Block of Na+ channel by moricizine hydrochloride in isolated feline ventricular myocytes.

The effect of moricizine hydrochloride, a potent class I antiarrhythmic agent, on Na+ current (INa) of single feline ventricular myocytes were studied using whole cell patch clamp techniques. Moricizine inhibited INa in a concentration-dependent manner without altering the current-voltage relationship for INa. INa inhibition was expressed by the Hill equation with a Hill coefficient of 1.3 and dissociation constant of 105 microM in the resting state (holding potential = -140 mV). Moricizine 30 microM shifted the steady state inactivation curve for INa toward more negative potentials by 7.3 +/- 2.4 mV without causing significant changes in the slope factor. Recovery of INa from inactivation was retarded (time constant = 8 s) at a holding potential of -140 mV in the presence of 30 microM moricizine. When the start of INa block was studied in experiments using a double pulse protocol, moricizine reduced INa by only 4% after a 4-ms prepulse, but strongly inhibited it after prepulses longer than 200 ms. Intracellular application of 100 microM moricizine did not produce significant resting or use-dependent INa block. These results suggest that (1) moricizine blocks INa by binding to the Na+ channel with a 1:1 stoichiometry, (2) the drug has a higher affinity to the inactivated state than to the activated and resting states of the Na+ channel, (3) recovery kinetics of moricizine from Na+ channel inactivation, or drug dissociation observed during the transition from inactivated to resting state was relatively slow, (4) the drug binding site appeared to be located on the external side of the membrane.