We investigated the mechanism of the antiatherosclerotic effect of the angiotensin-converting enzyme (ACE) inhibitor, ramipril, in the apolipoprotein (apo) E-deficient mice. Mice that received a high dose (5 mg/kg/day) of ramipril supplemented in their drinking water for 10 weeks showed reduced aortic lesion size by 75% compared with placebo-treated mice. At this dosage, ramipril significantly reduced blood pressure from 95+/-5 mm Hg before treatment to 68+/-4 mm Hg at the end of the treatment period. Ramipril also increased the resistance of the mouse low-density lipoprotein (LDL) to CuSO4-induced oxidation, as shown by a prolongation of the lag time required for the initiation of LDL oxidation from 90 min in the placebo-treated mice to >180 min in the ramipril-treated mice. Similarly, a reduction in the maximal LDL-associated conjugated dienes after 180 min of oxidation by 250% in comparison with placebo-treated mice was noted. Ramipril (1 mg/kg/day) that was still adequate to reduce their plasma ACE activity and LDL propensity to lipid peroxidation was insufficient to reduce their blood pressure. This dosage also inhibited the progression of atherosclerosis in the apo E-deficient mice by 74%. The contribution of bradykinin potentiation to the ACE-inhibitor action was assessed by cotreatment of ramipril with the bradykinin B2-receptor antagonist, icatibant (HOE-140, 0.5 mg/kg given subcutaneously twice a day) for a period of 10 weeks. HOE-140 had no effects on ACE activity, LDL lipid peroxidation, blood pressure, or atherosclerosis. In combination with ramipril, no additional effect of HOE-140 on LDL oxidation or on atherosclerosis was noted in comparison with ramipril treatment alone. We thus conclude that the antiatherogenic effect of ramipril in E(0) mice is independent of blood pressure reduction and is not mediated by bradykinin. It seems, therefore, that most of its antiatherosclerotic and antioxidative effects are mediated through the inhibition of angiotensin II production.