Nicorandil Prevents G Alpha(Q)-Induced Progressive Heart Failure And Ventricular Arrhythmias In Transgenic Mice

Background: 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 (G alpha(q)) -coupled receptor (GPCR) signaling still remains unknown. We investigated these inhibitory effects of nicorandil in transgenic mice with transient cardiac expression of activated G alpha(q) (G alpha(q)-TG).Methodology/Principal Findings: Nicorandil (6 mg/kg/day) or vehicle was chronically administered to G alpha(q)-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 G alpha(q)-TG. SUR-2B and SERCA2 gene expression was decreased in vehicle-treated G alpha(q)-TG but not in nicorandil-treated G alpha(q)-TG. eNOS gene expression was also increased in nicorandil-treated G alpha(q)-TG compared with vehicle-treated G alpha(q)-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 7 of 10 vehicle-treated G alpha(q)-TG but in none of 10 nicorandil-treated G alpha(q)-TG. The QT interval was significantly shorter in nicorandil-treated G alpha(q)-TG than vehicle-treated G alpha(q)-TG. Acute nicorandil administration shortened ventricular monophasic action potential duration and reduced the number of PVCs in Langendorff-perfused G alpha(q)-TG mouse hearts. Moreover, HMR1098, a blocker of cardiac sarcolemmal K-ATP channels, significantly attenuated the shortening of MAP duration induced by nicorandil in the G alpha(q)-TG heart.Conclusions/Significance: These 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.