title: Blunted proarrhythmic effect of nicorandil in a Langendorff-perfused phase-2 myocardial infarction rabbit model.
abstract: BACKGROUND
  Nicorandil (a K(ATP) opener) administration is reported to reduce ventricular arrhythmias 4.8 ± 2.2 hours after myocardial infarction (MI). The electrophysiological changes and the effects on dynamic factors and dynamically induced spatially discordant alternans by nicorandil during phase-2 MI are unclear.
  
  
  METHODS
  Simultaneous voltage and intracellular Ca(2+) (Ca(i)) optical mapping was performed in nine Langendorff-perfused hearts 4-5 hours after coronary artery ligation and nine control hearts. Action potential duration (APD) restitution was constructed and arrhythmogenic alternans was induced by dynamic pacing. Western blot studies (Kir6.1 and Kir6.2) were performed in six more hearts for both groups. Nicorandil (100 μM) was administered after baseline studies.
  
  
  RESULTS
  Phase-2 MI hearts showed longer APD, slower conduction velocity (CV), and higher ventricular fibrillation (VF) inducibility than the control hearts. Nicorandil shortened and restored APD without significant arrhythmogenic effects, and also increased the rate of Ca(i) reuptake and flattened CV restitution to suppress spatially discordant alternans, which might account for a tendency toward higher VF threshold with nicorandil infusion in phase-2 MI hearts. Immunoblotting studies showed significant down-regulation of K(ATP) protein expression, which was functionally correlated to the blunted APD shortening response to nicorandil.
  
  
  CONCLUSIONS
  K(ATP) expression is down-regulated in phase-2 MI hearts. Nicorandil restores APD, increases the rate of Ca(i) reuptake, and flattens CV restitution to suppress spatially discordant alternans induction, which ameliorates its proarrhythmic effects during phase-2 MI.
authors.affiliation: Department of Anesthesia, Chang Gung Memorial Hospital, Taipei, Taiwan.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Lee
authors.forename: Po-Cheng
authors.initials: PC
authors.lastname: Chang
authors.forename: Chung-Chuan
authors.initials: CC
authors.lastname: Chou
authors.forename: Hung-Ta
authors.initials: HT
authors.lastname: Wo
authors.forename: Yen
authors.initials: Y
authors.lastname: Chu
authors.forename: Ming-Shien
authors.initials: MS
authors.lastname: Wen
authors.forename: San-Jou
authors.initials: SJ
authors.lastname: Yeh
authors.forename: Delon
authors.initials: D
authors.lastname: Wu
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D009203:Myocardial Infarction / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*; D020108:Nicorandil / Q000627:therapeutic use*; D010477:Perfusion; D011817:Rabbits; D016896:Treatment Outcome; D014693:Ventricular Fibrillation / Q000175:diagnosis / Q000503:physiopathology* / Q000517:prevention & control*
chemical_list: D000889:Anti-Arrhythmia Agents; D020108:Nicorandil