Effects of combined neutral endopeptidase 24-11 and angiotensin-converting enzyme inhibition on femoral vascular conductance in streptozotocin-induced diabetic rats.
1. 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 microg 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 min(-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 FBF were decreased compared to C-SDs. CAP+RT increased them more effectively 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 Hoe-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 abolished. 5. 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.
Arbin
V
V
Laboratoire de Pharmacologie, U266 INSERM, UMR 8600 CNRS, U.F.R. des Sciences Pharmaceutiques et Biologiques, Paris, France.
Claperon
N
N
Fournié-Zaluski
M C
MC
Roques
B P
BP
Peyroux
J
J
D015097:3-Mercaptopropionic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002216:Captopril / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005263:Femoral Artery / Q000187:drug effects* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007704:Kininogens / Q000172:deficiency; D001121:Lysine Carboxypeptidase / Q000037:antagonists & inhibitors; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2; D015244:Thiorphan / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D004791:Enzyme Inhibitors; D007704:Kininogens; D011480:Protease Inhibitors; D043782:Receptor, Bradykinin B2; C029729:2-mercaptomethyl-3-guanidinoethylthiopropionic acid; C065679:icatibant; C072559:retrothiorphan; D002216:Captopril; D015097:3-Mercaptopropionic Acid; D015244:Thiorphan; D019001:Nitric Oxide Synthase; D007703:Peptidyl-Dipeptidase A; D001121:Lysine Carboxypeptidase; D015260:Neprilysin; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester