title: Nicorandil prevents Gαq-induced progressive heart failure and ventricular arrhythmias in transgenic mice.
abstract: 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 (Gα(q)) -coupled receptor (GPCR) signaling still remains unknown. We investigated these inhibitory effects of nicorandil in transgenic mice with transient cardiac expression of activated Gα(q) (Gα(q)-TG).
  
  
  RESULTS
  Nicorandil (6 mg/kg/day) or vehicle was chronically administered to Gα(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 Gα(q)-TG. SUR-2B and SERCA2 gene expression was decreased in vehicle-treated Gα(q)-TG but not in nicorandil-treated Gα(q)-TG. eNOS gene expression was also increased in nicorandil-treated Gα(q)-TG compared with vehicle-treated Gα(q)-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 7 of 10 vehicle-treated Gα(q)-TG but in none of 10 nicorandil-treated Gα(q)-TG. The QT interval was significantly shorter in nicorandil-treated Gα(q)-TG than vehicle-treated Gα(q)-TG. Acute nicorandil administration shortened ventricular monophasic action potential duration and reduced the number of PVCs in Langendorff-perfused Gα(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 Gα(q)-TG heart.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Iwate Medical University School of Pharmaceutical Sciences, Shiwa, Iwate, Japan. mhirose@iwate-med.ac.jp
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hirose
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakada
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shimojo
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kashihara
authors.forename: Ayako
authors.initials: A
authors.lastname: Nishio
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mende
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Naoko
authors.initials: N
authors.lastname: Matsushita
authors.forename: Eiichi
authors.initials: E
authors.lastname: Taira
authors.forename: Fumika
authors.initials: F
authors.lastname: Sato
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Yamada
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D006332:Cardiomegaly / Q000235:genetics / Q000517:prevention & control; D004562:Electrocardiography; D005260:Female; D005355:Fibrosis / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020108:Nicorandil / Q000008:administration & dosage / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D050052:TRPC Cation Channels / Q000378:metabolism; D018879:Ventricular Premature Complexes / Q000188:drug therapy / Q000235:genetics
chemical_list: D000889:Anti-Arrhythmia Agents; D054086:KATP Channels; D012333:RNA, Messenger; D050052:TRPC Cation Channels; D020108:Nicorandil; D019001:Nitric Oxide Synthase; D043802:GTP-Binding Protein alpha Subunits, Gq-G11