METABOLISM OF BRADYKININ ANALOGS BY ANGIOTENSIN-I CONVERTING ENZYME AND CARBOXYPEPTIDASE-N

Bradykinin (BK) analogs such as Lys-Lys-BK, des-Arg9-BK and [Leu8]des-Arg9-BK were poor substrates for angiotensin I converting enzyme (ACE), and analogs containing D-Phe7 residues, or a pseudopeptide C-terminal bond, were completely resistant. However, many of these analogs were metabolized by carboxypeptidase N (CPN) including Lys-Lys-BK, [Tyr8(OMe)]BK and D-Phe7-containing analogs, with K(m) and V(max) values comparable to those for BK. The only analogs completely resistant to both ACE and CPN were the B2 agonist [Phe8-psi-(CH2NH)Arg9]BK, the B2 antagonist D-Arg[Hyp3,D-Phe7,Phe8-psi-(CH2NH)Arg9]BK, and the B1 agonist [D-Phe8]des-Arg9-BK. These data indicate an important role for plasma CPN and vascular CPN-like activity in the metabolism of the widely used ACE-resistant/D-Phe7-containing antagonists of B2 kinin receptors.