Effects of combined neutral endopeptidase 24-11 and angiotensin-convertingenzyme inhibition on femoral vascular conductance in streptozotocin-induced diabetic rats

1 The successive effects of the angiotensin-converting enzyme inhibitor cap topril (CAP, 2 mg kg(-1) + 1 mg kg(-1) 30 min(-1) infusion) and the neutral endopeptidase 24-11 inhibitor retrothiorphan (RT, 25 mg kg-(1) +12.5 mg kg (-1) 30 min(-1) infusion) were studied on femoral vascular conductance (FVC ) in streptozotocin-induced diabetic (STZ-SD) and control Sprague-Dawley (C SD) rats. The role of the kinin-nitric oxide (NO) pathway was assessed by ( 1) using pre-treatments: a bradykinin (BK) B2 receptor antagonist (Hoe-140, 300 mu g kg(-1)), a NO-synthase inhibitor (N-omega nitro-L-arginine methyl ester, L-NAME, 10 mg kg(-1)), a kininase I inhibitor (DL-2-mercaptomethyl- 3-guanidinoethylthiopropanoic acid, MGTA, 10 mg kg(-1) + 20 mg kg(-1) 20 mi n(-1) infusion) and (2) comparing the effects in STZ-induced diabetic (STZ- BN) and control Brown-Norway kininogen-deficient (C-BN) rats. 2 In C-SDs, CAP and CAP + RT increased FVC similarly. In STZ-SDs, FVC and F BF were decreased compared to C-SDs. CAP + RT increased them more effective ly than CAP alone. 3 In both C-SDs and STZ-SDs, the femoral bed vasodilatation elicited by CAP was inhibited by Hoe-140 and L-NAME. The FVC increase elicited by CAP + RT was not significantly reduced by Hoe-140 but was inhibited by L-NAME and H oe-140 + MGTA. 4 In C-BNs, the vasodilatator responses to CAP and CAP + RT were abolished and highly reduced, respectively. In STZ-BNs, these responses were abolishe d. 5 These results show that in STZ-SDs, CAP+ RT improve FBF and FVC more effe ctively than CAP alone. These effects are linked to an increased activation of the kinin-NO pathway. BK could lead to NO production by BK B2 receptor activation and another pathway in which kininase I may be involved.