Block of wild-type and inactivation-deficient cardiac sodium channels IFM/QQQ stably expressed in mammalian cells

The role of inactivation as a central mechanism in blockade of the cardiac Na+ channel by antiarrhythmic drugs remains uncertain. We have used whole-c ell and single channel recordings to examine the block of wild-type and ina ctivation-deficient mutant cardiac Na+ channels, IFM/QQQ, stably expressed in HEK-293 cells. We studied the open-channel blockers disopyramide and fle cainide, and the lidocaine derivative RAD-243. All three drugs blocked the wild-type Na+ channel in a use-dependent manner. There was no use-dependent block of IFM/QQQ mutant channels with trains of 20 40-ms pulses at 150-ms interpulse intervals during disopyramide exposure. Flecainide and RAD-243 r etained their use-dependent blocking action and accelerated macroscopic cur rent relaxation. All three drugs reduced the mean open time of single chann els and increased the probability of their failure to open. From the abbrev iation of the mean open times, we estimated association rates of similar to 10(6)/M/s for the three drugs. Reducing the burst duration contributed to the acceleration of macroscopic current relaxation during exposure to fleca inide and RAD-243. The qualitative differences in use-dependent block appea r to be the result of differences in drug dissociation rate. The inactivati on gate may play a trapping role during exposure to some sodium channel blo cking drugs.