The aim of this study was to examine the effects of chronic (8-day) oral treatment with the dual angiotensin-converting enzyme (ACE) and neutral endopeptidase 24-11 (NEP) inhibitor mixanpril (25 mg/kg twice a day), compared with the ACE inhibitor captopril (25 mg/kg twice a day), on whole body insulin-mediated glucose disposal in young (10-week) and old (19-week) obese Zucker rats (ZOs). Moreover, the effects of chronic mixanpril administration on femoral blood flow at rest and during an insulin infusion were assessed. In the young ZOs, mixanpril decreased the glucose response during an IV glucose tolerance test more effectively than did captopril (-49 and -30%, respectively, p < 0.05). Incremental glucose area under the curve in mixanpril-treated ZOs was then no longer different from that observed in vehicle-treated lean rats (1,592 +/- 175 and 1, 470 +/- 104 mg/dl x min, respectively). The beneficial effects resulting from mixanpril or captopril administration were observed in ZOs but not in lean littermates. In the old ZOs, mixanpril induced higher glucose infusion rates to maintain euglycemia than did captopril during a hyperinsulinemic euglycemic clamp test (+92 and +35%, respectively, p < 0.001). However, the glucose infusion rates in mixanpril-treated ZOs remained much lower than that observed in vehicle-treated lean rats (9.4 +/- 0.7 mg/kg/min vs 28.6 +/- 1.0 mg/kg/min, p < 0.001). Mixanpril did not affect resting femoral vascular bed hemodynamics but restored the femoral blood flow response to insulin infusion. In conclusion, in ZOs, chronic dual ACE/NEP inhibition improves whole body insulin-mediated glucose disposal more effectively than does ACE inhibition alone. This beneficial effect seems to be restricted to conditions of insulin resistance and not directly linked to the improvement in the femoral blood flow response to insulin.