Antiarrhythmic and hemodynamic effects of the calcium channel antagonist verapamil were compared with those of tiapamil, a congener, in open-chest pigs with anterior descending coronary artery ligation. Tiapamil (6 mg/kg i.v.) decreased the incidence of ventricular fibrillation to 4 of 10 versus 22 of 25 in controls (p less than 0.05) and maintained left ventricular dP/dtmax after ligation (predrug value: 2,312 +/- 112 mm Hg/sec; 20 minutes after ligation: 2,139 +/- 229 mm Hg/sec). Tiapamil increased blood flow in the peripheral ischemic zone (24 +/- 3.2% vs. 16.9 +/- 1.6% of preligation value in controls, p less than 0.05) as well as in the peri-ischemic and nonischemic zones (153.9 +/- 12.7% and 186.3 +/- 17.1%, respectively; both p less than 0.0001 vs. 97.9 +/- 5% and 91.3 +/- 4.7% in controls). Verapamil (0.6 mg/kg i.v.) decreased the incidence of ventricular fibrillation to 0 of 7 versus 22 of 25 in controls (p less than 0.005); left ventricular dP/dtmax decreased from 2,062 +/- 144 to 1,060 +/- 168 mm Hg/sec (p less than 0.0001). Verapamil did not change blood flow in the peripheral, peri-ischemic, or nonischemic zones. Thus, tiapamil, and not verapamil, decreased ischemic ventricular fibrillation while maintaining left ventricular mechanical function. Verapamil congeners warrant further evaluation as antiarrhythmic agents in acute myocardial ischemia.