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.

Cellular electrophysiology of the new antiarrhythmic agent recainam (Wy-42,362) in canine cardiac Purkinje fibers.

Recainam, [N-2,6-dimethylphenyl-N'-3-(1-methylethyl-amino)propylurea] hydrochloride (Wy-42,362), is a new class I antiarrhythmic agent that has been shown to be very effective in suppressing premature ventricular contractions in humans. To clarify the mechanism of antiarrhythmic action, the electrophysiologic effects of recainam were examined in canine cardiac Purkinje fibers using standard microelectrode techniques. Recainam at 3-100 microM (1-30 micrograms/ml) produced concentration-dependent decreases in action potential duration (APD), membrane responsiveness, and maximal upstroke velocity (Vmax). The reduction in Vmax was strongly modulated by the frequency of stimulation--i.e., Vmax block was use dependent. The rate of development of use-dependent block produced by recainam was much slower than typically seen with lidocaine, but comparable with that of the class Ia agents disopyramide and procainamide. However, unlike agents of the Ia subclass, recainam did not prolong APD at any concentration or cycle length tested. In summary, recainam appears to possess a novel cardiac cellular electrophysiologic profile, in that it shares characteristics with all three current class I antiarrhythmic subclasses.

Efficacy of the antidepressant iprindole against experimental arrhythmias.

The antiarrhythmic activity of iprindole was compared to that of imipramine in a variety of experimental arrhythmia models. Iprindole at 20 mg/kg i.v. showed efficacy in reverting ouabain- and aconitine-induced arrhythmias in pentobarbital anesthetized dogs, and at 15-30 mg/kg i.v. reduced the severity of the ventricular arrhythmias following acute coronary artery occlusion in anesthetized pigs. Imipramine (5-10 mg/kg i.v.) was also effective in reverting ouabain- and aconitine-induced arrhythmias, but appeared to exacerbate arrhythmias during coronary occlusion. In microelectrode experiments on isolated dog Purkinje fibers, iprindole reduced maximal upstroke velocity (Vmax) and action potential duration (characteristics of Class Ib antiarrhythmic agents) at concentrations greater than 1 microgram/ml. Significant decreases in Vmax occurred at lower iprindole concentrations when membrane potential was reduced by increasing external potassium from 4 to 10 mM, suggesting that electrical activity in depolarized cells may be selectively suppressed by iprindole. The present data indicate that iprindole may exert beneficial therapeutic effects in the treatment of cardiac arrhythmias, mediated, at least in part, through a Class I mechanism of action.