Abstract P170: Nicorandil Inhibits Gáq-Induced Chronic Heart Failure in Transgenic Mice

Abstract

Introduction: Beneficial effects of nicorandil on the treatment of hypertensive heart failure (HF) and ischemic heart disease have been suggested. However, whether nicorandil has inhibitory effects on HF and ventricular arrhythmias caused by the activation of G protein alpha q (Gαq) -coupled receptor (GPCR) signaling pathway still remains unknown. We examined effects of chronic and acute administration of nicorandil on the development of HF and ventricular action potential (VAP) in transgenic mice with transient cardiac expression of activated Gαq (Gαq-TG), respectively. Method and Results: Nicorandil (6 mg/kg/day) or vehicle was chronically administered in Gαq-TG mice for 24 weeks from 8 weeks of age, and then ventricular function, and electrical and structural changes were investigated in the hearts. Chronic nicorandil administration improved the reduction of left ventricular fractional shortening (p < 0.001) in Gαq-TG hearts. During 10 min of electrocardiogram recording, premature ventricular contractions (more than 20 beats/min) were observed in 7 of 10 vehicle-treated Gαq-TG but in none of 10 nicorandil-treated Gαq-TG hearts (p < 0.01). QT interval was significantly shorter in nicorandil-treated Gαq-TG than in vehicle-treated Gαq-TG hearts (p < 0.05). Chronic nicorandil administration improved the increased ventricular interstitial fibrosis (p < 0.05) but not cardiac hypertrophy in Gαq-TG left ventricles. Real time RT-PCR revealed that mRNA expression levels of s sulfonylurea receptor 2B (SUR-2B) were decreased in vehicle-treatd Gαq-TG but not in nicorandil-treated Gαq-TG. In addition, chronic nicorandil increased endotherial nitric oxide syntheses gene expression in Gαq-TG hearts (p < 0.05). Acute nicorandil administration (1 microM) significantly shortened the prolonged VAP duration and reduced the number of PVCs in vehicle treated Gαq-TG hearts. Conclusions: These findings suggest that nicorandil inhibits ventricular electrical and structural remodeling and arrhythmias through the shortening of VAP duration and the increased expression of SUR-2B and eNOS in a mouse model of HF.