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.

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The effect of chronic treatment with zidovudine (AZT) on the inflammatory response was examined in the rat. AZT was administered orally for 36 days. On day 35, inflammation was induced by hindpaw injection of 1% carrageenan lambda. Paw edema over a 24-hour period was used as a marker of the local inflammatory reaction. On day 36, quantification of immunoreactive T-kininogen and alpha 1-inhibitor-3 in liver and serum was used to assess the systemic inflammatory response. Albumin was selected as a protein whose concentration is modified only slightly or not at all during the acute-phase response. Animals treated with AZT transiently exhibited significantly greater (18%) paw edema 3 hours after carrageenan injection. AZT treatment alone induced a 1.8-fold increase in serum T-kininogen concentration, but it had no effect on albumin and alpha 1-inhibitor-3. In rats with inflamed paws, AZT administration led to a significant increase in liver (3.4-fold) and serum (1.8-fold) immunoreactive T-kininogen content. Dot blot analysis of total RNA isolated from liver correlated with the protein measurements. Our results indicate that chronic treatment with AZT potentiates the nonspecific local and the systemic inflammatory responses in the rat.