ELECTROPHYSIOLOGICAL EFFECTS OF RO-22-9194, A NEW ANTIARRHYTHMIC AGENT, ON GUINEA-PIG VENTRICULAR CELLS

1 Cardiac effects of Ro 22-9194 were examined in papillary muscles and single ventricular myocytes isolated from guinea-pigs and compared wi th those of moricizine. 2 In papillary muscles, both Ro22-9194 (greate r than or equal to 10 mu M) and moricizine (greater than or equal to 1 mu M) caused a significant dose-dependent decrease in the maximum ups troke velocity (V-max) and a shortening of the action potential durati on. 3 In the presence of either drug, trains of stimuli at rates great er than or equal to 0.2 Hz led to an exponential decline in V-max. Thi s use-dependent block was enhanced at higher stimulation frequencies. A time constant (tau R) for V-max,,, recovery from the use-dependent b lock was 9.3 s for Ro 22-9194 and 26.4 s for moricizine. 4 The curves relating membrane potential and V-max,, in single myocytes were shifte d by Ro 22-9194 (30 mu M) or by moricizine (3 mu M) in a hyperpolarizi ng direction by 8.4 mV and 8.0 mV respectively. 5 In myocytes treated with Ro22-9194 (30 mu M), a 10 ms conditioning clamp to 0 mV caused a significant decrease in V-max,, of the subsequent test action potentia l; further prolongation of the clamp pulse duration resulted in a mode st enhancement of the V-max inhibition. In the presence of moricizine (3 mu M), a similar conditioning clamp > 200 ms caused a significant V -max,, reduction; the longer the clamp pulse duration, the greater the V-max reduction. 6 Ro 22-9194 greater than or equal to 30 mu M caused a slight decrease of calcium inward current (I-Ca) of myocytes withou t affecting the delayed rectifier potassium current (I-K). 7 These fin dings suggest that the primary electrophysiological effect of Ro 22-91 94 as an antiarrhythmic agent is, like moricizine, a use- and voltage- dependent inhibition of sodium channels. From the onset and offset kin etics of the use-dependent block, Ro 22-9194 belongs to the intermedia te kinetic Class I drugs, while moricizine is a slow kinetic drug. Fro m the state-dependence of sodium channel block, Ro 22-9194 may belong to activated channel blockers, while moricizine belongs to inactivated channel blockers.