title: Effects of disopyramide and mexiletine on the terminal repolarization process of the in situ heart assessed using the halothane-anesthetized in vivo canine model.
abstract: This study was designed to assess the effects of typical class I drugs on the terminal repolarization process of the in situ heart, which is a useful marker of the potential of drug-induced long QT syndrome. Disopyramide (0.3 and 3.0 mg/kg per 10 min, n = 6) or mexiletine (0.3 and 3.0 mg/kg per 30s, n = 6) was intravenously administered to halothane-anesthetized beagle dogs under the monitoring of multiple cardiovascular parameters. Antiarrhythmic concentrations were obtained with the high dose of each drug. The low dose of disopyramide or mexiletine hardly affected any of the electrophysiological parameters assessed. The high dose of disopyramide prolonged the monophasic action potential duration (MAP90) and effective refractory period (ERP) to a similar extent, thus displacing the terminal repolarization period backward, which might provide a potential proarrhythmic substrate, particularly at a slow heart rate. On the other hand, the high dose of mexiletine shortened the MAP90, but prolonged the ERP, resulting in the disappearance of the terminal repolarization period, which could prevent premature excitation with its associated conduction slowing. These electrophysiological effects of disopyramide and mexiletine on the terminal repolarization phase may at least in part explain their clinically described antiarrhythmic and proarrhythmic properties.
authors.affiliation: Department of Pharmacology, Yamanashi Medical University, Nakakoma-gun, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
authors.forename: Yoshioki
authors.initials: Y
authors.lastname: Satoh
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ishida
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kugiyama
authors.forename: Keitaro
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D018685:Anesthetics, Inhalation; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects*; D004195:Disease Models, Animal; D004206:Disopyramide / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D004562:Electrocardiography; D006221:Halothane; D006339:Heart Rate / Q000187:drug effects; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D008801:Mexiletine / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D018685:Anesthetics, Inhalation; D000889:Anti-Arrhythmia Agents; D008801:Mexiletine; D004206:Disopyramide; D006221:Halothane