Frequency and voltage dependent effects of AN-132, a new class I anti-arrhythmic agent, on max of action potential upstroke in guinea pig ventricular muscles

Abstract

The in vitro electrophysiological properties of a newly synthesised antiarrhythmic agent, AN-132, were evaluated by recording transmembrane action potentials from guinea pig papillary muscles. AN-132 (10-100 .mu.mol .cntdot. litre-1) caused a dose dependent decrease in the maximum upstroke velocity (.ovrhdot.Vmax) of the action potential without affecting the resting potential. In the presence of AN-132, trains of stimuli at rates .gtoreq. 0.1 Hz led to an exponential decline in .ovrhdot.Vmax. This use dependent block was enhanced at higher stimulation frequency. The time constant for the recovery for .ovrhdot.Vmax from the use dependent block was 39.5-41.2 s. The curves relating membrane potential and .ovrhdot.Vmax were shifted by AN-132 (100 .mu.mol .cntdot. litre-1) in the direction of more negative potentials (6.1 mV). In preparations treated with AN-132 (30 and 100 .mu.mol .cntdot. litre-1), the .ovrhdot.Vmax of test action potentials preceded by conditioning clamp pulses of 0 mV was progressively decreased with an increasing number of pulses. A single prolonged clamp pulse to 0 mV reduced .ovrhdot.Vmax much less than multiple brief clamp pulses. These findings suggest that AN-132 has use dependent inhibitory action on the fast sodium channel by binding to the channel mainly during its activated state and that the unbinding rate of the drug during diastole is very slow. This use dependency and its greater inhibition of .ovrhdot.Vmax in depolarised muscles through the increase in tonic block may play a major role in preventing ventricular arrhythmias.