Open and inactivated sodium channel block by class-I antiarrhythmic drugs

Inhibitory action of six Class-I antiarrhythmic drugs on cardiac sodium channel was examined in isolated guinea-pig ventricular muscles. Transmembrane potential of the tissue was controlled by single sucrose gap voltage clamp technique. Following 30 sec quiescent period, a conditioning clamp pulse was applied from resting potential level to 0 mV for 10 msec to 800 msec. 100 msec after returning to the resting potential, voltage clamp was released and an action potential was elicited to measure its maximum upstroke velosity (Vmax) as an index of sodium channel availability. Under control condition such clamp pulse application did not affect the value of Vmax. In preparations treated with quinidine, and disopyramide, Vmax was decreased appreciably by the shortest clamp pulse application, but the Vmax reduction was enhanced only slightly by prolongation of the clamp pulse duration. In cases with lidocaine, mexiletine, tocanide and aprindine, the decrease in Vmax was enhanced much more remarkably by similar prolongation of the clamp pulse duration. These findings suggest the quinidine and disopyramide may block sodium channel mainly during open state. In contrast, lidocaine, mexiletine, tocainide and aprindine may block the channel mainly during inactivated state. Such a difference would cause wide variety of action potential duration dependency for the effects of Class-I drugs.