Effects of combined neutral endopeptidase 24‐11 and angiotensin‐converting enzyme inhibition on femoral vascular conductance in streptozotocin‐induced diabetic rats

The successive effects of the angiotensin‐converting enzyme inhibitor captopril (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 μg kg −1 ), a NO‐synthase inhibitor (N ω ‐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 min −1 infusion) and (2) comparing the effects in STZ‐induced diabetic (STZ‐BN) and control Brown‐Norway kininogen‐deficient (C‐BN) rats. In C‐SDs, CAP and CAP+RT increased FVC similarly. In STZ‐SDs, FVC and FBF were decreased compared to C‐SDs. CAP+RT increased them more effectively than CAP alone. 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 Hoe‐140+MGTA. In C‐BNs, the vasodilatator responses to CAP and CAP+RT were abolished and highly reduced, respectively. In STZ‐BNs, these responses were abolished. These results show that in STZ‐SDs, CAP+RT improve FBF and FVC more effectively 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.British Journal of Pharmacology (2000) 130 , 1297–1304; doi: 10.1038/sj.bjp.0703442