Bradykinin and des-Arg⁹-bradykinin metabolic pathways and kinetics of activation of human plasma

Abstract

In the serum of 116 healthy individuals, exogenous bradykinin (BK) half-life (27 +/- 10 s) was lower than that of des-Arg(9)-BK (643 +/- 436 s) and was statistically different in men compared with women. The potentiating effect of an angiotensin-converting enzyme (ACE) inhibitor was, however, more extensive for BK (9.0-fold) than for des-Arg(9)-BK (2.2- fold). The activities of ACE, aminopeptidase P (APP), and kininase I were respectively 44 +/- 12, 22 +/- 9, and 62 +/- 10 nmol x min(-1) x ml(-1). A mathematical model (y = kt(alpha)e(-beta t), t > 0), applied to the BK kinetically released from endogenous high-molecular-weight kininogen (HK) during plasma activation in the presence of an ACE inhibitor, revealed a significant difference in the rate of formation of BK between men and women. For des-Arg(9)-BK, the active metabolite of BK, the rate of degradation was higher in women compared with men, correlating significantly with serum APP activity (r(2) = 0.6485, P < 0.001). In conclusion, these results constitute a basis for future pathophysiological studies of inflammatory processes where activation of the contact system of plasma and the kinins is involved.

Expression of Metallopeptidases and Kinin Receptors in Swine Oropharyngeal Tissues: Effects of Angiotensin I-Converting Enzyme Inhibition and Inflammation

“…ACE activity was determined by Bü hlmann ACE radioenzymatic assay (ALPCO: American Labora-tory Products Company, Windham, NH) according to the manufacturer's instructions. The activity of aminopeptidase P and carboxypeptidase N was assessed by fluorimetric assay as described previously (Cyr et al, 2001). The metabolism of the endogenous kinins, bradykinin and its active metabolite des-Arg 9 -BK, was studied through in vitro plasma contact system activation as described extensively elsewhere (Cyr et al, 2001;Molinaro et al, 2002), using two specific competitive chemiluminescent enzyme immunoassays, as previously described (Decarie et al, 1994;Raymond et al, 1995).…”

“…In various cell types and tissues, such as kidney, endothelial cells, and cardiomyocytes, neutral endopeptidase 24.11 (NEP, neprilysin) plays an important role in the degradation of bradykinin (Raut et al, 1999). In human plasma, bradykinin is metabolized mostly by three metallopeptidases (Decarie et al, 1996;Cyr et al, 2001). Angiotensin I-converting enzyme (ACE) constitutes the main degradation pathway.…”

“…Carboxypeptidase N transforms bradykinin and kallidin into their active metabolites, des-arginine 9 -bradykinin (des-Arg 9 -BK) and Lys-des-Arg 9 -BK (des-Arg 10 -kallidin), respectively (a minor metabolic pathway in plasma unless ACE is inhibited). We have also shown that aminopeptidase P (X-prolyl aminopeptidase, APP) plays an important role in the metabolism of kinins in plasma, mostly for des-Arg 9 -BK (Cyr et al, 2001). Although the carboxytruncated metabolites of bradykinin and kallidin are largely inactive under normal conditions, they are the agonists of the strongly regulated B 1 receptors, of which receptor synthesis is increased in experimental models of inflammation under the control of cytokines, MAP kinases, and specific transcription factors (LeebLundberg et al, 2005).…”

A ligand-based approach to investigate the expression and function of angiotensin converting enzyme in intact human umbilical vein endothelial cells

“…2A). The des-Arg 9 -kinins that are B 1 receptor agonists exhibit only very little capacity to compete for [ 3 H]enalaprilat in the applied assay, although ACE is a significant but slow and nonexclusive degradation pathway for these peptides in various physiological settings [7,11]. The binding site differs from the BK B 2 receptor by the low or null affinity of ligands that have been designed to resist to inactivation (the agonist B-9972 and the nonpeptide antagonist LF 16-0687, Fig.…”

“…It exerts its cardiovascular actions largely via stimulation of B 2 receptors located in endothelial cells [19]. BK is rapidly disposed of in vivo and ACE seems to be the most effective kininase, with high affinity and substrate turnover [4,7,8]. ACE inhibitors assume an important place in cardiovascular and renal disease management; they prevent the activation reaction of angiotensin I, but a fraction of their beneficial effects may derive from the potentiation of endogenous BK in humans [12,26,33].…”