Early afterdepolarization (EAD)-induced triggered activity is thought to contribute to the cardiac arrhythmogenic effects of several class I antiarrhythmic agents. The combination of quinidine therapy, bradycardia, and hypokalemia is known to predispose to torsade de pointes, which is a form of atypical polymorphous ventricular tachycardia commonly associated with long QT intervals. Recent clinical reports have shown suppression of quinidine-induced torsade de pointes with intravenous administration of magnesium sulfate. To provide further understanding of these relations, we used standard microelectrode techniques to examine the time course of quinidineinduced action potential prolongation, EAD, and triggered activity development and the dependence of these changes on [K+]0, [Mg2+]O, and stimulation frequency in isolated Purkinje fiber preparations exposed to low concentrations of the drug. At slow stimulation rates, the quinidineinduced increase of action potential duration was slow to develop and failed to reach a steady state after 3 hours of exposure to the drug. EAD and EAD-induced triggered activity generally became apparent 70-90 minutes after adding the drug. Quinidine produced triggered activity in 10 of 22 preparations superfused with Tyrode's solution containing normal [K+]0 (3.5-4.0 mM) and in six other preparations when [K%]0 was reduced. In the presence of normal [K]0, two types of EAD and triggered activity were distinguished. In four of 10 preparations, this activity arose from phase 2 of the action potential; in eight of 10, it was associated with phase 3; and in two experiments, both types were present in the same preparation. The incidence of both forms of triggered responses depended greatly on the rate of stimulation. Triggered activity arising from phase 3 was always manifest at rates considerably slower than those giving rise to phase 2 activity. Both forms of triggered activity were sensitive to changes in the extracellular concentration of potassium and magnesium. Lower-than-normal levels of these electrolytes facilitated the manifestation of triggered activity, whereas elevated levels suppressed or caused a shift in the frequency-dependence of the activity. In the clinic, the combination of bradycardia, hypokalemia, and quinidine is known to predispose to torsade de pointes, which is a form of atypical polymorphous ventricular tachycardia characterized in the electrocardiogram by "twisting" of the ventricular complexes around the isoelectric line. Torsade de pointes is commonly associated with QT