Enhancing effects of salicylate on quinidine-induced block of human wild type and LQT3 related mutant cardiac Na + channels

Abstract

It is unknown whether salicylate enhances the action of antiarrhythmic agents on human Na+ channels with state dependency and tissue speciicity. We therefore investigated effects of salicylate on quinidine-induced block of human cardiac and skeletal muscle Na + channels. Human cardiac wild-type (hH1), LQT3-related mutant (ΔKPQ), and skeletal muscle (hSkM1) Na + channel α subunits were expressed in COS7 cells. Effects of salicylate on quinidine-induced tonic and usedependent block of Na + channel currents were examined by the whole-cell patch-clamp technique. Salicylate enhanced the quinidine-induced tonic and use-dependent block of both hH1 and hSkM1 currents at a holding potential (HP) of -100 mV but not at -140 mV. Salicylate decreased the IC 50 value for the quinidine-induced tonic block of hH1 at an HP of -100 mV, and produced a negative shift in the steady-state inactivation curve of hH1 in the presence of quinidine. According to the modulated receptor theory, it is probable that salicylate decreases the dissociation constant for quinidine binding to inactivated-state channels. Furthermore, salicylate signiicantly enhanced the quinidine-induced tonic and use-dependent block of the peak and steady-state ΔKPQ channel currents. The results suggest that salicylate enhances quinidine-induced block of Na + channels via increasing the afinity of quinidine to inactivated state channels.