Serum interspecies differences in metabolic pathways of bradykinin and [des-Arg9]BK: influence of enalaprilat.
Among the different enzymes responsible for the metabolism of bradykinin (BK), three peptidases look relevant in vivo: kininase I (KI), which transforms BK into its active metabolite, [des-Arg9]BK; kininase II (KII); and neutral endopeptidase, which inactivate BK and [des-Arg9]BK. The in vitro incubation of BK and [des-Arg9]BK in the serum of four species with or without enalaprilat and the quantification of the immunoreactivity of both peptides at different time intervals allowed the measurement of the kinetic parameters characterizing their metabolic pathways. Highly sensitive chemiluminescent enzyme immunoassays were used to measure the residual concentrations of BK and [des-Arg9]BK. Half-life (t1/2) of BK showed significant difference among species: rats (10 +/- 1 s) = dogs (13 +/- 1 s) < rabbits (31 +/- 1 s) < humans (49 +/- 2 s). t1/2 values of [des-Arg9]BK were also species dependent: rats (96 +/- 6 s) < < rabbits (314 +/- 6 s) = dogs (323 +/- 11 s) = humans (325 +/- 12 s). Enalaprilat significantly prevented the rapid BK and [des-Arg9]BK degradation in all species except that of [des-Arg9]BK in rat serum. Relative amount of BK hydrolyzed by serum KII was given as follows: rabbits (93.7 +/- 14.8%) = rats (83.6 +/- 6.7%) = humans (76.0 +/- 7.5%) > dogs (50.0 +/- 3.9%). Its importance in the hydrolysis of [des-Arg9]BK was 5.2 +/- 0.5% in rats < < 33.9 +/- 1.5% in humans < 52.0 +/- 1.1% in rabbits < 65.1 +/- 3.4% in dogs. The participation of serum KI in the transformation of BK into [des-Arg9]BK was dogs (67.2 +/- 5.3%) > > humans (3.4 +/- 1.2%) = rabbits (1.8 +/- 0.2%) = rats (1.4 +/- 0.3%). Finally, no significant difference on t1/2 values for BK and [des-Arg9]BK could be demonstrated between serum and plasma treated with either sodium citrate or a thrombin inhibitor. These results revealed striking species differences in the serum metabolism of kinins that could address at least partially some of the controversial data related to the cardioprotective role of kinins.
Département de Physiologie, Faculté de Médecine, Faculté de Pharmacie, Université de Montréal, Québec, Canada.
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A
Décarie
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Raymond
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Gervais
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R
Couture
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Adam
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000991:Antithrombins / Q000494:pharmacology; D001777:Blood Coagulation / Q000502:physiology; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D004285:Dogs; D015773:Enalaprilat / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D001121:Lysine Carboxypeptidase / Q000378:metabolism; D009994:Osmolar Concentration; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D013045:Species Specificity
D000806:Angiotensin-Converting Enzyme Inhibitors; D000925:Anticoagulants; D000991:Antithrombins; C024626:bradykinin, des-Arg(9)-; D007703:Peptidyl-Dipeptidase A; D001121:Lysine Carboxypeptidase; D015773:Enalaprilat; D001920:Bradykinin