The possible antifibrillatory effect of cicletanide, a new diuretic antihypertensive drug, was investigated at random in 50 anesthetized dogs subjected to left circumflex coronary artery ligation for 60 min and later reperfused. In this model, standard electrocardiographic leads 2 and 3 were continuously registered to measure delta R wave percent changes, to count the number of ventricular premature beats, and to document the onset of ventricular fibrillation; aortic pressure was recorded; 6-keto PGF1 alpha and TXB2 plasma levels were determined. Cicletanide significantly reduced early (Phase 1a) postischemic ventricular fibrillation (5 of 25 vs. 12 of 25, p = 0.036) but failed to reduce the incidence of global ischemia-induced ventricular fibrillation. On the other hand, the incidence of postreperfusion ventricular fibrillation was lower in the cicletanide group (1 of 14 vs. 5 of 9, p = 0.04). In addition, the total survival rate was improved in cicletanide treated dogs (p = 0.0257). While the rate-pressure product was lowered by the drug independent of the presence of ischemia, delta R% changes after occlusion were less in treated dogs than in controls. Moreover, the drug reduced significantly the number of ventricular premature beats in the early (Phase 1a) postischemic period. Finally, the drug increased (mean two-fold) the plasma levels of 6-keto PGF1 alpha as compared with controls; however, this increase was less than that achieved (mean 20-fold) after 100 ng/kg/min epoprostenol (prostacyclin) given in a further series of animals. Thus, improved outcome follows 10 mg/kg i.v. cicletanide administration in this model.