title: Mechanisms of preventive effect of nicorandil on ischaemia-induced ventricular tachyarrhythmia in isolated arterially perfused canine left ventricular wedges.
abstract: Whether nicorandil is effective at preventing ventricular tachyarrhythmia (VT) during acute myocardial ischaemia is still controversial. We examined effects of nicorandil on the induction of VT during acute myocardial ischaemia. Optical action potentials were recorded from the entire transmural wall of arterially perfused canine left ventricular wedges. Ischaemia was produced by arterial occlusion for 20 min. During endocardial pacing, nicorandil shortened mean action potential duration (APD) in the transmural wall before ischaemia and further shortened it during ischaemia without increasing dispersion of APD. HMR1098, a selective blocker of sarcolemmal ATP-sensitive K(+) channels, inhibited the shortening of APD by nicorandil before and during ischaemia. Ischaemia decreased transmural conduction velocity (CV). Nicorandil partially restored CV to a similar extent in the absence and presence of HMR1098. In contrast, HMR1098 did not suppress the ischaemic conduction slowing in the absence of nicorandil. Nicorandil suppressed the increased dispersion of local CV during ischaemia. Isochrone maps on the initiation of VT showed that reentry in the transmural surface resulted from the excitation of the epicardial region of transmural surface. Nicorandil significantly increased the size of non-excited area in the epicardial region of the transmural wall, thereby significantly reducing the incidence of VT induced during ischaemia. HMR1098 inhibited this effect of nicorandil. These results suggest that nicorandil prevents VT during acute global ischaemia primarily by augmenting the inactivation of epicardial muscle through the activation of sarcolemmal K(ATP) channels.
authors.affiliation: Department of Molecular Pharmacology, Shinshu University School of Medicine, Nagano, Japan. hirose@sch.md.shinshu-u.ac.jp
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hirose
authors.forename: Natsuko
authors.initials: N
authors.lastname: Tsujino
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakada
authors.forename: Shiharu
authors.initials: S
authors.lastname: Yano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Imamura
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Yamada
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D004336:Drug Antagonism; D004558:Electric Stimulation; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology* / Q000517:prevention & control; D020108:Nicorandil / Q000627:therapeutic use*; D009924:Organ Culture Techniques; D010477:Perfusion; D013050:Spectrometry, Fluorescence / Q000379:methods; D013610:Tachycardia / Q000503:physiopathology* / Q000517:prevention & control; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology* / Q000517:prevention & control
chemical_list: D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D020108:Nicorandil; C410297:HMR 1098