title: Des-Arg9-bradykinin metabolism in patients who presented hypersensitivity reactions during hemodialysis: role of serum ACE and aminopeptidase P.
abstract: 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.
authors.affiliation: Faculté de pharmacie, Université de Montréal, Québec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Blais
authors.forename: J
authors.initials: J
authors.lastname: Marc-Aurèle
authors.forename: W H
authors.initials: WH
authors.lastname: Simmons
authors.forename: G
authors.initials: G
authors.lastname: Loute
authors.forename: P
authors.initials: P
authors.lastname: Thibault
authors.forename: R A
authors.initials: RA
authors.lastname: Skidgel
authors.forename: A
authors.initials: A
authors.lastname: Adam
mesh_terms: 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*
chemical_list: 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