Effects of AWD 23-111, a new antiarrhythmic substance, on cardiac conduction and refractoriness

In isolated spontaneously beating guinea pig hearts, the effects of AWD 23-111 (N-(dicyclohexylcarbamoylmethyl)-N-(3-diethylamino-propyl)-4-nit robenzamid -hydrochloride), a new synthetic class III antiarrhythmic agent with sodium antagonistic properties, were investigated on cardiac electrophysiological parameters, that is, conduction and refractoriness. Concentration-dependent prolongation of the atrioventricular, intraventricular, and His bundle conduction times and of sinus node cycle length were present. At 0.3 microM the repolarization period was prolonged significantly. No reverse use-dependent effect on the repolarization period was observed. During rapid pacing (pacing cycle length = 120 ms for the ventricle and 180 ms for the atrium) the rate-dependent intraventricular (QRS) or atrioventricular conduction time (AVCT) prolongation follows an exponential function of the beat number and is characterized by a drug-specific time constant. The time constant for the intraventricular conduction time prolongation in the presence of 0.1 microM AWD 23-111 was very long at 150 +/- 29 beats (mean +/- SEM; n = 6), indicating a slow binding kinetic to the sodium channel. At 0.1 microM AWD 23-111, a significant increase in the ventricular effective refractory period was reached when the interstimulus interval (S1-S1) was 120 ms and the number of conditioning stimuli (S1) was higher than the time constant. The time constant for the rate-dependent AVCT prolongation in the presence of 0.3 microM AWD 23-111 was 34 +/- 6 beats (n = 6). The effective refractory period of the atrioventricular conduction significantly increased with the number of conditioning stimuli (S1), until the number was comparable with the time constant. In conclusion, AWD 23-111 exerts a wide variety of actions on the cardiac conduction system. Its combined effects on the potassium and sodium channels seem to be responsible for the marked rate-dependent effect on ventricular refractoriness and for the lack of a reverse use-dependency on JT prolongation.