Enhancing effects of salicylate on tonic and phasic block of Na + channels by class 1 antiarrhythmic agents in the ventricular myocytes and the guinea pig papillary muscle

Abstract

Objective: To study the interaction between salicylate and class 1 antiarrhythmic agents. Methods: The effects of salicylate on class 1 antiarrhythmic agent-induced tonic and phasic block of the Na + current ( I Na) of ventricular myocytes and the upstroke velocity of the action potential ( V max) of papillary muscles were examined by both the patch clamp technique and conventional microelectrode techniques. Results: Salicylate enhanced quinidine-induced tonic and phasic block of I Na at a holding potential of −100 mV but not at a holding potential of −140 mV; this enhancement was accompanied by a shift of the h ∞ curve in the presence of quinidine in a further hyperpolarized direction, although salicylate alone did not affect I Na. Salicylate enhanced the tonic and phasic block of V max induced by quinidine, aprindine and disopyramide but had little effect on that induced by procainamide or mexiletine; the enhancing effects were related to the liposolubility of the drugs. Conclusions: Salicylate enhanced tonic and phasic block of Na + channels induced by class 1 highly liposoluble antiarrhythmic agents. Based on the modulated receptor hypothesis, it is probable that this enhancement was mediated by an increase in the affinity of Na + channel blockers with high lipid solubility to the inactivated state channels.