Serum metabolism of bradykinin and des-Arg(9)-bradykinin in patients with angiotensin-converting enzyme inhibitor-associated angioedema

Angioedema (AE) associated with angiotensin-converting enzyme inhibitors (A CEi) is a rare, but potentially life-threatening adverse reaction. Several studies have suggested that bradykinin (BK) is responsible for ACEi-induced AE, but the mechanism remains unclear. We investigated the metabolism of B K and des-Arg(9)-BK in the serum of 20 patients with a history of ACEi-asso ciated AE and 21 control (C) subjects. Synthetic BK was incubated with the sera for various periods of time and residual BK and generated des-Arg(9)-B K were quantified by specific and sensitive enzyme immunoassays, No signifi cant difference of half-life (t(1/2)) of both BK and des-Arg(9)-BK could be measured between C subjects and patients with AE (AE) in absence of ACEi H owever, an analysis according to the prolonged (+) or not (-) t(1/2) of des -Arg(9)-BK allowed a new stratification of C subjects and AE patients in fo ur subgroups. The preincubation of sera with enalaprilat at a concentration inhibiting ACE significantly prevented the rapid degradation of BK and des -Arg(9)-BK in these four subgroups. In presence of ACEi, a subgroup (50%) o f AE patients (AE+) had a particularly significant rise of the t(1/2) of de s-Arg(9)-BK. Once ACE was inhibited, the concentration or the nature of the ACEi had no significant effect on the t(1/2) of des-Arg(9)-BK. However, a test dilution of AE + sera with a control (C) serum showed that an enzyme d efect rather than a circulating inhibitor could be responsible for the abno rmal metabolism of des-Arg(9)-BK when ACE is inhibited. In conclusion, half of the patients with ACEi-associated AE present in serum had an enzyme def ect involved in the des-Arg(9)-BK metabolism leading to its accumulation. T he B-1 agonist could be responsible, at least in part, for the local inflam matory reaction associated with the AE. (C) 1999 Elsevier Science B.V. All rights reserved.