We studied the relation between [K+]o and the electrophysiologic changes during a "Harris two-stage ligation," which is an occlusion of a coronary artery, preceded by a 30-minute period of 50% reduction of flow through the artery. This two-stage ligation has been reported to be antiarrhythmic. Local direct current electrograms and [K+]o signals from up to 48 intramural sites were simultaneously recorded in isolated, perfused dog hearts. A second period of one-stage ligation was compared with a consecutive two-stage ligation because reproducibility in [K+]o and electrophysiologic changes are established only after the first period of ischemia. In control experiments, no difference was found between the second and third period of one-stage ligation in the electrophysiologic changes and in increases in [K+]o. After complete occlusion during two-stage ligation, activation block in the ischemic tissue occurred about 6 minutes earlier than during one-stage ligation, but the average potassium concentration at which block occurred was identical. This [K+]o during total ischemia was achieved earlier during two-stage ligation than during one-stage ligation. No indication was found for a large decrease of intracellular potassium content during the period of low flow perfusion. Early activation block may explain the previously reported reduced incidence of ventricular fibrillation during two-stage ligation.