Nicorandil Prevents Gαq-Induced Progressive Heart Failure and Ventricular Arrhythmias in Transgenic Mice

Masamichi Hirose,Kiyoshi Matsumoto,Naoko Matsushita,Satoshi Suzuki,Fumika Sato,Hisashi Shimojo,Mitsuhiko Yamada,Eiichi Taira,Ulrike Mende,Ulrike Mende,Yasuchika Takeishi,Tsutomu Nakada,Toshihide Kashihara,Ayako Nishio,Vladimir E Bondarenko

doi:10.1371/journal.pone.0052667

Abstract

BackgroundBeneficial 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 still remains unknown. We investigated these inhibitory effects of nicorandil in transgenic mice with transient cardiac expression of activated Gαq (Gαq-TG).Methodology/Principal FindingsNicorandil (6 mg/kg/day) or vehicle was chronically administered to Gαq-TG from 8 to 32 weeks of age, and all experiments were performed in mice at the age of 32 weeks. Chronic nicorandil administration prevented the severe reduction of left ventricular fractional shortening and inhibited ventricular interstitial fibrosis in Gαq-TG. SUR-2B and SERCA2 gene expression was decreased in vehicle-treated Gαq-TG but not in nicorandil-treated Gαq-TG. eNOS gene expression was also increased in nicorandil-treated Gαq-TG compared with vehicle-treated Gαq-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 7 of 10 vehicle-treated Gαq-TG but in none of 10 nicorandil-treated Gαq-TG. The QT interval was significantly shorter in nicorandil-treated Gαq-TG than vehicle-treated Gαq-TG. Acute nicorandil administration shortened ventricular monophasic action potential duration and reduced the number of PVCs in Langendorff-perfused Gαq-TG mouse hearts. Moreover, HMR1098, a blocker of cardiac sarcolemmal KATP channels, significantly attenuated the shortening of MAP duration induced by nicorandil in the Gαq-TG heart.Conclusions/SignificanceThese findings suggest that nicorandil can prevent the development of HF and ventricular arrhythmia caused by the activation of GPCR signaling through the shortening of the QT interval, action potential duration, the normalization of SERCA2 gene expression. Nicorandil may also improve the impaired coronary circulation during HF.

Highlights

It is well known that the abnormalities in coronary hemodynamics in systolic heart failure (HF) are frequent
Conclusions/Significance: These findings suggest that nicorandil can prevent the development of HF and ventricular arrhythmia caused by the activation of G protein aq-coupled receptor (GPCR) signaling through the shortening of the QT interval, action potential duration, the normalization of sarco(endo)plasmic reticulum Ca2+-ATPase 2 (SERCA2) gene expression
We found that chronic administration of nicorandil for 24 weeks prevented the progression of heart failure and ventricular arrhythmia in G protein alpha q (Gaq)-TG mice

Summary

Introduction

It is well known that the abnormalities in coronary hemodynamics in systolic heart failure (HF) are frequent. Myocardial oxygen demand and consumption are increased and myocardial perfusion is impaired in HF, which can result in myocardial ischemia, necrosis and apoptosis This is potentially a factor contributing to progressive heart failure. Chronic nicorandil administration prevented the development of HF in Dahl salt-sensitive hypertensive rats as a result of the promotion of myocardial capillary and arteriolar growth [5]. These findings support the notion that nicorandil may ameliorate HF associated with defective coronary microcirculation. Whether nicorandil has inhibitory effects on HF and ventricular arrhythmias caused by the activation of G protein alpha q (Gaq) -coupled receptor (GPCR) signaling still remains unknown. We investigated these inhibitory effects of nicorandil in transgenic mice with transient cardiac expression of activated Gaq (Gaq-TG)

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Results

Conclusion