Prolongation of the cardiac action potential (AP), leading eventually to early afterdepolarizations (EADs), is believed to underlie drug-induced long QT syndromes and torsade de pointes. Episodes of torsade de pointes frequently occur after a prolonged pause. We studied the effects of quinidine and disopyramide on AP duration (APD) in canine cardiac Purkinje fibers after pauses of 2,000-10,000 ms. Standard intracellular microelectrode techniques were used to record APs from canine Purkinje fibers at an interstimulus interval (ISI) of 1,000 ms. Pauses of 2,000-10,000 ms were introduced into the basic drive cycle in the presence and absence of subtherapeutic and therapeutic concentrations of quinidine and disopyramide. We observed a biphasic response in APD to quinidine and disopyramide at ISI = 1,000 ms. Quinidine but not disopyramide produced a marked dose- and time-dependent additional prolongation of APD immediately after the pauses. This effect was highly statistically significant. We conclude that disopyramide and quinidine have qualitatively different effects on APD after a pause and that this observation may cast some light on the apparently greater frequency of torsade de pointes occurring with quinidine than with disopyramide. Possible mechanisms include differential drug effects on outward potassium or inward sodium channels.