The role of inactivation in the cumulative blockage of voltage-dependent sodium channels by local anesthetics and antiarrythmics.

Previously published results (Khodorov 1973; Khodorov et al. 1974, 1976; Zaborovskaya 1976) showed that along with a decrease in the maximum sodium permeability ('tonic block') the tertiary amine local anesthetics (LA), procaine and trimecain cause a drastic slowing of Na channel reactivation after membrane depolarization. This effect ("drug-induced slow Na inactivation") underlies a use-dependent Na current (JNa) inhibition during repetitive membrane depolarization. A detailed analysis of these data led Khodorov et al. (1976) to conclude that inactivation of Na channels increased their affinity to LA which in turn resulted in stabilization of the inactivated channel conformation. The aim of the present work was to test this hypothesis using chloramine-T as a reagent capable of removing the ordinary ('fast') Na channels inactivation (Wang 1983). We have examined the effect of chloramine T (CT) treatment of the nodal membrane on use-dependent (cumulative) inhibition of JNa by lidocaine, tetracain, and the antiarrhythmic compounds N-propyl ajmaline (NPA) and KC 3791 (KC) (see Fig. 2A).