Nicorandil Improves Post-Ischemic Myocardial Dysfunction in Association With Opening the Mitochondrial K&lt;sub&gt;ATP&lt;/sub&gt; Channels and Decreasing Hydroxyl Radicals in Isolated Rat Hearts

Lu, Chuanjiang; Minatoguchi, Shinya; Arai, M.; Wang, Ningyuan; Chen, Xuehai; Bao, Narentuoya; Kawamura, Itta; Yasuda, Shinji; Kobayashi, Hiroyuki; Wu, Dongshuang; Takemura, Genzou; Fujiwara, Hisayoshi

doi:10.1253/circj.70.1650

Cited by 17 publications

(12 citation statements)

References 33 publications

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“…4,17,23,31 In a clinical study, Ono et al reported that intravenous injection of nicorandil before and after reperfusion therapy in patients with acute myocardial infarction was associated with suppression of urinary 8-epi-prostaglandin F2α, a marker for ROS in vivo. 23 In a recent study by Ishibashi et al, a similar antioxidative effect of oral nicorandil therapy was demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Nicorandil Attenuates FeCl3-Induced Thrombus Formation Through the Inhibition of Reactive Oxygen Species Production

Eguchi

Takahari

Higashijima

et al. 2009

Circ J

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Section: Discussionmentioning

confidence: 99%

Nicorandil Attenuates FeCl3-Induced Thrombus Formation Through the Inhibition of Reactive Oxygen Species Production

Eguchi

Takahari

Higashijima

et al. 2009

Circ J

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“…Therefore, nicorandil increases coronary blood flow, reduces preload and afterload, and exerts an anti-anginal effect (19). Although perfusion with nicorandil had previously been demonstrated to produce pharmacological preconditioning-induced cardioprotection in normal hearts (21,23), few studies have been conducted on whether it still exerts cardioprotective effects on hypercholesterolemic hearts, particularly when administrated at the onset of reperfusion or reoxygenation. In the present study, five different concentrations of nicorandil were administrated either before ischemia, or at the onset of reperfusion, in order to induce pharmacological preconditioning and postconditioning, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…A previous randomized and placebo-controlled trial, termed the 'Impact Of Nicorandil in Angina' (20), demonstrated that nicorandil reduced the incidence of major cardiovascular events in patients with stable angina. Nicorandil is not only an antianginal; previous studies have demonstrated that it may also exert potentially cardioprotective effects on I/R myocardium, some of which are likely due to its ability to mimic IPC by opening mitoKATP channels (21)(22)(23). 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).…”

Section: Introductionmentioning

confidence: 99%

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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“…Nicorandil is a K ATP channel opener combining an organic nitrate and a nicotinamide group, respectively, conferring to nicorandil the additional properties of NO donor and antioxidant (Taira 1989;Mano et al 2000). Acute low doses of nicorandil (0.01-1 mg/kg range) have been shown to lower blood pressure, reduce oxidized K ATP channels and restore their activity (Yanagisawa et al 1979;Lu et al 2006), induce dilation of different types of arteries through NO delivery and K ATP channel opening (Kreye et al 1992;Kukovetz et al 1992) and improve the global condition of patients with angina pectoris (Shetty 1994). Acute higher doses of nicorandil (25-100 lg/kg) also result, in a cardiac infarction model in rats, in a decreased formation of microvascular obstruction and reduction of the infarct size (Krombach et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Nicorandil protects ATP-sensitive potassium channels against oxidation-induced dysfunction in cardiomyocytes of aging rats

2008

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ATP-sensitive potassium channels (K(ATP) channels) regulate vascular tone and cardiac contraction through their action on the membrane potential of smooth muscle cells and cardiomyocytes. Because aging and diseases alter K(ATP) channel activity, many pharmacological treatments aimed at improving their function, therefore cardiovascular function, have been evaluated. Nicorandil, a K(ATP) channel opener, nitric oxide donor and antioxidant, is used as a treatment of angina pectoris and induces vasodilation, blood pressure decrease and cardioprotection in aging as well as after ischemia-reperfusion. Here, using the patch-clamp technique, we have studied the effect a chronic low dose of nicorandil (0.1 mg/kg per day for 2 months), on the activity of cardiomyocyte K(ATP) channels as a function of age, in newborn, 4-, 12- and 24-month old rats. Nicorandil exerted an anti-oxidant and protective action on cardiomyocyte K(ATP) channels, especially in aged animals, leading to restoration of a normal channel activity. These findings could justify further therapeutical applications.

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Nicorandil Improves Post-Ischemic Myocardial Dysfunction in Association With Opening the Mitochondrial K<sub>ATP</sub> Channels and Decreasing Hydroxyl Radicals in Isolated Rat Hearts

Cited by 17 publications

References 33 publications

Nicorandil Attenuates FeCl3-Induced Thrombus Formation Through the Inhibition of Reactive Oxygen Species Production

Nicorandil Attenuates FeCl3-Induced Thrombus Formation Through the Inhibition of Reactive Oxygen Species Production

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

Nicorandil protects ATP-sensitive potassium channels against oxidation-induced dysfunction in cardiomyocytes of aging rats

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