Cardiovascular Drugs and Therapy

, Volume 18, Issue 1, pp 13–22

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

  • Shigeo Horinaka
  • Naohiko Kobayashi
  • Akihisa Yabe
  • Hiroshi Asakawa
  • Hiroshi Yagi
  • Yousuke Mori
  • Yusuke Tsubokou
  • Koutarou Yoshida
  • Shigefumi Nakano
  • Hiroaki Matsuoka
Article

DOI: 10.1023/B:CARD.0000025751.82774.a9

Cite this article as:
Horinaka, S., Kobayashi, N., Yabe, A. et al. Cardiovasc Drugs Ther (2004) 18: 13. doi:10.1023/B:CARD.0000025751.82774.a9

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.

nicorandilmyocardial infarctionarrhythmiaendothelial nitric oxideadenosine triphosphate sensitive potassium channel

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Shigeo Horinaka
    • 1
  • Naohiko Kobayashi
    • 1
  • Akihisa Yabe
    • 1
  • Hiroshi Asakawa
    • 1
  • Hiroshi Yagi
    • 1
  • Yousuke Mori
    • 1
  • Yusuke Tsubokou
    • 1
  • Koutarou Yoshida
    • 1
  • Shigefumi Nakano
    • 1
  • Hiroaki Matsuoka
    • 1
  1. 1.Department of Hypertension and Cardiorenal MedicineDokkyo University School of MedicineMibu, TochigiJapan