Effects of bepridil on the electrophysiologic properties of isolated canine and rabbit myocardial fibers

Abstract

Bepridil hydrochloride is a relatively new calcium antagonist which appears to have a complex pharmacologic profile, but its concentration-response characteristics with respect to its electrophysiologic properties of varying concentrations (0.1 to 10.0 μg/ml) of the drug were therefore determined in rabbit and canine myocardial fiber preparations in vitro by standard microelectrode techniques. The following were measured: sinus cycle length (SCL), action potential amplitude (APA), maximum diastolic potential (MDP), threshold potential (TP), slope of phase 4 depolarization, action potential duration (APD), and dV dt max of phase 0 depolarization (V max) in rabbit sinoatrial (SA) node. Also measured were APA, membrane resting potential (MRP), V max, APD at 50% and 90% repolarization (APD 50 and APD 90), and effective refractory period (ERP) in rabbit atria and canine Purkinje fibers and ventricular muscle. At the lowest concentrations bepridil selectively prolonged SCL by reducing the slope of phase 4 and decreased APA and MDP in a concentration-dependent manner in the sinus node. At higher concentrations, bepridil exerted additional effects in producing concentration-dependent decreases in APA and V max in rabbit atria and in canine Purkinje fibers and ventricular muscle. During superfusion with 1.0 μg/ml bepridil, V max fell by 22.2% ( p < 0.05) in Purkinje fibers and by 11.8% (NS) in ventricular muscle; at 10.0 μg/ml, V max fell by 46.5% ( p < 0.01), respectively. The depression of V max was frequency dependent. There was a differential effect of bepridil on repolarization in Purkinje fibers as compared to that in ventricular muscle. The APD 50 and APD 90 in Purkinje fibers were shortened, respectively, by 29.6% ( p < 0.05) and 5.5% (NS) at 1.0 μg/ml, and by 45.0% ( p < 0.01) and 14.1% ( p < 0.05) at 10.0 μg/ml. By contrast, in ventricular muscle, they were lengthened by 17.1% (NS) and 16.7% ( p < 0.05) at 1.0 μg/ml, and by 37.9% ( p < 0.05) and 33.7% ( p < 0.01) at 10.0 μg/ml. Slow-response potentials induced by high K + (20 mM) and isoproterenol (2 × 10 −6M) were suppressed by bepridil (0.1 μg/ml) but reversed by high Ca 2+ concentrations (7.2mM). Automatic firing induced by isoproterenol (1 × 10 −6M) in Purkinje fibers was slowed by bepridil (0.01 μg/ml) by both the depression of phase 4 depolarization and the elevation of the threshold potential. The data indicate that bepridil has a relative selectivity of inhibitory action for the slow channel with a significant depressant effect on the fast sodium inward current at higher concentrations. Bepridil differs from most fast-channel inhibitors in exerting a differential effect on repolarization in Purkinje fibers vs ventricular muscle.