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Vol. 303, Issue 1, 232-237, October 2002

Angiotensin-Converting Enzyme Inhibitor-Associated Angioedema Is Characterized by a Slower Degradation of des-Arginine9-Bradykinin

Giuseppe Molinaro, Massimo Cugno, Mélissa Perez, Yves Lepage, Nicole Gervais, Angelo Agostoni and Albert Adam

Faculté de Pharmacie (G.M., M.P., N.G., A.Ad.) and Faculté des Arts et des Sciences, Département de Mathématiques et de Statistique (Y.L.), Université de Montréal, Montréal, Canada, and Department of Internal Medicine, Università di Milano, Milano, Italy (M.C., A.Ag.)

Angioedema (AE) is a rare but potentially life-threatening side effect of therapy with inhibitors of angiotensin-converting enzyme (ACE), the main bradykinin (BK)- inactivating metallopeptidase in humans. The pathogenesis of ACE inhibitor (ACEi)- associated AE (AE+) is presently unknown, although there is increasing evidence of a kinin role. We analyzed the metabolism of endogenous BK (B2 receptor agonist) and its active metabolite, des-Arg9-BK (B1 receptor agonist), in the presence of an ACEi during in vitro contact activation of plasma from hypertensive patients (n = 39) who presented AE+. Kinetic parameters were compared with those measured in a control group (AE-) of hypertensive patients (n = 39) who never manifested any acute or chronic side effects while treated with an ACEi. The different kinetic parameters were analyzed using a mathematical model (y = k talpha e-beta t) previously applied to a normal, healthy population. The slope of BK degradation, but not its formation from high-molecular-weight kininogen, was lower in AE+ patients when compared with the AE- controls. des-Arg9-BK accumulation during the kinetic measurements was significantly higher in AE+ plasma. This accumulation of the B1 agonist in AE+ patients paralleled its half-life of degradation. In conclusion, our results show, for the first time, that an abnormality of endogenous des-Arg9-BK degradation exists in the plasma of patients with ACEi-associated AE, suggesting that its pathogenetic mechanism lies in the catabolic site of kinin metabolism.

0022-3565/02/3031-0232$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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