title: Utilization of an isolated, blood-perfused canine papillary muscle preparation as a model to assess efficacy and adversity of class I antiarrhythmic drugs.
abstract: To develop a model to predict the efficacy and adversity of class I antiarrhythmic drugs, intraventricular conduction time (IVCT), coronary blood flow (CBF), developed tension of papillary muscle (DT) and idioventricular automaticity rate (VR) were measured following drug administration in an isolated canine papillary muscle preparation cross-circulated with the heparinized blood of a donor dog. Tetrodotoxin, the prototypic fast Na+ channel blocker, and class I drugs increased IVCT and CBF, but decreased DT and VR, in a dose-dependent manner. The profiles of known class I drugs, procainamide, disopyramide, lidocaine, mexiletine and flecainide were similar, but the potencies of each drug were different. Two new class I drugs, ME3202 and AN-132, were also tested and found to have effects that were similar to that of tetrodotoxin. There was a good correlation between the doses of drugs prolonging IVCT by 50% and the canine antiarrhythmic plasma concentrations in our previous study. This model can also be used to estimate the use-dependency and the kinetics of use-dependent sodium channel block; however, it is not suitable for extensive investigation of cellular and molecular mechanisms. Thus, the use of this model facilitates the comparison of multiple cardiac effects of class I drugs and may be an effective way to better assess new antiarrhythmic drugs.
authors.affiliation: Department of Pharmacology, Yamanashi Medical University, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Sugiyama
authors.forename: S
authors.initials: S
authors.lastname: Motomura
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003427:Cross Circulation; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D013779:Tetrodotoxin; D014700:Verapamil