Transmembrane electrical activity was recorded from endo- and epicardium of isolated segments of guinea pig right ventricles with standard microelectrode techniques. An ECG was also recorded by two electrodes placed at opposite ends of the tissue bath. Regular stimulation was delivered to the endocardium. Tissues were exposed to simulated ischemia for 15 min and then were reperfused with "normal" Tyrode's solution. Rapid sustained or nonsustained ventricular tachycardia, bigeminy or trigeminy with characteristics of transmural reentry occurred in early reperfusion in 14 of 20 hearts (70%). Arrhythmias were accompanied by prolongation of transmural conduction time and abbreviation of endocardial effective refractory period. With lidocaine, at 1, 5, 10 and 50 microM, reperfusion arrhythmias occurred in 53.3, 22.2, 20.8 and 14.3% of hearts, respectively. The decreased incidence of arrhythmias was statistically significant for 5 to 50 microM lidocaine (P less than .01). The antiarrhythmic effect did not correlate with changes in transmural conduction time, endocardial effective refractory period, or endocardial excitability. However, antiarrhythmic concentrations of lidocaine selectively depressed epicardial excitability and significantly increased endo- to epicardial conduction block during late ischemic and early reperfusion periods. Epicardial inexcitability extended to late diastole and conduction block was not restricted to premature beats. Thus, in transmural reentry in which the epicardium is an essential component of the circuit, lidocaine may interrupt the circuit by selectively rendering this component inexcitable.