Nicorandil Protects Against Lethal Ischemic Ventricular Arrhythmias and Up-regulates Endothelial Nitric Oxide Synthase Expression and Sulfonylurea Receptor 2 mRNA in Conscious Rats with Acute Myocardial Infarction

Abstract

Nicorandil is an adenosine triphosphate sensitive K (K-ATP) channel opener and a nitric oxide donor. K-ATP channels and nitric oxide are important factors in ischemic preconditioning, which in turn suppresses reperfusion arrhythmias. The present study sought to evaluate whether nicorandil suppresses ischemic-induced ventricular arrhythmias and enhances sulfonylurea receptors (SUR 2; subunit of K-ATP channel), endothelial nitric oxide (eNOS), and inducible nitric oxide (iNOS) expression in the left ventricle after myocardial infarction without reperfusion. Thirty male Sprague-Dawley rats at 7 weeks of age were separated into three groups, as follows. Acute myocardial infarction was induced in twenty rats by ligating the left main coronary artery. Ten of these twenty rats were continuously administered nicorandil at 3 mg/kg/day i.p. The other ten rats were left untreated. The ten controls were untreated and sham-operated. After coronary ligation, ventricular arrhythmias were evaluated from stored ECG signals. At 24 hours after treatment, eNOS, iNOS, and SUR2 mRNA levels and eNOS, iNOS expression in the left ventricle were determined by reverse transcription polymerase chain reaction (RT-PCR) and by immunohistochemical staining, respectively. Nicorandil suppressed the total number of ventricular arrhythmias from 1 to 2 hours, the total duration of ventricular tachycardia from 2 to 3 hours, and that of ventricular fibrillation from 1 to 2 and from 4 to 5 hours after coronary ligation. Nicorandil improved the survival rate 24 hours after coronary ligation. Levels of SUR2 mRNA increased only in left ventricles treated with nicorandil, particularly in the non-ischemic myocardium. eNOS mRNA was enhanced 2.2-fold in the area at risk in infarcted controls compared to sham-operated rats. In the non-ischemic area and area at risk of rats treated with nicorandil compared to sham-operated rats, eNOS mRNA was enhanced 3.3- and 2.7-fold, respectively. Staining indicated that the highest concentrations of eNOS occurred in the endothelium and myocardium of the non-ischemic area of rats treated with nicorandil. iNOS mRNA was present in both the area at risk and the non-ischemic area only in infarcted rats, and levels thereof were higher in the area at risk than in the non-ischemic area. However, there was no difference in iNOS mRNA levels between nicorandil-treated rats and controls. iNOS exhibited stronger staining in the area at risk than in the non-ischemic area of both nicorandil-treated and infarcted controls, with no differences between these two groups of rats. The mechanisms of protection against lethal ventricular tachyarrhythmia in nicorandil may increase nitric oxide release by upregulated eNOS expression through the opening of K-ATP channels and/or a K-ATP channels opener itself after acute myocardial infarction.

Benefit of nicorandil using an immunologic murine model of experimental colitis

“…As mentioned previously, nicorandil contains a nitrate moiety in its chemical structure, allowing it to function as a NO donor. On the other hand, other investigations [56,57] showed that nicorandil is able to upregulate eNOS expression and increase NO release following ischemia. Thus, it seems that upregulation of eNOS, which leads to acute production of NO, in addition to the NO donor property of nicorandil and the nicotinamide moiety that makes it a potent hydroxyl radical scavenger, is partially or totally responsible for its beneficial effects in remission of IBD.…”

Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes

“…Although doses of nicorandil and cromakalim used in the current study were higher than previous study in dogs they failed to shorten QT interval in the anesthetized rabbits. This is may be due to the differences in pharmacokinetics and pharmacodynamics of drugs in different animal species (D'Alonzo et al, 1994a(D'Alonzo et al, , 1994bHorinaka et al, 2004). The finding of the current study showed that pinacidil induced VF in about 20% of the anesthetized rabbits.…”

Drugs modulating the L-arginine:NO:cGMP pathway – current use in therapy

“…In the ischemic myocardium, nicorandil has revealed cardioprotective effects. This is demonstrated by reduced myocardial necrosis and improved myocardial stunning [22] following administration. Angina pectoris is brought about by transient episodes of myocardial ischemia which create an imbalance in the myocardial oxygen supply and demand relationship.…”

“…Both mechanisms of its action contribute to vasodilation, but are independent. At lower concentrations, nicorandil activates the K ATP channel, while at higher concentrations, it acts through NO donation [21,22]. Nicorandil brings about sustained vasodilation, it markedly relaxes coronary vascular smooth muscle and increases the coronary blood flow.…”