BACKGROUND Acute heart failure syndrome (AHFS) remains a major clinical challenge because of its poor prognosis. Nicorandil, a hybrid compound of a potassium-channel opener and nitric oxide donor, has been reported to improve the prognosis of ischemic heart disease. We sought to evaluate the effect of intravenous nicorandil on the mid-term prognosis of AHFS. METHODS AND RESULTS A total of 402 consecutive patients who were hospitalized for AHFS were divided into 2 groups according to the use of intravenous nicorandil: 78 patients in the Nicorandil group and 324 patients in the Control group. During the 180-day follow-up, death or rehospitalization for heart failure occurred in 7 patients in the Nicorandil group (9.0%) and in 75 patients (23.2%) in the Control group. Event-free survival rates were significantly higher in the Nicorandil group than in the Control group (P=0.006). Multivariate Cox hazard analysis revealed that age (hazard ratio (HR)=1.066, P<0.0001), systolic blood pressure (HR=0.983, P=0.0023), New York Heart Association class III/IV (HR=6.550, P<0.0001), log creatinine (HR=3.866, P=0.0106), and use of intravenous nicorandil (HR=0.179, P<0.0001) were significant predictive factors for the occurrence of death or rehospitalization for heart failure. CONCLUSIONS Intravenous nicorandil treatment from the urgent phase of AHFS may improve the prognosis.

OBJECTIVES: We assessed whether the intravenous administration of nicorandil, an adenosine triphosphate (ATP)-sensitive K+ channel opener, exerts beneficial effect on microvascular function and functional and clinical outcomes in patients with acute myocardial infarction (AMI). BACKGROUND: Experimental studies documented that ATP-sensitive K+ channel opener exerts cardioprotection after prolonged ischemia. METHODS: We randomly divided 81 patients with a first anterior AMI into two groups, nicorandil (n = 40) and control groups (n = 41). All patients received successful coronary angioplasty within 12 h after the symptom onset and underwent myocardial contrast echcardiography (MCE) with the intracoronary injection of sonicated microbubbles. In the nicorandil group, we injected 4 mg of nicorandil followed by the infusion at 6 mg/h for 24 h and by oral nicorandil (15 mg/day). RESULTS: The improvement in regional left ventricular function, wall motion score and regional wall motion was significantly better in the nicorandil group then in the control group. Intractable congestive heart failure, malignant ventricular arrhythmia and pericardial effusion were more frequently found in the control group than in the nicorandil group (15% vs. 37%, 5% vs. 20% and 8% vs. 37%, p < 0.05, respectively). The frequency of sizable MCE no reflow phenomenon was significantly lower in the nicorandil group than in the control group (15% vs. 33%, p < 0.05). CONCLUSIONS: Intravenous nicorandil in conjunction with coronary angioplasty is associated with better functional and clinical outcomes compared to angioplasty alone in patients with an anterior AMI. Myocardial contrast echocardiography findings imply that an improvement in microvascular function with nicorandil may be attributable to this better outcome.

AIMS To assess the anti-ischaemic and anti-arrhythmic effects and overall safety of nicorandil, an ATP sensitive potassium (K+) channel opener, with 'cardioprotective' effects, in patients with unstable angina. METHODS In a multicentre, randomized, double-blind, parallel-group, placebo-controlled study, oral nicorandil 20 mg twice daily or a matching placebo was administered for a minimum of 48 h to patients admitted with unstable angina. Treatment was standardized to include, where tolerated, oral aspirin, a beta-blocker and diltiazem. Continuous Holter ECG monitoring was performed for 48 h to assess the frequency and duration of transient myocardial ischaemia and any tachyarrhythmia, as the predefined end-points of the study. A pain chart recorded the incidence and severity of chest pain throughout the study period. Patients with myocardial infarction identified retrospectively from troponin-T analysis were excluded. RESULTS Two hundred and forty-five patients were recruited into the study. Forty-three patients were excluded with an index diagnosis of myocardial infarction, two were not randomized and 12 had unsatisfactory tape data. In the remaining 188 patients, six out of 89 patients (6.7%) on nicorandil experienced an arrhythmia, compared with 17 out of 99 patients (17.2%) on placebo (P=0.04). Three nicorandil patients experienced three runs of non-sustained ventricular tachycardia compared to 31 runs in 10 patients on placebo (P=0.087 patients; P<0.0001 runs). Three nicorandil patients had four runs of supraventricular tachycardia, compared to 15 runs in nine patients on placebo (P=0.14 patients; P=0.017 runs). Eleven (12.4%) patients on nicorandil had 37 episodes of transient myocardial ischaemia (mostly silent) compared with 74 episodes in 21 (21.2%) patients on placebo (P=0.12 patients; P=0.0028 episodes). In the overall safety analysis, which included all patients who received at least one dose of study medication, there were no significant differences in the rates of myocardial infarction or death between the nicorandil or placebo-treated groups. CONCLUSIONS Nicorandil, added to aggressive anti-anginal treatment for unstable angina, reduces transient myocardial ischaemia, non-sustained ventricular, and supraventricular arrhythmia compared to placebo. The anti-arrhythmic activity with nicorandil is probably a secondary effect resulting from its anti-ischaemic action and we suggest that this may be related to its effect on the ATP sensitive potassium channel causing pharmacological preconditioning.

OBJECTIVES: This study focused on 1) the determination of the optimal preconditioning (PC) duration, and 2) the protective effect of nicorandil (NC), a hybrid nitrate with a KATP channel opening effect, during a percutaneous transluminal coronary angioplasty (PTCA) model in humans. BACKGROUND: The ischemic PC effect is induced in 180 s ischemia, but not in 120 s ischemia in rabbit hearts. However, the duration of ischemia that induces PC effect and the role of the KATP channel in the PC effect in humans are still unclear. METHODS: Forty-six patients with stable angina were randomly allocated to four groups: the duration of the first inflation as PC ischemia was 60 s in the PC60 group (n = 12), and 180 s in the PC180 group (n = 12). In the other groups, NC (80 microg/kg) was intravenously given for 1 min in the NC group (n = 12), and isosorbide dinitrate (ISDN)(40 microg/kg) was given in the ISDN group (n = 10). Five minutes after first inflation or drug administration, a second inflation was conducted for 120 s in each group. In the ECG, the lead with the largest shift in ST segment (deltaST max), and the sum of elevated ST levels in all leads (sigmaST) were determined. RESULTS: In the PC60 group, no significant difference was observed in either deltaST max or sigmaST between the first and second inflation. However, the second inflation in the PC180 group showed significantly lower levels of deltaST max and sigmaST compared with those of the first inflation. In the NC group, both deltaST max and sigmaST measured at 30 s and 60 s after balloon inflation were significantly lower than those of the first inflation in the PC60 and PC180 control groups. In the ISDN group, no significant difference was observed in deltaST max or sigmaST. CONCLUSION: In human PTCA models, a PC effect is observed in 180 s ischemia, but not in 60 s ischemia. A pharmacological PC effect is induced by NC, a KATP channel opener with a nitrate-like effect but not ISDN. This suggests that the opening of KATP channels plays an important role in the protecting effect of NC.

Diabetic patients are more prone to develop postinfarction complications. It remained unclear whether diabetes mellitus- or sulfonylureas-associated changes of ATP-sensitive potassium (K(ATP)) channels, an integral player in ischemic preconditioning, are responsible for the increased mortality. The purpose of this study was to determine the impact of diabetes mellitus per se and different sulfonylurea administration on cardioprotective effects in diabetic patients undergoing coronary angioplasty. Myocardial ischemia after coronary angioplasty was evaluated in 20 nondiabetic and 23 diabetic patients chronically taking either glibenclamide or glimepiride. Nondiabetic patients treated with glimepiride significantly lowered the ischemic burden assessed by an ST-segment shift, chest pain score, and myocardial lactate extraction ratios compared with the glibenclamide-treated patients, implying that acute administration of glimepiride did not abolish cardioprotection. In the diabetic glibenclamide-treated group, the reduction in the ST-segment shift afforded by nicorandil in the first inflation (-58% vs. the first inflation in the glibenclamide group alone) was similar to that afforded by preconditioning (-59% during the second vs. the first inflation). In glimepiride-treated groups, the magnitude of attenuated lactate production was less in diabetes than that in nondiabetes at the second inflation, suggesting that diabetes mellitus per se plays a role in determining lactate production. Our results show that both diabetes mellitus and sulfonylureas can act in synergism to inhibit activation of K(ATP) channels in patients undergoing coronary angioplasty. The degree of inhibition assessed by metabolic and electrocardiographic parameters is less severe during treatment with glimepiride than with glibenclamide. Restitution of a preconditioning response in glimepiride-treated patients may be the potential beneficial mechanism.

BACKGROUND Patients who have acute myocardial infarction remain at major risk of cardiovascular events. We aimed to assess the effects of either human atrial natriuretic peptide or nicorandil on infarct size and cardiovascular outcome. METHODS We enrolled 1216 patients who had acute myocardial infarction and were undergoing reperfusion treatment in two prospective, single-blind trials at 65 hospitals in Japan. We randomly assigned 277 patients to receive intravenous atrial natriuretic peptide (0.025 microg/kg per min for 3 days) and 292 the same dose of placebo. 276 patients were assigned to receive intravenous nicorandil (0.067 mg/kg as a bolus, followed by 1.67 microg/kg per min as a 24-h continuous infusion), and 269 the same dose of placebo. Median follow-up was 2.7 (IQR 1.5-3.6) years for patients in the atrial natriuretic peptide trial and 2.5 (1.5-3.7) years for those in the nicorandil trial. Primary endpoints were infarct size (estimated from creatine kinase) and left ventricular ejection fraction (gauged by angiography of the left ventricle). FINDINGS 43 patients withdrew consent after randomisation, and 59 did not have acute myocardial infarction. We did not assess infarct size in 50 patients for whom we had fewer than six samples of blood. We did not have angiographs of left ventricles in 383 patients. Total creatine kinase was 66,459.9 IU/mL per h in patients given atrial natriuretic peptide, compared with 77,878.9 IU/mL per h in controls, with a ratio of 0.85 between these groups (95% CI 0.75-0.97, p=0.016), which indicated a reduction of 14.7% in infarct size (95% CI 3.0-24.9%). The left ventricular ejection fraction at 6-12 months increased in the atrial natriuretic peptide group (ratio 1.05, 95% CI 1.01-1.10, p=0.024). Total activity of creatine kinase did not differ between patients given nicorandil (70 520.5 IU/mL per h) and controls (70 852.7 IU/mL per h)(ratio 0.995, 95% CI 0.878-1.138, p=0.94). Intravenous nicorandil did not affect the size of the left ventricular ejection fraction, although oral administration of nicorandil during follow-up increased the left ventricular ejection fraction between the chronic and acute phases. 29 patients in the atrial natriuretic peptide group had severe hypotension, compared with one in the corresponding placebo group. INTERPRETATION Patients with acute myocardial infarction who were given atrial natriuretic peptide had lower infarct size, fewer reperfusion injuries, and better outcomes than controls. We believe that atrial natriuretic peptide could be a safe and effective adjunctive treatment in patients with acute myocardial infarction who receive percutaneous coronary intervention.

Endothelium-derived hyperpolarizing factor (EDHF) contributes to endothelium-dependent relaxation of isolated arteries, but it is not known whether this also occurs in the case of humans in vivo. The present study examined the role of EDHF in human forearm circulation. Forearm blood flow (FBF) was measured by strain-gauge plethysmography in 31 healthy, normal subjects (mean+/-SE age, 23+/-2 years; 24 men and 7 women). After oral administration of aspirin (486 mg), we infused NG-monomethyl-L-arginine (8 micromol/min for 5 minutes) into the brachial artery. We used tetraethylammonium chloride (TEA, 1 mg/min for 20 minutes), a KCa channel blocker, as an EDHF inhibitor, and nicorandil as a direct K+ channel opener. TEA significantly reduced FBF (P<0.05) but did not change systemic arterial blood pressure. Furthermore, TEA significantly inhibited the FBF increase in response to substance P (0.8, 1.6, 3.2, and 6.4 ng/min, n=8) and bradykinin (12.5, 25, 50, and 100 ng/min, n=8; both P<0.001), whereas it did not affect the FBF increase in response to acetylcholine (4, 8, 16, and 32 microg/min, n=8), sodium nitroprusside (0.4, 0.8, 1.6, and 3.2 microg/min, n=8), or nicorandil (0.128, 0.256, 0.512, and 1.024 mg/min, n=8). These results suggest that EDHF contributes substantially to basal forearm vascular resistance, as well as to forearm vasodilatation evoked by substance P and bradykinin in humans in vivo.

The objective of the present study was to develop once-daily sustained-release matrix tablets of nicorandil, a novel potassium channel opener used in cardiovascular diseases. The tablets were prepared by the wet granulation method. Ethanolic solutions of ethylcellulose (EC), Eudragit RL-100, Eudragit RS-100, and polyvinylpyrrolidone were used as granulating agents along with hydrophilic matrix materials like hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose, and sodium alginate. The granules were evaluated for angle of repose, bulk density, compressibility index, total porosity, and drug content. The tablets were subjected to thickness, diameter, weight variation test, drug content, hardness, friability, and in vitro release studies. The granules showed satisfactory flow properties, compressibility, and drug content. All the tablet formulations showed acceptable pharmacotechnical properties and complied with in-house specifications for tested parameters. According to the theoretical release profile calculation, a once-daily sustained-release formulation should release 5.92 mg of nicorandil in 1 hour, like conventional tablets, and 3.21 mg per hour up to 24 hours. The results of dissolution studies indicated that formulation F-I (drug-to-HPMC, 1:4; ethanol as granulating agent) could extend the drug release up to 24 hours. In the further formulation development process, F-IX (drug-to-HPMC, 1:4; EC 4% wt/vol as granulating agent), the most successful formulation of the study, exhibited satisfactory drug release in the initial hours, and the total release pattern was very close to the theoretical release profile. All the formulations (except F-IX) exhibited diffusion-dominated drug release. The mechanism of drug release from F-IX was diffusion coupled with erosion.

BACKGROUND This study aimed to clarify the effect of intracoronary administration of combined adenosine and nicorandil on the no-reflow phenomenon. METHODS AND RESULTS Fifty patients (67+/-10 years, 30 male) with acute myocardial infarction (AMI) who developed no-reflow phenomenon during primary percutaneous coronary intervention (PCI) between June 2001 and May 2003 comprised the study group, which was divided into 2 groups: group I [25 patients, 67+/-10 years, 13 male; adenosine (24 microg/ml) alone in addition to nitrate] and group II [25 patients, 66+/-9 years, 17 male; combined intracoronary administration of adenosine and nicorandil (2 mg/ml) in addition to nitrate]. In-hospital and 6-month major adverse cardiac events (MACE) after PCI were compared between the 2 groups. Risk factors of coronary disease, left ventricular ejection fraction and wall motion score were not significantly different between the 2 groups (p=NS). Time interval from the onset of chest pain to PCI, number of involved vessels, lesion type according to ACC/AHA classification and TIMI flow grade (TFG) were not significantly different in both groups (p=NS). Incidence of thrombosis or dissection after balloon angioplasty, diameter and length of stent, and use of Reopro during PCI were not significantly different. TFG after PCI (2.0+/-0.9 vs 2.6+/-0.6, p=0.024), DeltaTFG (1.5+/-1.1 vs 2.2+/-1.0, p=0.033) and difference in TIMI frame count (TFC) before and after PCI (DeltaTFC) were greater in group II than group I (45.2+/-24.5 vs 63.6+/-23.2, p=0.014). Myocardial blush score 3 was obtained more frequently in group II than group I (44% vs 76%, p=0.014). In-hospital death did not occur in any of group II, but 4 patients of group I died (p=0.043). Two cases of MACE developed in each group and heart failure occurred in 3 (12%) of group I and 1 (4%) of group II patients during the 6-month follow-up (p=NS). CONCLUSIONS Intracoronary administration of adenosine combined with nicorandil may improve both the occurrence of no-reflow in patients during PCI for AMI and short-term clinical outcome, compared with adenosine alone.

PURPOSE Ischaemic preconditioning (PC) is a cardioprotective phenomenon in which short periods of myocardial ischaemia result in resistance to decreased contractile dysfunction during a subsequent period of sustained ischaemia. Nicorandil, an ATP-sensitive potassium channel opener, can induce PC effects on sympathetic nerves during myocardial ischaemia. However, its effects on cardiac sympathetic nerve activity (CSNA) and left ventricular remodelling have not been determined. In this study, we sought to determine whether nicorandil administration improves CSNA in patients with acute myocardial infarction (AMI). METHODS We studied 58 patients with first anterior AMI, who were randomly assigned to receive nicorandil (group A) or isosorbide dinitrate (group B) after primary coronary angioplasty. The nicorandil or isosorbide dinitrate was continuously infused for >48 h. The extent score (ES) was determined from 99mTc-pyrophosphate scintigraphy, and the total defect score (TDS) was determined from 201Tl scintigraphy 3-5 days after primary angioplasty. The left ventricular end-diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF) were determined by left ventriculography 2 weeks later. The delayed heart/mediastinum count (H/M) ratio, delayed TDS and washout rate (WR) were determined from 123I-meta-iodobenzylguanidine (MIBG) images 3 weeks later. The left ventriculography results were re-examined 6 months after treatment. RESULTS Fifty patients originally enrolled in the trial completed the entire protocol. After treatment, no significant differences were observed in ES or left ventricular parameters between the two groups. However, in group A (n=25), the TDSs determined from 201Tl and 123I-MIBG were significantly lower (26+/-6 vs 30+/-5, P<0.01, and 32+/-8 vs 40+/-6, P<0.0001, respectively), the H/M ratio significantly higher (1.99+/-0.16 vs 1.77+/-0.30, P<0.005) and the WR significantly lower (36%+/-8% vs 44%+/-12%, P<0.005) than in group B (n=25). Moreover, 6 months after treatment, LVEDV and LVEF were better in group A than in group B. CONCLUSION These findings indicate that nicorandil can have beneficial effects on CSNA and left ventricular remodelling in patients with first anterior AMI.