KINETICS OF INTERACTION OF DISOPYRAMIDE WITH THE CARDIAC SODIUM-CHANNEL - FAST DISSOCIATION FROM OPEN CHANNELS AT NORMAL REST POTENTIALS

Block of cardiac sodium channels is enhanced by repetitive depolarizat ion. It is not clear whether the changes in drug binding result from a change in affinity that is dependent on voltage or On the actual stat e of the channel. This question was examined in rabbit ventricular myo cytes by analyzing the kinetics of block of single sodium channel curr ents with normal gating kinetics or channels with inactivation and dea ctivation slowed by pyrethrin toxins. At -20 and -40 mV, disopyramide 100 muM blocked the unmodified channel. Mean open time decreased 45 an d 34% at -20 and -40 mV during exposure to disopyramide. Exposure of c ells to the pyrethrin toxins deltamethrin or fenvalrate caused at leas t a tenfold increase in mean open time, and prominent tail currents co uld be recorded at the normal resting potential. The association rate constant of disopyramide for the normal and modified channel at -20 mV was similar, approximately 10 x 10(6)/m/sec. During exposure to disop yramide, changes in open and closed times and in open channel noise at -80 and -100 mV are consistent with fast block and unblocking events at these potentials. This contrasts with the slow unbinding of drug fr om resting channels at similar potentials. We conclude that the sodium channel state is a critical determinant of drug binding and unbinding kinetics.