The hemodynamic effects of enalaprilat (MK-422) and lisinopril (MK-521) were compared with the calcium channel blocker felodipine in dogs with ischemic left ventricular (LV) failure. The combination of nitrendipine plus enalapril was also examined in ischemic failure and in rats with spontaneous hypertension. In anesthetized dogs coronary embolization with 50 μm plastic microspheres reduced cardiac output and LV dP/dt max by ∼40%, and LV end-diastolic pressure increased to >13 mm Hg. Enalaprilat and lisinopril reduced mean arterial pressure by a maximum of 20 mm Hg and total peripheral resistance by ∼30%. Left ventricular dP/ dt:LVP, which was substantially decreased by embolization, was slightly increased by both angiotensin converting enzyme (ACE) inhibitors. The calcium entry blockers felodipine and nitrendipine qualitatively produced many of the same hemodynamic effects as the ACE inhibitors, but, in addition, they markedly reduced coronary resistance, increased myocardial blood flow, and did not alter cardiac contractility (LV dP/dt max). In spontaneously hypertensive rats single doses of nitrendipine (1.25 to 5.0 mg/kg per os) and enalapril (0.3 and 3.0 mg/kg per os) reduced mean arterial pressure, but differences were observed in the onset (enalapril 2 h versus nitrendipine 0.5 h), the duration of action, and magnitude of effect. In terms of blood pressure lowering, nitrendipine, 5.0 mg/kg per os, was clearly additive to 3.0 mg/kg per os of enalapril, but other combinations (enalapril, 3 mg/kg per os plus 0.625 mg/kg of nitrendipine or enalapril, 0.3 mg/kg per os plus 0.625 mg/kg nitrendipine) were not. In summary, the present experiments demonstrated that enalaprilat- and lisinopril-induced reduction in afterload contributes to the beneficial effects of these agents in heart failure. A further improvement (increased myocardial perfusion) in the hemodynamic status of dogs with acute failure was evident following the administration of a calcium channel blocker. In spontaneously hypertensive rats the combination of a calcium channel blocker with an ACE inhibitor produced additive antihypertensive activity. Thus, in at least two experimental models of cardiovascular disease it has been possible to demonstrate beneficial effects of combining a calcium channel blocker with an ACE inhibitor.