Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin.
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 (B(2) receptor agonist) and its active metabolite, des-Arg(9)-BK (B(1) 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 t(alpha) 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-Arg(9)-BK accumulation during the kinetic measurements was significantly higher in AE+ plasma. This accumulation of the B(1) 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-Arg(9)-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.
Molinaro
Giuseppe
G
Faculté de Pharmacie, Département de Mathématiques et de Statistique, Université de Montréal, Canada.
Cugno
Massimo
M
Perez
Mélissa
M
Lepage
Yves
Y
Gervais
Nicole
N
Agostoni
Angelo
A
Adam
Albert
A
D000799:Angioedema / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects*; D001711:Biotransformation; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D007700:Kinetics; D008297:Male; D008433:Mathematics; D008962:Models, Theoretical; D012016:Reference Values
D000806:Angiotensin-Converting Enzyme Inhibitors; C024626:bradykinin, des-Arg(9)-; D001920:Bradykinin