| First Author | Hirose M | Year | 2012 |
| Journal | PLoS One | Volume | 7 |
| Issue | 12 | Pages | e52667 |
| PubMed ID | 23285142 | Mgi Jnum | J:195749 |
| Mgi Id | MGI:5485133 | Doi | 10.1371/journal.pone.0052667 |
| Citation | Hirose M, et al. (2012) Nicorandil prevents Galphaq-induced progressive heart failure and ventricular arrhythmias in transgenic mice. PLoS One 7(12):e52667 |
| abstractText | 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 (Galpha(q)) -coupled receptor (GPCR) signaling still remains unknown. We investigated these inhibitory effects of nicorandil in transgenic mice with transient cardiac expression of activated Galpha(q) (Galpha(q)-TG). METHODOLOGY/PRINCIPAL FINDINGS: Nicorandil (6 mg/kg/day) or vehicle was chronically administered to Galpha(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 Galpha(q)-TG. SUR-2B and SERCA2 gene expression was decreased in vehicle-treated Galpha(q)-TG but not in nicorandil-treated Galpha(q)-TG. eNOS gene expression was also increased in nicorandil-treated Galpha(q)-TG compared with vehicle-treated Galpha(q)-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 7 of 10 vehicle-treated Galpha(q)-TG but in none of 10 nicorandil-treated Galpha(q)-TG. The QT interval was significantly shorter in nicorandil-treated Galpha(q)-TG than vehicle-treated Galpha(q)-TG. Acute nicorandil administration shortened ventricular monophasic action potential duration and reduced the number of PVCs in Langendorff-perfused Galpha(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 Galpha(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. |
