We have previously shown that combination therapy with mexiletine and quinidine is more effective and causes fewer side effects than either agent alone in the treatment of patients with serious ventricular arrhythmias. To further assess this enhanced antiarrhythmic effect, the electrophysiologic actions of mexiletine and quinidine alone and in combination were evaluated in isolated perfused rabbit hearts. Dose-response curves were constructed for right ventricular effective refractory period, epicardial monophasic action potential duration, and conduction time (the time from pacing stimulus to the upstroke of the monophasic action potential signals) during constant rate pacing. No significant changes in these parameters were seen in 15 preparations treated with saline over a duration of 1 h (a time equal to the longest experiments). With gradually increasing concentrations of mexiletine (2.3-36 microM) prolongation of conduction time (12 +/- 5 msec, mean +/- SE, p less than 0.05) paralleled change in ventricular refractoriness (20 +/- 5 msec, mean +/- SE, p less than 0.05) but occurred in the absence of any significant change in monophasic action potential duration. With gradually increasing concentrations of quinidine (0.55-34 microM/L) prolongation of ventricular refractoriness (65 +/- 7 msec, mean +/- SE, p less than 0.01) and monophasic action potential duration (65 +/- 7 msec, mean +/- SE, p less than 0.01) occurred in parallel and at concentrations less than those required to prolong conduction time.(ABSTRACT TRUNCATED AT 250 WORDS)