Serum metabolism of bradykinin and des-Arg9-bradykinin in patients with angiotensin-converting enzyme inhibitor-associated angioedema.
Angioedema (AE) associated with angiotensin-converting enzyme inhibitors (ACEi) 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 BK and des-Arg9-BK in the serum of 20 patients with a history of ACEi-associated AE and 21 control (C) subjects. Synthetic BK was incubated with the sera for various periods of time and residual BK and generated des-Arg9-BK were quantified by specific and sensitive enzyme immunoassays. No significant difference of half-life (t1/2) of both BK and des-Arg9-BK could be measured between C subjects and patients with AE (AE) in absence of ACEi. However, an analysis according to the prolonged (+) or not (-) t1/2 of des-Arg9-BK allowed a new stratification of C subjects and AE patients in four subgroups. The preincubation of sera with enalaprilat at a concentration inhibiting ACE significantly prevented the rapid degradation of BK and des-Arg9-BK in these four subgroups. In presence of ACEi, a subgroup (50%) of AE patients (AE + ) had a particularly significant rise of the t1/2 of des-Arg9-BK. Once ACE was inhibited, the concentration or the nature of the ACEi had no significant effect on the t1/2 of des-Arg9-BK. However, a test dilution of AE + sera with a control (C) serum showed that an enzyme defect rather than a circulating inhibitor could be responsible for the abnormal metabolism of des-Arg9-BK when ACE is inhibited. In conclusion, half of the patients with ACEi-associated AE present in serum had an enzyme defect involved in the des-Arg9-BK metabolism leading to its accumulation. The B1 agonist could be responsible, at least in part, for the local inflammatory reaction associated with the AE.
Blais
C
C
Faculté de Pharmacie, Université de Montréal, Canada.
Rouleau
J L
JL
Brown
N J
NJ
Lepage
Y
Y
Spence
D
D
Munoz
C
C
Friborg
J
J
Geadah
D
D
Gervais
N
N
Adam
A
A
D000328:Adult; D000368:Aged; D000799:Angioedema / Q000139:chemically induced* / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects*; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D001121:Lysine Carboxypeptidase / Q000502:physiology; D008297:Male; D008875:Middle Aged
D000806:Angiotensin-Converting Enzyme Inhibitors; C024626:bradykinin, des-Arg(9)-; D001121:Lysine Carboxypeptidase; D001920:Bradykinin