Protective mechanism of nicorandil on rat myocardial ischemia-reperfusion

Wang, Ailing; Chen, Feng; Xie, Yangjing; Yu, Yuanxun

doi:10.2459/jcm.0b013e3283542031

Cited by 25 publications

(19 citation statements)

References 33 publications

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“…Nishikawa et al (25) demonstrated that nicorandil inhibited hypoxia-induced Bcl-2 downregulation and Bax upregulation in mitochondria, and thus protected cardiomyocytes. Furthermore, Wang et al (26) also found that, when administered before/during ischemia or at the onset of reperfusion, nicorandil increased Bcl-2 expression and reduced Bax expression in normal Sprague-Dawley rats. In agreement with these observations, the present study demonstrated that respective nicorandil preconditioning and postconditioning significantly upregulated the expression of Bcl-2 and downregulated the expression of Bax in hypercholesterolemic hearts, suggesting that the cardioprotective effects of nicorandil may be mediated by regulation of the Bcl-2 family.…”

Section: Discussionmentioning

confidence: 97%

“…Fig. 4 26.18±4.82%) respectively, as compared with untreated samples. Together, these results suggested that nicorandil preconditioning and postconditioning may protect hypercholesterolemic hearts against I/R-induced infarction and apoptosis, which are both stimulated by the opening of mitoKATP channels and a NO/sGC dependent mechanism.…”

Section: Effects Of a High-cholesterol Diet On Serum Lipid Levelsmentioning

confidence: 99%

“…However, previous studies have shown that nicorandil, as a NO donor, may inhibit oxidative stress-or hypoxia-induced apoptosis in cardiomyocytes, through the activation of mitoKATP channels and a NO/soluble guanylyl cyclase (sGC)-dependent mechanism (24,25). Furthermore, nicorandil has been shown to be associated with the regulation of apoptosis-related proteins (25,26).…”

Section: Introductionmentioning

confidence: 99%

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

Shu

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. 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.

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Section: Discussionmentioning

confidence: 97%

Section: Effects Of a High-cholesterol Diet On Serum Lipid Levelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Shu

et al. 2015

Experimental and Therapeutic Medicine

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“…Sakai (17) reported that nicorandil exerted blood pressure-lowing effects, which subsequently reduced cardiac hypertrophy in animals (17). Regardless of the precise mechanism of nicorandil in cardiovascular diseases, our previous study also demonstrated the protective effects of nicorandil against myocardial ischemia-reperfusion injury, which were due in part to the opening of mitoK ATP channels (13). It was found in the present study that long-term oral administration of nicorandil is beneficial for the reduction of cardiac hypertrophy and modulation of myocardial Cx43 in Iso-induced rat models of cardiac hypertrophy.…”

Section: A B C D Ementioning

confidence: 87%

“…Activation of the K ATP channel inhibits GJ permeability and subsequently attenuates arrhythmias in the acute ischemic myocardium (10). Numerous studies have demonstrated the protective effect of Cx43 against ischemic injury by the administration of a K ATP channel agonist (11)(12)(13). However, no favorable effects have been shown in transgenic animals with a Cx43 deficiency (10).…”

Section: Introductionmentioning

confidence: 99%

Reduction of isoproterenol-induced cardiac hypertrophy and modulation of myocardial connexin43 by a KATP channel agonist

Sun

Wang

Hao

et al. 2014

Molecular Medicine Reports

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Abstract. Cardiac hypertrophy is a compensatory mechanism that occurs in conjunction with cardiovascular diseases. Although hypertrophy of the myocardium provides certain benefits during the early stages of cardiovascular disease, prolonged hypertrophy is potentially harmful to the heart and can result in arrhythmia and heart failure. The aim of this study was to investigate whether an ATP-sensitive K + (K ATP ) channel agonist was capable of reducing isoproterenol (Iso)-induced cardiac hypertrophy and modulating myocardial connexin43 (Cx43) expression. Fifty male Sprague Dawley rats were randomly assigned to five groups: Normal, vehicle, nicorandil, glibenclamide and nicorandil plus glibenclamide. Rats in the four treatment groups received Iso injection for seven days, followed by administration with saline, nicorandil, glibenclamide or a combination of nicorandil and glibenclamide, respectively, for four weeks. Cardiac hypertrophy was then evaluated by measuring body weight, heart weight and left-ventricular weight, and plasma B-type natriuretic peptide levels were evaluated by ELISA. Immunocytochemistry and a reverse transcription-polymerase chain reaction were performed to detect the spatial distribution and gene expression of myocardial Cx43, respectively. The K ATP channel agonist nicorandil markedly attenuated the degree of myocardial hypertrophy induced by Iso as compared with the vehicle group. Myocardial Cx43 expression was significantly decreased and redistributed following cardiac hypertrophy. The decrease and redistribution of Cx43 was reduced following treatment with the K ATP channel agonist nicorandil. Addition of the K ATP channel blocker glibenclamide eliminated the beneficial effects of nicorandil against hypertrophy and on connexin43.In conclusion, the present study indicated that chronic use of K ATP channel agonists following cardiac hypertrophy can attenuate ventricular remodeling and upregulate the expression level and spatial distribution of Cx43.

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Nicorandil inhibits cardiomyocyte apoptosis and improves cardiac function by suppressing the HtrA2/XIAP/PARP signaling after coronary microembolization in rats

Zheng

Long

Qin

et al. 2021

Pharmacology Res & Perspec

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Cardiomyocyte apoptosis is a key factor in the deterioration of cardiac function after coronary microembolization (CME). Nicorandil (NIC) affects myocardial injury, which may be related to the inhibition of apoptosis. However, the specific mechanism of cardioprotection has not been elucidated. Therefore, we analyzed the impact of NIC on cardiac function in rats subjected to CME and its effect on the high‐temperature requirement peptidase 2/X‐linked inhibitor of apoptosis protein/poly ADP‐ribose polymerase (HtrA2/XIAP/PARP) pathway. Sprague Dawley rats were divided into four groups: Sham, CME, CME + NIC, and CME + UCF. Echocardiography was performed 9 hours after CME. Myocardial injury markers were evaluated in blood samples, and the heart tissue was collected for hematoxylin‐eosin staining, hematoxylin basic fuchsin picric acid staining staining, TdT‐mediated DUTP nick end labeling (TUNEL) staining, Western blot analysis of the HtrA2/XIAP/PARP pathway, and transmission electron microscopy. NIC ameliorated cardiac dysfunctioncaused by CME and reduced serum levels of CK‐MB and LDH. In addition, NIC decreased myocardial microinfarct size and apoptotic index. NIC reduced the Bax/Bcl‐2 ratio, levels of cleaved caspase 3/9, cytoplasmic HtrA2, and cleaved PARP, and increased the level of XIAP. The effects of NIC were similar to those of the HtrA2 inhibitor, UCF101. This study demonstrated that NIC reduces CME‐induced myocardial injury, reduces mitochondrial damage, and improves myocardial function. The reduction in cardiomyocyte apoptosis by NIC may be mediated by the HtrA2/XIAP/PARP signaling pathway.

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Protective mechanism of nicorandil on rat myocardial ischemia-reperfusion

Abstract: A suitable level of nicorandil has a protective effect on rats' myocardial ischemia-reperfusion injury, and is mainly based on the opening of the mitochondrial KATP channel and the lowing of Ca overload.

Cited by 25 publications

References 33 publications

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

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

Reduction of isoproterenol-induced cardiac hypertrophy and modulation of myocardial connexin43 by a KATP channel agonist

Nicorandil inhibits cardiomyocyte apoptosis and improves cardiac function by suppressing the HtrA2/XIAP/PARP signaling after coronary microembolization in rats

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