = 5; 26%, n = 10 vs 5% [placebo]) (p < 0.05). Time to onset of 1 mm of ST-segment depression increased in the nicorandil-treated groups compared with that in the placebo group (27%, n = 5; 25%, n = 10 vs 8% [placebo]). Calculated total exercise work increased in both nicorandil groups compared with exercise work in the placebo group (30%, n = 5; 19%, n = 10 vs 3% [placebo]). A decrease in resting systolic blood pressure (12%) in the 10-mg group was the only significant alteration in the hemodynamic parameters. After 2 weeks of treatment there was a significant increase in time to onset of angina both 2 hours (38%, n = 10; 32%, n = 20 vs −2%) and 12 hours (23%—n = 10, n = 20 vs −2% [placebo]) (p < 0.05) after dose administration in both nicorandil groups compared with placebo group. Exercise duration, time to 1 mm of ST-segment depression and total exercise work increased in the nicorandil groups but these did not reach statistical significance. There was no significant change in the hemodynamic parameters at rest, peak exercise or recovery. Thus, nicorandil, 10 or 20 mg, administered twice daily improves exercise capacity both acutely and after chronic administration without significant alteration in blood pressure or heart rate.

Assessment of the antiarrhythmic activity of nicorandil during myocardial ischemia and reperfusion

The potential pro- and antiarrhythmiceffects of nicorandil (1–100 μM) were assessed in isolated rat hearts subjected to coronary artery ligation and reperfusion under conditions of normal (5.9 mM) and lowered (3.2 mM) perfusate K +. Nicorandil dose dependently increased coronary flow, induced a moderate negative inotropic effect but had no chronotropic effects. During ligation (15 min), only high concentrations of nicorandil (50 and 100 μM) significantly reduced the incidence of ventricular premature beats and ventricular tachycardia in normal perfusate, but ventricular fibrillation was observed in 2 9 hearts. No antiarrhytmic effects were observed with hypokalemic conditions. During reperfusion, nicorandil was associated with a more rapid degeneration into ventricular fibrillation in normal perfusate while the incidence of ventricular fibrillation was only reduced by 100 μM nicorandil. No antiarrhythmic effects were observed during reperfusion with lowered K + and all drug-treated hearts demonstrated irreversible ventricular fibrillation. Nicorandil perfusion (50 μM; 5.9 mM K +) did not affect the depression of ATP or elevation of lactate within the ischemic tissue during coronary artery ligation. These data do not support an effect of nicorandil against ischemia- or reperfusion-induced arrhytmias in the intact heart in vitro and may suggest a proarrhythmic effect particularly at lowered K + concentrations.

Nicorandil, a new vasodilator drug, in patients with essential hypertension

In 12 mild to moderate hypertensive patients we investigated the acute antihypertensive efficacy of three different doses of nicorandil, a new vasodilating agent which probably acts by increasing the potassium efflux from smooth muscle cells and causing a cellular hyperpolarization. After a 3-day placebo period the patients were given, according to a double-blind Latin-square randomized design, 10, 20 and 30 mg nicorandil as a single acute dose every other day. Blood pressure and the heart rate were measured in both supine and upright positions at various times for 24 h after the dosing; fractional urine collections were obtained at the end of the placebo period and after each active dose. All doses of nicorandil similarly and significantly (P less than 0.01) reduced supine blood pressure, with a peak after 4-6 h (10 mg: -21/-8 mmHg; 20 mg: -20/-9 mmHg; 30 mg: -29/-17 mmHg), and the effect was still present, though reduced, after 24 h; no change in the heart rate was observed. The results from the upright position were similar. There were no significant changes in urine volume and electrolyte excretion during the nicorandil administration. The three different doses of nicorandil caused similar acute blood pressure reductions without change in the heart rate, nor in the urine volume and urinary sodium.

Coronary vasodilatory action after a single dose of nicorandil

Coronary hemodynamics and vasodilatory effects on major epicardial arteries were investigated after a single dose of nicorandil in 22 patients undergoing cardiac catheterization for suspected coronary artery disease. Nicorandil, 20 mg, was administered sublingually to 11 consecutive patients and 40 mg to 11 others. Systemic blood pressure decreased significantly without affecting the heart rate. Coronary sinus blood flow did not change significantly. As the mean aortic pressure decreased significantly by 13% after 20 mg and 21% after 40 mg of nicorandil, the calculated coronary vascular resistance decreased but did not reach statistical significance. There was a decrease in myocardial oxygen consumption (−14% and −22%, respectively), and this was consistent with a significant decrease in the calculated pressure-rate product of 19% and 24%, respectively. A total of 103 selected coronary segments, including 17 stenotic segments, were analyzed quantitatively using a computer-assisted coronary angiography analysis system. After 20 or 40 mg of nicorandil, a significant increase of the mean diameter was observed in the proximal (+9% and +7%), midportion (+10% and +11%) and distal (+15% and +13%) parts of the left anterior descending coronary artery. Corresponding values for the proximal (+13% and +10%) and distal (+10% and +15%) segments of the circumflex artery were observed. An increase in the obstruction diameter was also observed in all but 3 of the analyzed stenotic segments. The results demonstrate that nicorandil, in the route and doses used, causes a significant vasodilatation in the major epicardial coronary segments, including most stenotic segments, and decreases the myocardial oxygen demand with little effect on the resistance vessels.