EFFECTS OF AWD-23-111, A NEW ANTIARRHYTHMIC SUBSTANCE, ON CARDIAC CONDUCTION AND REFRACTORINESS

In isolated spontaneously beating guinea pig hearts, the effects of AW D 23-111 iethylamino-propyl)-4-nitrobenzamidhydrochloride), a new synt hetic class III antiarrhythmic agent with sodium antagonistic properti es, were investigated on cardiac electrophysiological parameters, that is, conduction and refractoriness. Concentration-dependent prolongati on of the atrioventricular, intraventricular, and His bundle conductio n times and of sinus node cycle length were present. At 0.3 mu M the r epolarization period was prolonged significantly. No reverse use-depen dent effect on the repolarization period was observed. During rapid pa cing (pacing cycle length = 120 ms for the ventricle and 180 ms for th e atrium) the rate-dependent intraventricular (QRS) or atrioventricula r conduction time (AVCT) prolongation follows an exponential function of the beat number and is characterized by a drug-specific time consta nt. The time constant for the intraventricular conduction time prolong ation in the presence of 0.1 mu M AWD 23-111 was very long at 150 +/- 29 beats (mean +/- SEM; n = 6), indicating a slow binding kinetic to t he sodium channel. At 0.1 mu M AWD 23-111, a significant increase in t he ventricular effective refractory period was reached when the inters timulus interval (S1-S1) was 120 ms and the number of conditioning sti muli (S1) was higher than the time constant. The time constant for the rate-dependent AVCT prolongation in the presence of 0.3 mu M AWD 23-1 11 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 t ime constant. In conclusion, AWD 23-111 exerts a wide variety of actio ns on the cardiac conduction system. Its combined effects on the potas sium and sodium channels seem to be responsible for the marked rate-de pendent effect on ventricular refractoriness and for the lack of a rev erse use-dependency on JT prolongation.