The electrophysiological effects of propafenone, a class Ic antiarrhythmic drug, were studied and compared in isolated sheep Purkinje fibers and ventricular muscles. At concentrations between 10(-7)-10(-6) propafenone decreased the amplitude and maximum of depolarization (Vmax) of the action potential in both the ventricular muscle and Purkinje fibers, without altering the resting potential. At higher concentrations these effects were accompanied by depolarization of the membrane potential, a shift in the membrane responsiveness curve, and a progressive depression of conduction velocity through the Purkinje fiber-ventricular muscle junction leading to conduction block. In addition, propafenone exerted differential effects on the repolarization time course of Purkinje fibers and the ventricular muscle. At concentrations up to 10(-6) M, propafenone shortened the action potential duration at 90% of repolarization (APD90) in Purkinje fibers, while it lengthened the APD90 in the ventricular muscle, which resulted in a more uniform repolarization. However, at higher concentrations, propafenone increased the disparity in APD between Purkinje fibers and the ventricular muscle, which results in an increased inhomogeneity of ventricular repolarization. It is concluded that propafenone may aggravate and/or induce sustained ventricular tachyarrhythmias by increasing the likelihood of incessant reentry, i.e., by slowing conduction with a minor prolongation of refractoriness and producing a nonuniform recovery of excitability.