Electrophysiological effects of OPC‐88117, a new antiarrhythmic agent on papillary muscles and single ventricular myocytes isolated from guinea‐pig hearts

Abstract

1 The effects of OPC-88117, a new antiarrhythmic agent, on transmembrane action potentials were examined in right ventricular papillary muscles and in single ventricular myocytes isolated from guinea-pig hearts. 2 In papillary muscles, OPC-88117 above 3 x 10-6M caused a dose-dependent prolongation of action potential duration (APD). The curves relating membrane potential and V,,ax were shifted by OPC-88117 to the direction of more negative potentials (9 mV at 10-M).6 In single ventricular myocytes treated with OPC-88117 (1-3 x 1O-4M), the V,,.ax of test action potentials preceded by conditioning clamp pulses to 0 mV was decreased progressively as the clamp pulse duration was prolonged. 7 These findings suggest that the primary electrophysiological effect of OPC-88117 on the cardiac muscle cell is prolongation of APD (Class III action) and that at high concentrations, it may also possess a lignocaine-like sodium channel inhibitory effect (Class I action).

Electropharmacology of OPC‐88117, A New Antiarrhythmic Agent

“…The small tonic block of Vmax by OPC-88 1 17 in normally polarized papillary muscle (22) is consistent with such an assumption. The recovery process of Vmax from the use-dependent block may reflect the dissociation of drug molecule from the inactivated or the resting sodium channels (8).…”

“…IC, of Vmax inhibition by OPC-88 1 17, which was obtained by interpolation in a graph of log molar concentrations versus responses, was 9.4 X 1 O-' M . The prolongation of APD was not affected by stimulation frequencies ranging from 0.5 to 2.0 Hz, whereas the inhibition of Vmax was enhanced at higher frequencies (22).…”

Effects of antiarrhythmic drugs on canine ventricular arrhythmia models: Which electrophysiological characteristics of drugs are related to their effectiveness?

“…Also, the effectiveness of Na channel blockers can be explained by their action suppressing the responsiveness. An investigational drug, OPC 88117 [14,45], was reported to specifically suppress triggered activity in vitro, but it was effective both on the triggered arrhythmia and on spontaneously occurring arrhythmias, especially adrenaline arrhythmia.…”

Effects of OPC‐88117, a new antiarrhythmic agent, on the electrophysiological properties of rabbit isolated hearts

“…This inhibition of ,V"= by OPC-88117 was shown to be augmented at higher stimulation frequencies Toyama et al, 1989). The different threshold concentration of OPC-88117 required to prolong H-V and St-LV intervals in the rabbit hearts can be explained by the frequency-dependent inhibition of V., The H-V interval was measured under right atrial stimulation at a cycle length of 400 ms (2.5 Hz), whereas the St-LV interval was measured under His bundle stimulation at a cycle length of 1000 ms (1 Hz).…”

“…The threshold concentration for this action (3 x 10-6 M) was lower than that for the negative dromotropic effect. In guinea-pig papillary muscles, OPC-88117 above 3 x 10-6M was shown to prolong the action potential duration (APD) in a dosedependent manner Toyama et al, 1989). The prolongation of ERPHB, FRPHB and ERPVM is, therefore, most likely due to the prolongation of APD in Purkinje and ventricular muscle fibres.…”