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

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 μmol·litre−1) caused a dose dependent decrease in the maximum upstroke velocity (![Graphic][1] max) of the action potential without affecting the resting potential. In the presence of AN-132, trains of stimuli at rates ≥0.1 Hz led to an exponential decline in ![Graphic][2] max. This use dependent block was enhanced at higher stimulation frequency. The time constant for the recovery of ![Graphic][3] max from the use dependent block was 39.5-41.2 s. The curves relating membrane potential and ![Graphic][4] max were shifted by AN-132 (100 μmol·litre−1) in the direction of more negative potentials (6.1 mV). In preparations treated with AN-132 (30 and 100 μmol·litre−1), the ![Graphic][5] max of test action potentials preceded by conditioning clamp pulses to 0 mV was progressively decreased with an increasing number of pulses. A single prolonged clamp pulse to 0 mV reduced ![Graphic][6] max much less than multiple brief clamp pulses. These findings suggest than 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 ![Graphic][7] max in depolarised muscles through the increase in tonic block may play a major role in preventing ventricular arrhythmias. [1]: /embed/inline-graphic-2.gif [2]: /embed/inline-graphic-3.gif [3]: /embed/inline-graphic-4.gif [4]: /embed/inline-graphic-5.gif [5]: /embed/inline-graphic-6.gif [6]: /embed/inline-graphic-7.gif [7]: /embed/inline-graphic-8.gif