AHEART April 47/4

Kuoppala, Antti, Ken A. Lindstedt, Juhani Saarinen, Petri T. Kovanen, and Jorma O. Kokkonen. Inactivation of bradykinin by angiotensin-converting enzyme and by carboxypeptidase N in human plasma. Am J Physiol Heart Circ Physiol 278: H1069–H1074, 2000.—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 5 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 CPNlike 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.