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, Albert Adam

Research output: Contribution to journalArticle

Abstract

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 tα e-β 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.

Original languageEnglish
Pages (from-to)232-237
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume303
Issue number1
DOIs
Publication statusPublished - Oct 2002

ASJC Scopus subject areas

  • Pharmacology

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