The contribution of nondegraded bradykinin to the metabolic effects of the angiotensin-converting enzyme (ACE)-kininase II inhibitor ramipril was evaluated in rats rendered hypertensive, hyperinsulinemic, and hypertriglyceridemic by a fructose-enriched diet. The response of blood pressure, insulin, and triglyceride levels to concomitant administration of ramipril and the bradykinin antagonist HOE 140 was studied. Rats that received ramipril, HOE 140, or not treated at all served as controls. Treatment with ramipril reduced levels of both insulin (from 6.6 ± 2.0 to 3.6 ± 1.7 ng/ml; p < 0.05) and triglycerides (from 292 ± 88 to 164 ± 35 mg/dl; p < 0.001) as well as blood pressure (from 144 ± 6 to 116 ± 6 mm Hg; p < 0.001). In contrast, treatment with HOE 140 did not alter any of these parameters. The combined treatment, however, blunted the beneficial metabolic effects of ramipril on insulin (7.8 ± 4.4 ng/ml before and 7.7 ± 2.9 ng/ml after treatment) and triglycerides (290 ± 135 mg/dl before and 285 ± 152 mg/dl after treatment), whereas the hypotensive effect of ramipril was preserved (151 ± 8 mm Hg before and 122 ± 6 mm Hg after treatment (p < 0.001). The data suggest that whereas the hypotensive effect is mostly angiotensin-II dependent, the advantageous metabolic affect of ramipril is highly dependent on the accumulation of bradykinin.