Dataset Information

Suppressive effect of distinct bradykinin B2 receptor antagonist on allergen-evoked exudation and leukocyte infiltration in sensitized rats.

ABSTRACT: 1. Bradykinin is suggested to play a role in the pathophysiology of several acute and chronic diseases, including allergic disorders such as asthma. In the present study, we have investigated the importance of bradykinin in mediating allergic inflammation in rats. 2. To this end we have tested the effects of the B2 receptor antagonists Hoe 140, FR173657 or FR172357 on the pleural inflammatory response triggered by intrapleural (i.pl.) injection of allergen (ovalbumin, 12 microg cavity(-1)) in 14 day-actively sensitized Wistar rats. Analysis of the pleural fluid effluent revealed a sequence of mast cell-dependent inflammatory events, including early protein exudation and neutrophilia and late pleural eosinophil influx. 3. Local treatment with Hoe 140 (0.1 and 1 microg cavity(-1)), FR173657 (1 and 10 microg cavity(-1)) or FR172357 (1 and 10 microg cavity(-1)) inhibited dose-dependently allergen-induced mast cell activation with impairment of pleural plasma leakage, neutrophil accumulation and late eosinophil influx. 4. Moreover, the B2 receptor antagonists also dose-dependently inhibited the allergic like inflammatory pleurisy triggered by bradykinin (50 microg cavity(-1)), which is characterized by acute mast cell degranulation, protein leakage and pleural eosinophil infiltration. 5. Taken together, our findings provide substantial evidence to suggest that bradykinin acting on its B2 receptors play a critical role in mediating allergic mast cell-dependent inflammation in rats, and suggest that B2 receptor antagonists may be useful therapeutically to control allergic dysfunction.

SUBMITTER: Bandeira-Melo C

PROVIDER: S-EPMC1566018 | biostudies-literature | 1999 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Suppressive effect of distinct bradykinin B2 receptor antagonist on allergen-evoked exudation and leukocyte infiltration in sensitized rats.

Bandeira-Melo C C Calheiros A S AS Silva P M PM Cordeiro R S RS Teixeira M M MM Martins M A MA

British journal of pharmacology 19990501 2

1. Bradykinin is suggested to play a role in the pathophysiology of several acute and chronic diseases, including allergic disorders such as asthma. In the present study, we have investigated the importance of bradykinin in mediating allergic inflammation in rats. 2. To this end we have tested the effects of the B2 receptor antagonists Hoe 140, FR173657 or FR172357 on the pleural inflammatory response triggered by intrapleural (i.pl.) injection of allergen (ovalbumin, 12 microg cavity(-1)) in 14 ...[more]

PMID: 10385228

Similar Datasets

Project description:We here report the discovery and early characterization of Compound 3, a representative of a novel class of small molecule bradykinin (BK) B2 receptor antagonists, and its superior profile to the prior art B2 receptor antagonists Compound 1 and Compound 2. Compound 3, Compound 2, and Compound 1 are highly potent antagonists of the human recombinant B2 receptor (Kb values 0.24, 0.95, and 1.24 nM, respectively, calcium mobilization assay). Compound 3 is more potent than the prior art compounds and icatibant in this assay (Kb icatibant 2.81 nM). The compounds also potently inhibit BK-induced contraction of endogenous B2 receptors in a human isolated umbilical vein bioassay. The potencies of Compound 3, Compound 2, Compound 1, and icatibant are (pA2 values) 9.67, 9.02, 8.58, and 8.06 (i.e. 0.21, 0.95, 2.63, and 8.71 nM), respectively. Compound 3 and Compound 2 were further characterized. They inhibit BK-induced c-Fos signaling and internalization of recombinant human B2 receptors in HEK293 cells, and do not antagonize the venous effects mediated by other G protein-coupled receptors in the umbilical vein model, including the bradykinin B1 receptor. Antagonist potency of Compound 3 at cloned cynomolgus monkey, dog, rat, and mouse B2 receptors revealed species selectivity, with a high antagonist potency for human and monkey B2 receptors, but several hundred-fold lower potency for the other B2 receptors. The in vitro off-target profile of Compound 3 demonstrates a high degree of selectivity over a wide range of molecular targets, including the bradykinin B1 receptor. Compound 3 showed a lower intrinsic clearance in the microsomal stability assay than the prior art compounds. With an efflux ratio of 1.0 in the Caco-2 permeability assay Compound 3 is predicted to be not a substrate of efflux pumps. In conclusion, we discovered a novel chemical class of highly selective and very potent B2 receptor antagonists, as exemplified by Compound 3. The compound showed excellent absorption in the Caco-2 assay, predictive of good oral bioavailability, and favourable metabolic stability in liver microsomes. Compound 3 has provided a significant stepping stone towards the discovery of the orally bioavailable B2 antagonist PHA-022121, currently in phase 1 clinical development.

Dataset Information

Suppressive effect of distinct bradykinin B2 receptor antagonist on allergen-evoked exudation and leukocyte infiltration in sensitized rats.

Publications

Suppressive effect of distinct bradykinin B2 receptor antagonist on allergen-evoked exudation and leukocyte infiltration in sensitized rats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets