Cardiac electrophysiology of the antiarrhythmic agent recainam (Wy-42,362) in anesthetized dogs: relation to plasma and myocardial concentrations.
The present study was undertaken to characterize the cardiac electrophysiologic effects of the investigational class I antiarrhythmic agent recainam (Wy-42,362) on the canine heart in situ, and to determine the possible relationship between these effects and the concentration of drug in plasma and myocardium. Cardiac conduction times and refractory periods were measured at a paced cycle length of 300 ms in open-chest anesthetized dogs by recording atrial, ventricular, and His bundle electrograms. Recainam was infused intravenously (as a loading + maintenance dose) at either (a) 7.5 mg/kg/20 min + 5 mg/kg/60 min (low-dose group) or (b) 15 mg/kg/20 min + 10 mg/kg/60 min (high-dose group). Samples of plasma and ventricular myocardium were removed at selected times for subsequent analysis. At the end of the maintenance infusion, low-dose recainam produced a plasma concentration of 4.1 +/- 0.5 micrograms/ml and significantly increased atrial conduction time only. Plasma levels with high-dose recainam reached 9.4 +/- 3.5 micrograms/ml at end infusion, and produced significant increases in all measured electrophysiologic parameters except ventricular refractory period. Myocardial levels of recainam were undetectable in the low-dose group, but increased linearly with plasma concentration in the high-dose group with a myocardium/plasma ratio of nearly 1:1. Changes in ventricular conduction time, H-V interval, atrial and ventricular refractory periods, and Wenckebach cycle length correlated significantly with recainam concentration in plasma. In addition, drug levels in the ventricle correlated with the observed changes in both ventricular conduction time and ventricular refractory period. The data suggest that recainam plasma levels may serve as a useful guide in monitoring electrophysiologic response to this agent.
D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000502:physiology*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D010671:Phenylurea Compounds; C039524:recainam