Electrophysiologic effects of TYB-3823, a new antiarrhythmic agent, on isolated guinea pig ventricular muscles

The effects of a newly synthesized antiarrhythmic agent, TYB-3823 on the transmembrane action potential were examined in isolated papillary muscles of guinea pig. TYB-3823 (3 x 10(-6)-3 x 10(-5)M) caused a dose-dependent decrease in the maximum upstroke velocity (Vmax) and a shortening of action potential duration (APD). In the presence of TYB-3823, trains of stimuli at rates greater than or equal to 0.2 Hz led to an exponential decline in Vmax. This use-dependent block was enhanced at higher stimulation frequency. The time constant for the recovery of Vmax from the use-dependent block was 12.6-13.4 s. The curves relating membrane potential and Vmax were shifted by TYB-3823 (3 x 10(-5)M) to the direction of more negative potentials (5.7 mV). In preparations treated with TYB-3823 (10(-5)-3 x 10(-5) M), the Vmax of test action potentials preceded by conditioning clamp pulses to 0 mV was progressively decreased by increasing the duration of a single clamp pulse or by increasing the number of multiple brief clamp pulses. These findings suggest that TYB-3823 has use- and voltage-dependent inhibitory action on the fast sodium channel by binding to the channel during its activated and inactivated states, and that the unbinding rate of the drug from the channel is very slow. Such characteristics of sodium channel block in combination with APD shortening effect would provide unique antiarrhythmic activities of this substance.