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Am J Physiol Heart Circ Physiol 278: H1069-H1074, 2000;
0363-6135/00 $5.00
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Vol. 278, Issue 4, H1069-H1074, April 2000

Inactivation of bradykinin by angiotensin-converting enzyme and by carboxypeptidase N in human plasma

Antti Kuoppala1, Ken A. Lindstedt1, Juhani Saarinen2, Petri T. Kovanen1, and Jorma O. Kokkonen1,3

1 Wihuri Research Institute, FIN-00140 Helsinki; 2 Institute of Biotechnology, University of Helsinki Biocentrum, FIN-00710 Helsinki; and 3 Division of Cardiology, Helsinki University Hospital, FIN-00290 Helsinki, Finland

Because bradykinin (BK) appears to have cardioprotective effects ranging from improved hemodynamics to antiproliferative effects, inhibition of BK-degrading enzymes should potentiate such actions. The purpose of this study was to find out which enzymes are responsible for the degradation of BK in human plasma. Human plasma from healthy donors (n = 10) was incubated with BK in the presence or absence of specific enzyme inhibitors. At high (micromolar) concentrations, BK was mostly (>90%) degraded by carboxypeptidase N (CPN)-like activity. In contrast, at low (nanomolar) substrate concentrations, at which the velocity of the catalytic reaction is equivalent to that under physiological conditions, BK was mostly (>90%) converted into an inactive metabolite, BK-(1-7), by angiotensin-converting enzyme (ACE). BK-(1-7) was further converted by ACE into BK-(1-5), with accumulation of this active peptide. A minor fraction (<10%) of the BK was converted into another active metabolite, BK-(1-8), by CPN-like activity. The present study shows that the most critical step in plasma kinin metabolism, i.e., inactivation of BK, is mediated by ACE. Thus inhibition of plasma ACE activity would be cardioprotective by elevating the concentration of BK in the circulation.

kininase I; kininase II; peptides


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