Electropharmacology of Ro 22-9194, a new antiarrhythmic agent

Abstract

1. 1. Ro 22-9194 (⩾10 μM) caused a concentration-dependent decrease in the maximum upstroke velocity (V̇ max) and shortening of action potential duration in guinea-pig ventricular cells. 2. 2. The V̇ max inhibition by Ro 22-9194 was enhanced in a use-dependent manner. A time constant for V̇ max recovery from the use-dependent block was 9.3 sec. Conditioning depolarizing clamp experiments in ventricular cells indicated that Ro 22-9194 may block sodium channels, mainly during the activated state. 3. 3. Ro 22-9194⩾30 μM inhibited calcium inward current (I Ca) of the ventricular cells. 4. 4. In dogs in vivo Ro 22-9194 (0.1–3 mg/kg, IV) caused a dose-dependent prolongation of atrioven-tricular conduction time with greater prolongation of His-ventricular (HV) than atrio-His (AH) intervals. Ro 22-9194 had a potent inhibitory action against various types of model arrhythmias. 5. 5. Ro 22-9194 may exert its antiarrhythmic activity primarily by a use-dependent sodium channel block. From the onset and offset kinetics of the use-dependent block, it belongs to the intermediate kinetic Class I drugs. From the state-dependence of the channel block, it belongs to activated channel blockers.