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

Objective: To study the interaction between salicylate and class 1 antiarrh ythmic agents. Methods: The effects of salicylate on class 1 antiarrhythmic agent-induced tonic and phasic block of the Na+ current (I-Na) of ventricu lar myocytes and the upstroke velocity of the action potential (V-max) of p apillary muscles were examined by both the patch clamp technique and conven tional microelectrode techniques. Results: Salicylate enhanced quinidine-in duced 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(infinity) curve in the presence of quinidine in a further hyperpolarized direction, although salicylate alone did not affect I-Na. Sa licylate enhanced the tonic and phasic block of V-max induced by quinidine, aprindine and disopyramide but had little effect on that induced by procai namide or mexiletine; the enhancing effects were related to the liposolubil ity of the drugs. Conclusions: Salicylate enhanced tonic and phasic block o f Na+ channels induced by class 1 highly liposoluble antiarrhythmic agents. Based on the modulated receptor hypothesis, it is probable that this enhan cement was mediated by an increase in the affinity of Na+ channel blockers with high lipid solubility to the inactivated state channels. (C) 1999 Else vier Science B.V. All rights reserved.