Des-Arg9-bradykinin metabolism in patients who presented hypersensitivity reactions during hemodialysis: role of serum ACE and aminopeptidase P.
Bradykinin (BK) has been proposed as the principal mediator of hypersensitivity reactions (HSR) in patients dialyzed using negatively charged membranes and concomitantly treated with angiotensin-converting enzyme (ACE) inhibitors. We investigated the metabolism of exogenous BK added to the sera of 13 patients dialyzed on an AN69 membrane with a history of HSR (HSR+ patients) and 10 others who did not present such a reaction (HSR- patients) while dialyzed under the same conditions. No significant difference in the t1/2 of BK was found between the patient groups. However, the t1/2 of generated des-Arg9-BK was significantly increased (2.2-fold) in HSR+ patients compared to HSR-subjects. Preincubation of the sera with an ACE inhibitor (enalaprilat) significantly increased the t1/2 of both BK and des-Arg9-BK in both groups. There was no significant difference between the groups with respect to the t1/2 of BK, but there was a significantly greater increase (3.8-fold) in the t1/2 of des-Arg9-BK in HSR+ patients compared to HSR-subjects. The level of serum aminopeptidase P (APP) activity showed a significant decrease in the HSR+ sera when compared to HSR-samples. In HSR- and HSR+ patients, a significant inverse relation (r2 = 0.6271; P < 0.00005) could be calculated between APP activity and des-Arg9-BK t1/2. In conclusion, HSR in hemodialyzed patients who are concomitantly treated with a negatively charged membrane and an ACE inhibitor can be considered as a multifactorial disease in that a decreased APP activity resulting in reduced degradation of des-Arg9-BK may lead to the accumulation of this B1 agonist that could be responsible, at least in part, for the signs and symptoms of HSR.
Blais
C
C
Faculté de pharmacie, Université de Montréal, Québec, Canada.
Marc-Aurèle
J
J
Simmons
W H
WH
Loute
G
G
Thibault
P
P
Skidgel
R A
RA
Adam
A
A
D000180:Acrylic Resins; D000181:Acrylonitrile / Q000031:analogs & derivatives; D000368:Aged; D000626:Aminopeptidases / Q000097:blood*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects*; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D015773:Enalaprilat / Q000009:adverse effects*; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy / Q000378:metabolism*; D001121:Lysine Carboxypeptidase / Q000378:metabolism; D008297:Male; D008567:Membranes, Artificial; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000097:blood*; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000819:agonists; D006435:Renal Dialysis / Q000009:adverse effects*
D000180:Acrylic Resins; D000806:Angiotensin-Converting Enzyme Inhibitors; D008567:Membranes, Artificial; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin; C024626:bradykinin, des-Arg(9)-; C016892:AN-69; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase; D007703:Peptidyl-Dipeptidase A; D001121:Lysine Carboxypeptidase; D015773:Enalaprilat; D000181:Acrylonitrile; D001920:Bradykinin