Depressor Action of Bradykinin Agonists Relative to Metabolism by Angiotensin-Converting Enzyme,Carboxypeptidase N,and Aminopeptidase P

Abstract

Abstract

Bradykinin (BK) receptor agonists and antagonists contain modifications that confer resistance to specific peptidases. In control studies, rat plasma degraded BK (10.3 ± 0.3 nmol/min/ml) via angiotensin-converting enzyme (ACE; EC 3.4.15.1; 5.2 ± 0.3 nmol/min/ml), carboxypeptidase N (CPN; EC 3.4.17.3; 3.2 ± 0.4 nmol/min/ml), aminopeptidase P (APP; EC 3.4.11.9; 0.6 ± 0.2 nmol/min/ml), and other (unidentified) activity (2.1 ± 0.6 nmol/min/ml). In contrast, BK agonist analogs were hydrolyzed more slowly due to selective resistance to these plasma peptidases. In addition to Lys-Lys-BK (B1087), which is partially resistant to ACE, [Hyp²,Phe⁸-r-Arg⁹]BK (B7642) was completely resistant to ACE, CPN, and the unidentified plasma activity (1.9 ± 0.3 nmol/min/ml), and D-Arg⁰[Hyp³,Phe⁸-r-Arg⁹]BK (B7644) was resistant to all plasma hydrolysis, including APP (<0.2 nmol/min/ml). In vivo ACE-resistant B1087 exhibited a depressor potency and duration of action greater than BK and equivalent to that of BK in the presence of the ACE inhibitor enalapril. Although the B7642 and B7644 agonists were also more potent and longer acting than BK, the increases were no more than that seen for B1087, despite their additional resistance to CPN (B7642) and CPN and APP (B7644). The duration of action of these analogs was, however, increased after renal ligation. These data demonstrate the importance of ACE to the metabolism of circulating BK and BK analogs. In contrast, resistance to CPN and APP are not associated with further potentiation. Beyond ACE resistance, it is likely that the development of more potent, longer-acting BK agonists and antagonists will relate to other factors, such as renal processing independent of CPN and APP.