Stereospecific Effects of Disopyramide Enantiomers Following Pretreatment of Canine Cardiac Purkinje Fibers with Verapamil and Nisoldipine

Abstract

The effect of racemic disopyramide and its enantiomers on the action potential was studied in Tyrodes (4.0 mM KCL)-superfused canine cardiac Purkinje fibers. Nonstereodependent depression of action potential amplitude and phase 0 Vmax was observed in control fibers and following pretreatment with either nisoldipine or verapamil. Stereospecific effects of the enantiomers were prominent during repolarization phases of the action potential and could be modified by pretreatment with the calcium channel blocking agents. R(-) disopyramide decreased action potential duration at 90% repolarization and shortened the effective refractory period. S(+) disopyramide increased action potential duration at 90% repolarization and prolonged refractoriness. This disparate effect of the enantiomers was eliminated following pretreatment with verapamil. Stereospecific effects on repolarization persisted when fibers were pretreated with nisoldipine, a more selective calcium channel blocking agent that lacks effects on outward plateau current. The data suggest that the increase in action potential duration and refractoriness produced by disopyramide is mediated by a stereospecific inhibition of outward repolarizing current by the S(+) enantiomer.