Cardioprotective Effects Of Nicorandil Research Articles

Perioperative myocardial injury in patients with coronary artery disease during elective lower limb surgery

Aim. To assess the prevalence of ischemic myocardial injury and the cardioprotective effect of nicorandil by assessing high-sensitivity cardiac troponin (hs-cTn) in patients with stable coronary artery disease (CAD) during elective lower limb surgery, as well as to identify predictors of adverse cardiac events.Material and methods. The study included 70 patients with stable coronary artery disease hospitalized for elective autogenous femoropopliteal bypass (FPB) surgery. After randomization, all patients were divided into two following groups: control group — 35 patients; main group — 35 patients, who, in addition to standard therapy, were prescribed nicorandil (Cordinic, PIQ-PHARMA) in a single dose of 20 mg 2 hours before surgery. In the postoperative period, the incidence of myocardial injury was assessed by hs-cTn increase. The obtained primary data were subjected to mathematical processing using the R-Studio software package (R language).Results. At baseline, patients in both groups were comparable in clinical characteristics, therapy, and duration of vascular surgery. In the main group of patients receiving nicorandil, a significant decrease in the incidence of perioperative myocardial injury was noted. In 5 patients of the control group, hs-cTn level 24 hours after surgery exceeded the threshold value, which indicated myocardial injury in the early postoperative period. In the nicorandil group, there was no hs-cTn increase (14% vs 0%, p=0,027). Regression analysis identified a predictor of perioperative myocardial injury — left ventricular ejection fraction (LVEF) <50%. LVEF <50% increases the risk of myocardial injury in the early postoperative period by 7,36 times (p=0,04) and 9,15 times (p=0,048) according to univariate and multivariate regression analysis, respectively.Conclusion. Perioperative myocardial injury is a common complication in patients with CAD undergoing lower extremity revascularization. The use of nicorandil (Cordinic, PIQ-PHARMA) before elective revascularization surgery helps reduce the incidence of ischemic myocardial injury in the early postoperative period and is not accompanied by adverse reactions, which rationales this approach to improve the clinical outcomes of lower extremity revascularization in patients with stable CAD. A predictor of myocardial injury, determined by hs-cTn, is a LVEF <50%.

Incidence and Severity of Acute Myocardial Injury after Thoracic Surgery: Effects of Nicorandil

Aim. To study the perioperative dynamics of myocardial injury biomarkers high-sensitivity cardiac troponin I (hs-cTnI), ischemia-modified albumin (IMA) and soluble ST2 (sST2) when taking nicorandil in lung cancer patients with concomitant coronary heart disease (CHD) undergoing surgical lung resection.Material and methods. The study included 54 patients (11 women and 43 men) with non-small cell lung cancer and concomitant stable CHD who underwent lung resection in the volume of lobectomy or pneumonectomy. Patients were randomly assigned to the nicorandil group (oral administration 10 mg BID for 7 days before and 3 days after surgery; n=27) and the control group (n=27). In the study groups, the perioperative dynamics of hscTnI, IMA and sST2, determined in the blood before and 24 and 48h after surgery, were compared. We calculated the incidence of acute myocardial injury in the groups, which was diagnosed in cases of postoperative hs-cTnI increase of more than one 99th percentile of the upper reference limit. The associations of nicorandil intake and acute myocardial injury were evaluated.Results. The groups were comparable in gender, age, basic clinical characteristics, as well as baseline levels of myocardial injury biomarkers. After the intervention, both samples showed an increase in the hs-cTnI and sST2 levels and a decrease in IMA concentration (all p<0.02 for related group differences). In the nicorandil group, in comparison with the control one, 48h after surgery, we found lower mean levels of hs-cTnI [16.7 (11.9;39.7) vs 44.3 (15.0;130.7) ng/l; p<0.05) and sST2 [62.8 (43.6;70.1) vs 76.5 (50.2;87.1) ng/ml; p<0.05), concentration increase rates of hs-cTnI [14.8 (0.7;42.2) vs 32.5 (14.0;125.0) ng/l; p<0.01) and sST2 [24.4 (10.3;42.4) vs 47.4 (17.5;65.3) ng/ml; p<0.05), as well as highest concentrations for the entire postoperative period of hs-cTnI [30.7 (12.0;53.7) vs 79.0 (20.3;203.3) ng/L, p<0.01] and sST2 [99.8 (73.6;162.5) vs 147.8 (87.8;207.7) ng/mL; p<0.05]. The serum IMA decreased when taking nicorandil to a greater extent [-8.0 (-12.6; -2.0) vs -2.7 (-6.0; +5.5) ng/ ml; p<0.01] 24h after surgery. Acute myocardial injury was diagnosed in 7 people in the nicorandil group (25.9%) and in 15 in the control one (55.6%; pχ2=0.027). The adjusted odds ratio of acute myocardial injury when taking nicorandil was 0.35 (95% confidence interval 0.15-0.83, p=0.017).Conclusion. Taking nicorandil in patients with lung cancer and concomitant CHD who underwent surgical lung resection is associated with a lower postoperative increase in hs-cTnI and sST2 and a reduced risk of acute myocardial injury, which may indicate the cardioprotective effect of nicorandil under acute surgical stress conditions.

Effect of the selective mitochondrial KATP channel opener nicorandil on the QT prolongation and myocardial damage induced by amitriptyline in rats.

The aim of this study is to evaluate the protective effect of nicorandil, a selective mitochondrial KATP channel opener, on QT prolongation and myocardial damage induced by amitriptyline. The dose of amitriptyline (intraperitoneal, i.p.) that prolong the QT interval was found 75 mg/kg. Rats were randomized into five groups the control group, amitriptyline group, nicorandil (selective mitochondrial KATP channel opener, 3 mg/kg i.p.) + amitriptyline group, 5-hdyroxydecanoate (5-HD, selective mitochondrial KATP channel blocker, 10 mg/kg i.p.) + amitriptyline group and 5-HD + nicorandil + amitriptyline group. Cardiac parameters, biochemical and histomorphological/immunohistochemical examinations were evaluated. p < 0.05 was accepted as statistically significant. Amitriptyline caused statistically significant prolongation of QRS duration, QT interval and QTc interval (p < 0.05). It also caused changes in tissue oxidant (increase in malondialdehyde)/anti-oxidant (decrease in glutathione peroxidase) parameters (p < 0.05), myocardial damage and apoptosis (p < 0.01 and p < 0.001). While nicorandil administration prevented amitriptyline-induced QRS, QT, QTc prolongation (p < 0.05), myocardial damage and apoptosis (p < 0.05), it did not affect the changes in oxidative parameters (p > 0.05). Our results suggest that nicorandil, a selective mitochondrial KATP channel opener, plays a protective role in amitriptyline-induced QT prolongation and myocardial damage. Mitochondrial KATP channel opening and anti-apoptotic effects may play a role in the cardioprotective effect of nicorandil.

Cardio protective effect of nicorandil in reperfusion injury among patients undergoing primary percutaneous coronary intervention.

To evaluate the effect of nicorandil in prevention of reperfusion injury during primary percutaneous coronary intervention by thrombolysis in myocardial infarction flow grade scoring. A total of 140 patients from Rawalpindi Institute of Cardiology were enrolled in this study conducted from 7th September to 10th of October 2021. These participants were allocated into two major groups. Control group received conventional acute coronary syndrome protocol regimen only whereas experimental group was given nicorandil along with conventional acute coronary syndrome protocol. During primary percutaneous coronary intervention, thrombolysis in myocardial infarction flow grade scoring was analyzed and compared. Majority of participants in nicorandil group achieved thrombolysis in myocardial infarction Grade-3 scoring which indicated reduced rate of no reflow phenomenon as compared to control group. A statistically significant difference was noted in score of both groups (p value = 0.001) signifying prophylactic use of nicorandil before primary percutaneous coronary intervention along with conventional acute coronary syndrome protocol is superior to only conventional acute coronary syndrome protocol regimen to cases in the control group. Use of nicorandil in ST elevated myocardial infarction patients before primary percutaneous coronary intervention prevents reperfusion injury thus decreasing the risk of post percutaneous coronary intervention complications and reducing mortality rate in cardiac patients suggesting its significant cardio protective role.

Cardioprotective effect of nicorandil on isoproterenol induced cardiomyopathy in the Mdx mouse model

BackgroundDuchenne muscular dystrophy (DMD) associated cardiomyopathy is a major cause of morbidity and mortality. In an in vitro DMD cardiomyocyte model, nicorandil reversed stress-induced cell injury through multiple pathways implicated in DMD. We aimed to test the efficacy of nicorandil on the progression of cardiomyopathy in mdx mice following a 10-day treatment protocol.MethodsA subset of mdx mice was subjected to low-dose isoproterenol injections over 5 days to induce a cardiac phenotype and treated with vehicle or nicorandil for 10 days. Baseline and day 10 echocardiograms were obtained to assess cardiac function. At 10 days, cardiac tissue was harvested for further analysis, which included histologic analysis and assessment of oxidative stress. Paired student’s t test was used for in group comparison, and ANOVA was used for multiple group comparisons.ResultsCompared to vehicle treated mice, isoproterenol decreased ejection fraction and fractional shortening on echocardiogram. Nicorandil prevented isoproterenol induced cardiac dysfunction. Isoproterenol increased cardiac fibrosis, which nicorandil prevented. Isoproterenol increased gene expression of NADPH oxidase, which decreased to baseline with nicorandil treatment. Superoxide dismutase 2 protein expression increased in those treated with nicorandil, and xanthine oxidase activity decreased in mice treated with nicorandil during isoproterenol stress compared to all other groups.ConclusionsIn conclusion, nicorandil is cardioprotective in mdx mice and warrants continued investigation as a therapy for DMD associated cardiomyopathy.

Vascular calcification abrogates the nicorandil mediated cardio-protection in ischemia reperfusion injury of rat heart

The present study was aimed to determine the efficacy of nicorandil in treating cardiac reperfusion injury with an underlying co-morbidity of vascular calcification (VC). Adenine diet was used to induce VC in Wistar rat and the heart was isolated to induce global ischemia reperfusion (IR) by Langendorff method, with and without the nicorandil (7.5mg/kg) pre-treatment and compared with those fed on normal diet. The adenine-treated rats displayed abnormal ECG changes and altered mitochondrial integrity compared to a normal rat heart. These hearts, when subjected to IR increased the infarct size, cardiac injury (measured by lactate dehydrogenase and creatine kinase activity in the coronary perfusate) and significantly altered the hemodynamics compared to the normal perfused heart. Nicorandil pretreatment in rat fed on normal diet enhanced the hemodynamics significantly (P<0.05) along with a substantial reduction in the mitochondrial dysfunction (measured by high ADP to oxygen consumption ratio, respiratory control ratio, enzyme activities and less swelling behavior) when subjected to IR. However, this cardio-protective effect of nicorandil was absent in rat heart with underlying calcification. Our results suggest that, the protective effect of nicorandil, a known mitochondrial ATP linked K+ channel opener, against myocardial reperfusion injury was confined to normal rat heart.

Pharmacological preconditioning and postconditioning with nicorandil attenuates ischemia/reperfusion-induced myocardial necrosis and apoptosis in hypercholesterolemic rats.

Pharmacological preconditioning and postconditioning may reduce myocardial necrosis and apoptosis during ischemia/reperfusion (I/R), however, hypercholesterolemia interferes with the associated cardioprotective mechanisms. The present study investigated whether pharmacological preconditioning and postconditioning with nicorandil could attenuate myocardial necrosis and apoptosis induced by I/R in hypercholesterolemic rats, and explored the possible mechanisms involved. Male Wistar rats (n=160) were fed normal (normocholesterolemic group, n=10) or high-cholesterol (hypercholesterolemic group, n=150) diets for 8 weeks. Hearts harvested from the normal and hypercholesterolemic rats were subsequently placed on modified Langendorff perfusion apparatus and 30-min global ischemia was performed, followed by 120-min reperfusion. Nicorandil (1, 3, 10, 30, 100 µmol/l), and mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channel blocker 5-hydroxydecanoic acid sodium salt (5-HD) (100 µmol/l) or soluble guanylyl cyclase (sGC) blocker 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 µmol/l) were perfused for 10 min, prior to ischemia or at the onset of reperfusion. The myocardial infarct size was determined by triphenyltetrazolium chloride staining, and cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. In order to investigate the potential mechanisms, the expression levels of caspase-3, B-cell lymphoma-2 (Bcl-2) proteins and Bcl-2-associated X protein (Bax) were measured using western blot analysis. The present study demonstrated that, in hypercholesterolemic rats, pharmacological preconditioning and postconditioning with nicorandil decreased I/R-induced myocardial necrosis and apoptosis in a concentration-dependent manner. The optimal preconditioning and postconditioning concentration of nicorandil determined to have anti-infarct and anti-apoptosis effects was 30 µmol/l, which significantly (P<0.05) reduced the infarct size to 14.88±3.25% and 15.96±3.29%, and attenuated the percentage of cardiomyocyte apoptosis to 25.20±3.93% and 26.18±4.82%, respectively, compared with the I/R group. However, the cardioprotective effects of nicorandil were partially suppressed by cotreatment with 5-HD or ODQ. Western blot analysis demonstrated that pharmacological preconditioning and postconditioning with nicorandil significantly downregulated caspase-3 and Bax expression, and upregulated Bcl-2 expression compared with the I/R group (P<0.05). The results of the present study suggest that pharmacological preconditioning and postconditioning with nicorandil may protect hypercholesterolemic hearts against I/R-induced necrosis and apoptosis; and the cardioprotective effects of nicorandil may be due to the dual pharmacological mechanisms of opening the mitoKATP channels and a nitric oxide/sGC-dependent mechanism, and regulation of the expression of caspase-3, Bax and Bcl-2.

Nicorandil improves electrical remodelling, leading to the prevention of electrically induced ventricular tachyarrhythmia in a mouse model of desmin-related cardiomyopathy

1. Transgenic (TG) mice overexpressing an arg120gly missense mutation in heat shock protein B5 (HSPB5; i.e. R120G TG mice) exhibit desmin-related cardiomyopathy. Recently, the cardioprotective effect of nicorandil has been shown to prolong the survival of R120G TG mice. However, whether the TG mice exhibit ventricular arrhythmias and whether nicorandil can inhibit these arrhythmias remain unknown. In the present study we examined the effects of chronic nicorandil administration on ventricular electrical remodelling and arrhythmias in R120G TG mice. 2. Mice were administered nicorandil (15 mg/kg per day) or vehicle (water) orally from 5 to 30 weeks of age. Electrocardiograms (ECG) and optical action potentials were recorded from R120G TG mouse hearts. In addition, the expression of ventricular connexin 43 and the cardiac Na(+) channel Nav1.5 was examined in TG mice. 3. All ECG parameters tested were prolonged in R120G TG compared with non-transgenic (NTG) mice. Nicorandil improved the prolonged P, PQ and QRS intervals in R120G TG mice. Interestingly, impulse conduction slowing and increases in the expression of total and phosphorylated connexin 43 and Nav1.5 were observed in ventricles from R120G TG compared with NTG mice. Nicorandil improved ventricular impulse conduction slowing and normalized the increased protein expression levels of total and phosphorylated connexin 43, but not of Nav1.5, in R120G TG mouse hearts. Electrical rapid pacing at the ventricle induced ventricular tachyarrhythmias (VT) in six of eight R120G TG mouse hearts, but not in any of the eight nicorandil-treated R120G TG mouse hearts (P < 0.05). 4. These findings demonstrate that nicorandil inhibits cardiac electrical remodelling and that the prevention of VT by nicorandil is associated with normalization of connexin 43 expression in this model.

Nicorandil ameliorates mitochondrial dysfunction in doxorubicin-induced heart failure in rats: Possible mechanism of cardioprotection

Despite of its known cardiotoxicity, doxorubicin is still a highly effective anti-neoplastic agent in the treatment of several cancers. In the present study, the cardioprotective effect of nicorandil was investigated on hemodynamic alterations and mitochondrial dysfunction induced by cumulative administration of doxorubicin in rats. Doxorubicin was injected i.p. over 2 weeks to obtain a cumulative dose of 18mg/kg. Nicorandil (3mg/kg/day) was given orally with or without doxorubicin treatment. Heart rate and aortic blood flow were recorded 24h after receiving the last dose of doxorubicin. Rats were then sacrificed and hearts were rapidly excised for estimation of caspase-3 activity, phosphocreatine and adenine nucleotides contents in addition to cytochrome c, Bcl2, Bax and caspase 3 expression. Moreover, mitochondrial oxidative phosphorylation capacity, creatine kinase activity and oxidative stress markers were measured together with the examination of DNA fragmentation and ultrastructural changes. Nicorandil was effective in alleviating the decrement of heart rate and aortic blood flow and the state of mitochondrial oxidative stress induced by doxorubicin cardiotoxicity. Nicorandil also preserved phosphocreatine and adenine nucleotides contents by restoring mitochondrial oxidative phosphorylation capacity and creatine kinase activity. Moreover, nicorandil provided a significant cardioprotection via inhibition of apoptotic signaling pathway, DNA fragmentation and mitochondrial ultrastructural changes. Interestingly, nicorandil did not interfere with cytotoxic effect of doxorubicin against the growth of solid Ehrlich carcinoma. In conclusion, nicorandil was effective against the development of doxorubicin-induced heart failure in rats as indicated by improvement of hemodynamic perturbations, mitochondrial dysfunction and ultrastructural changes without affecting its antitumor activity.

Cardioprotective Effects of Nicorandil, a Mitochondrial Potassium Channel Opener against Doxorubicin‐Induced Cardiotoxicity in Rats

Doxorubicin is a chemotherapeutic drug used to treat solid and haematopoietic tumours. Its use is limited by a major side effect of cardiotoxicity. It was reported that doxorubicin-induced cardiotoxicity is mediated through oxidative stress coupled with impaired NO bioavailability and NF-κB activation. Nicorandil, a mitochondrial ATP-dependent potassium (KATP ) channel opener, was reported to be cardioprotective on ischaemic myocardium. However, the effect of nicorandil against doxorubicin-induced cardiotoxicity has not yet been clarified. Accordingly, six groups of rats were used. The first three groups were injected with vehicle, nicorandil (3 mg/kg) orally and doxorubicin (a single intraperitoneal injection of 20 mg/kg), respectively. Group four was treated with nicorandil, whereas group five was treated with glibenclamide and then nicorandil starting 2 days before doxorubicin and continued for five consecutive days. Group six was treated with glibenclamide alone. At the end of the experiment, the rats were killed. Cardiac enzyme indexes were measured in serum. Heart tissues were processed for determination of nitrite/nitrate, NF-κB protein expression, glutathione (GSH), lipid peroxide (TBARS) levels and superoxide production. In addition to body-weight reduction, doxorubicin produced cardiotoxicity as indicated from the increase in lactate dehydrogenase (LDH), creatine kinase (CK) activities, TBARS, superoxide production, NF-κB expression and caspase-3 activity. Moreover, doxorubicin decreased GSH and nitrite/nitrate levels. Histopathological examination of doxorubicin-treated hearts revealed degenerative changes. On the other hand, nicorandil protected cardiac tissues against doxorubicin cardiotoxicity as demonstrated from normalization of cardiac biochemical and oxidative stress parameters and amelioration of histopathological changes. Glibenclamide, a blocker of the KATP channel, reversed most of the cardiac effects of nicorandil.

Myocardial protective effects of nicorandil, an opener of potassium channels on senile rat heart

The purpose of this study was to investigate the cardioprotective effects of nicorandil, an opener of potassium channels, on senile rat hearts from ischemic reperfusion injury. A modified working model of isolated perfused hearts of senile rats was used. After isolation, the hearts underwent 60 min of global hypothermic ischemia treatment, followed by 30 min of reperfusion. These hearts were distributed into three groups, each receiving different cardioplegic solutions: (1) St. Thomas' solution (Group S), (2) 100 micromol/L nicorandil (Group N), (3) St. Thomas' solution combined with 100 micromol/L nicorandil (Group S+N). The pre- and post-ischemic myocardial function were assessed by the percentage recovery of the heart rate (HR), +/- dp/dt(max) (maximal rate of change of left ventricular pressure) and cardiac output (CO). Upon reperfusion, the cardioplegic solution was collected from the coronary sinus and tested for lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) activity. During 30 min of reperfusion, the percentage recovery of HR, +dp/dt and left ventricular stroke work (LVSW) were significantly higher in Group S+N than in Group S and Group N (p < 0.05). The percentage of recovery in CO was higher in Group N and Group S+N than in Group S. The electrical activities arresting time (EAT) and mechanical activities arresting time (MAT) were longer in Group N than in Group S and Group N+S (p < 0.01). There were no statistical significance between Group S and Group N+S (p > 0.05). There were no significant differences in the levels of LDH and CK-MB. Electron microscopic examination revealed better preservation of the ultrastructures of the myocardial tissue in Group N+S than the other two groups. These results indicate that nicorandil combined with St. Thomas' solution can improve the left ventricular function of the post-ischemic senile rat and offer a better myocardial protective effect on the ischemic senile myocardium.

The Cardioprotective Effect of Intravenous Nicorandil for Ischemia/Reperfusion Injury

Background and Objectives:Nicorandil is a potassium channel opener, and it has been known to have a cardioprotective effect against ischemia/reperfusion injury. However, the exact mechanisms of the effect are not known. In the previous studies on cardioprotection, administration of nicorandil was started early during the coronary occlusion. Therefore, it is not clear whether nicorandil can also be beneficial when it is administered from the time of coronary recannalization. Materials and Methods:We studied 15 cats that had their chests surgically opened (8 nicorandil cats and 7 control cats). The proximal portion of the left anterior descending artery (LAD) was occluded with ligation for 90 minutes, then it was recannalized for 60 minutes. Intravenous injection of nicorandil was started at the time of recannalization of the artery (a bolus of 100 μg·kg-1 plus an infusion at a rate of 10 μg·kg -1 ·min -1 ). At each stage of the experiments, the risk area and myocardial perfusion were assessed using color microspheres and myocardial contrast echocardiography. The size of the infarction was evaluated by postmortem triphenyltetrazolium chloride staining. Myocardial contrast echocardio- graphy was performed with Pulse Inversion Harmonic Imaging (Sonoace9900, Medison). Results:The risk area during coronary occlusion was 18.8±12.6% in the nicorandil group and 19.3±9.6% in the control group (p=NS). The perfusion defect immediately after and 1 hour after reperfusion was 13.0±8.7% and 8.4±7.6%, respectively, in nicorandil group, and 16.7±11.1% and 13.4±8.8%, respectively, in the control group, (p=NS between groups). Myocardial blood flow in the LAD territory during occlusion immediately after and 1 hour after reperfusion was 56±31%, 73±31% and 69±28%, respectively, of the normal myocardium in the nicorandil group, and 65±20%, 101±75% and 77±42%, respectively, in the control group (p=NS between groups). The postmortem infarction size was 8.1±9.6% in the nicorandil group and 7.7±7.5% in the control group (p=NS). Conclusion:With administration of nicorandil from the time of recannalization in the ischemia/reperfusion injury model, we could not find any significant cardioprotective effect. The cardioprotective effect of nicorandil may be associated with preconditioning before reperfusion. (Korean Circulation J 2005;35:88-93)

Biochemical changes on the cardioprotective effect of nicorandil and amlodipine during experimental myocardial infarction in rats

The synergistic protective effect of nicorandil (K ATP channel opener) and amlodipine (calcium channel blocker) on mitochondrial respiration and mitochondrial lipid contents were examined on isoproterenol-induced myocardial infarction in rats. The rats given isoproterenol (150 mg kg −1 daily, i.p.) for 2 days showed significant changes in mitochondrial respiration and mitochondrial lipid profile levels. Pretreatment with nicorandil (2.5 mg kg −1 daily, p.o.) and amlodipine (5.0 mg kg −1 daily, p.o.) for 3 days significantly prevented these alterations and restored the mitochondrial respiration and mitochondrial lipid contents to near normal. Histopathological observations were also in correlation with the biochemical parameters. These findings indicate the synergistic protective effect of nicorandil and amlodipine on mitochondrial respiration and its membrane integrity during isoproterenol-induced cardiac damage.

Cardioprotective Effects of Nicorandil in Coronary Artery Bypass Graft Surgery

Cardioprotective Effects of Nicorandil in Coronary Artery Bypass Graft Surgery

Cardioprotective effects of nicorandil in rabbits anaesthetized with halothane: potentiation of ischaemic preconditioning via KATP channels.

1. The roles of ATP-sensitive K+ channels (KATP channels) in ischaemic or pharmacological preconditioning in the rabbit heart remain unclear. Infarct limitation by ischaemic preconditioning was abolished by the KATP channel blocker glibenclamide under ketamine/xylazine anaesthesia, but not under anaesthesia induced by pentobarbital. Infarct limitation by the KATP channel opener pinacidil was detected under ketamine/xylazine anaesthesia, but not under pentobarbital anaesthesia. Thus, these effects appear to be anaesthetic dependent. 2. In the present study, we examined whether nicorandil (a KATP channel opener nitrate) exhibits cardioprotective actions under halothane anaesthesia, another commonly used volatile anaesthetic. Control animals were subjected to 40 min coronary occlusion and 120 min reperfusion. Before 40 min ischaemia, the nicorandil group received nicorandil (100 microg/kg per min, i.v., for 10 min), the 5' preconditioning (PC) group received 5 min ischaemia/20 min reperfusion, the 2.5'PC group received 2.5 min preconditioning ischaemia/20 min reperfusion, the nicorandil +2.5'PC group received both nicorandil and 2.5 min ischaemia/20 min reperfusion, the nicorandil +2.5'PC + 5-hydroxydecanoate (5HD) group received both nicorandil and 2.5 min ischaemia/20 min reperfusion in the presence of 5-hydroxydecanoate (5HD; a KATP blocker) and the 5HD group received 5 mg/kg, i.v., 5HD alone. Myocardial infarct size in control (n = 7), nicorandil (n = 5), 5'PC (n = 8), 2.5'PC (n = 5), nicorandil + 2.5'PC (n = 5), nicorandil + 2.5'PC + 5HD (n = 5) and 5HD (n = 4) groups averaged 44.4 +/- 3.6, 41.7 +/- 5.7, 17.8 +/- 3.2,* 34.1 +/- 4.8, 21.3 +/- 4.2,* 39.1 +/- 5.6 and 38.9 +/- 5.0% of the area at risk, respectively (*P <0.05 vs control). 3. Thus, nicorandil alone did not have an infarct size-limiting effect in halothane-anaesthetized rabbits. However, the results suggest that even when nicorandil alone does not demonstrate a direct cardioprotective effect, it may enhance ischaemic preconditioning via KATP channels. Key words: ATP-sensitive K+ (KATP) channel, ischaemic preconditioning, myocardial infarction, nicorandil, rabbit.

Effect of nicorandil on cardiac dysfunction during reperfusion in normotensive and spontaneously hypertensive rats.

The cardioprotective effect of nicorandil, an opener of ATP-sensitive potassium channels, was studied in the isolated perfused hearts of the spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto (WKY) rat. The hearts were subjected to 30 min of global ischemia followed by 30 min of reperfusion. Controls received no drug. In the nicorandil group, the hearts were treated with 0.03 to 0.3 mmol/L nicorandil for 15 min before ischemia. Left ventricular developed pressure (LVDP) and end diastolic pressure (LVEDP) at 30 min of reperfusion were significantly lower and larger, respectively, in SHR than in WKY rats. Nicorandil improved LVDP and decreased LVEDP at 30 min of reperfusion in both SHR and WKY rats dose-dependently. The hypertensive heart in the early stage is already susceptible to reperfusion-cardiac dysfunction. Nicorandil has a beneficial effect on the post-ischemic dysfunction in both SHR and WKY rats.

Cardioprotective effects of nicorandil.

The effects of nicorandil, a nicotinamide nitrate with K(+)-channel-opening activity, was investigated in several models of ischemia-reperfusion injury in conscious and anesthetized dogs or isolated buffer-perfused rat hearts. In several models of reversible ischemic injury (stunned myocardium) in dogs, nicorandil resulted in an enhanced recovery of regional systolic shortening during reperfusion after a single episode of coronary artery occlusion (10-15 min). These beneficial actions of nicorandil were not shared by the nitrovasodilator sodium nitroprusside but were mimicked by the selective K(+)-channel opener EMD 52692. In a model of irreversible ischemia-reperfusion injury (i.e., 2 h of coronary occlusion followed by reperfusion) in anesthetized dogs, nicorandil produced a marked reduction of myocardial infarct size. An equihypotensive dose of the calcium antagonist nifedipine had no significant effect; however, EMD 52692 produced the same reduction in infarct size as had nicorandil. In isolated, perfused rat hearts subjected to 20 min of low-flow (1.0 ml/min) global ischemia followed by 30 min of reperfusion, nicorandil (7 microM) resulted in a significant improvement in the recovery of isovolumic left ventricular minute work during reperfusion compared with untreated hearts. Finally, the results of in vitro experiments indicated that nicorandil (10(-6) to 10(-3) M) produced a concentration-dependent inhibition of superoxide anion free radical production by human and canine neutrophils. The K(+)-channel opener EMD 52692 also inhibited superoxide production in canine neutrophils. These results indicate that nicorandil is a highly efficacious myocardial protective agent in several animal models of reversible or irreversible ischemia-reperfusion injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardioprotective effects of nicorandil on isoproterenol-induced injury

Nicorandil, a new anti-anginal drug, exerts a coronary vasodilation effect by mechanisms different from either nitrates or slow channel Ca+ + entry blockers. This agent has been demonstrated to increase membrane K+ conductance, elevate cyclic guanosine monophosphate content, and inhibit Ca+ + kinetics in vascular smooth muscle cells. In the myocardium, however, the direct effects of the agent have not been elucidated. We examined whether nicorandil could antagonize myocardial injury in chick hearts induced by a toxic dose of isoproterenol. Isoproterenol treatment (240 mg/kg subcutaneously twice a day for 4 days) caused a significant increase in heart/body weight ratio and induced a remarkable histological perturbation. A substantial accumulation of Ca+ + and a profound decrease of creatine kinase and lactate dehydrogenase activity were observed in the myocardium from isoproterenol-treated chick. Oral administration of nicorandil (4 mg/day for 4 days, 15 min prior to each isoproterenol treatment) attenuated the deterioration induced by isoproterenol. The present study suggests that nicorandil partially protects the myocardium from the isoproterenol-induced injury.

Cardioprotective effects of nicorandil on calcium paradox‐induced injury

AbstractNicorandil, a new antianginal drug, exerts a coronary vasodilation effect by mechanisms different from either nitrates or slow‐channel Ca++ entry blockers. This agent has been demonstrated to increase membrane K+ conductance, elevate cyclic guanosine monophosphate (GMP) content, and depress Ca++ current kinetics in vascular smooth muscle cells. In the myocardium, however, the direct effects of the agent have not been elucidated. We examined whether or not nicorandil could antagonize myocardial injury in the Langendorff‐perfused chick heart induced by the Ca++ paradox. The Ca++ paradox was produced by 15 min of Ca++‐free perfusion, followed by 10 min of Ca++ reperfusion. Nicorandil was added to the perfusing solution only during the Ca++ reperfusion phase. In the Ca++ paradox hearts, the following were observed: (1) depression of myocardial creatine phosphokinase and adenosine triphosphate (ATP) contents; (2) elevations of myocardial H2O, Na+, and Ca++ contents; and (3) ultrastructural derangement, which included contraction bands, interstitial edema, and mitochondrial swelling. Nicorandil treatment significantly attenuated the histological perturbation and part of the biochemical alterations. The present study suggests that nicorandil partially protects the myocardium against the Ca++ paradox‐induced injury.