The purpose of this study was to determine whether specific angiotensin II (AII) type 1 receptor blockade with losartan would affect arrhythmia generation in an isolated guinea pig ventricular model of simulated ischemia and reperfusion. Effects of losartan were evaluated in the presence and absence of exogenous AII. Transmembrane potentials and an electrocardiogram were recorded during perfusion with normal Tyrode's solution, exposure to simulated ischemia for 15 min (hypoxia, acidosis, lactate, hyperkalemia, glucose-free) and reperfusion for 30 min. Under normal conditions, losartan did not affect endocardial or transmural conduction times, action potential duration at 90% repolarization or effective refractory period (ERP). However, losartan and AII each had significant effects on electrophysiological parameters during simulated ischemia and reperfusion. Further, losartan and AII, both independently and in combination, exerted antiarrhythmic effects in early reperfusion. Neither losartan nor AII affected action potential duration at 90% repolarization during simulated ischemia or reperfusion. However, AII exerted antiarrhythmic effects by preventing pronounced shortening of ERP in simulated ischemia and early reperfusion. Losartan by itself had no effect on ERP, but completely blocked the antiarrhythmic action of AII on ERP. Nevertheless, losartan preserved antiarrhythmic efficacy by attenuating prolongation of transmural conduction times in stimulated ischemia and early reperfusion. This antiarrhythmic action occurred in the absence or presence of AII. Our results indicate that losartan has antiarrhythmic efficacy which is independent of AII type 1 receptor blockade.