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Long‐lasting inhibitory activity of the hetrazepinic BN 50730 on exudation and cellular alterations evoked by PAF and LPS
Author(s) -
Pires Ana L.A.,
Silva Patricia M.R.,
Pasquale Claudia,
CastroFariaNeto Hugo C.,
Bozza Patricia T.,
Cordeiro Renato S.B.,
Rae Giles A.,
Braquet Pierre,
Lagente Vincent,
Martins Marco A.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb17091.x
Subject(s) - eosinophil , histamine , platelet activating factor , pharmacology , bradykinin , chemotaxis , leukotriene d4 , in vitro , chemistry , inhibitory postsynaptic potential , ic50 , leukotriene , leukotriene b4 , endocrinology , medicine , antagonist , immunology , biology , inflammation , biochemistry , receptor , asthma
1 Inhibitory effects of the hetrazepinic derivative BN 50730 on the rat pleural inflammatory response, triggered by PAF or lipopolysaccharides (LPS), were examined. The type of pharmacological blockade exerted by this antagonist in in vitro assays of eosinophil chemotaxis and platelet aggregation were also investigated. 2 Intrathoracic injection of PAF (1 μg per cavity) caused a 4 fold increase in the extravasated protein within 15min and led to a marked eosinophil accumulation 24 h post‐challenge. BN 50730 (0.5–10 μg per cavity) inhibited exudation by PAF dose‐dependently without modifying the response induced by histamine, bradykinin or 5‐hydroxytryptamine (5‐HT). 3 The kinetics of the inhibitory effect on exudation revealed that the actions of WEB 2086 and BN 52021 (10 μg per cavity) were over within 2 and 4h respectively, whereas BN 50730 (10 μg per cavity) retained 80% of its inhibitory activity for 4 days. 4 Oral treatment with BN 50730 (10–20 mg kg −1 , 1 h beforehand) suppressed the leucocyte accumulation and late eosinophilia observed 6 and 24 h after PAF respectively, but did not modify the eosinophilia induced by leukotriene B 4 (LTB 4 ) or bradykinin. BN 50730 also failed to reduce the eosinophil accumulation induced by LPS but drastically inhibited the neutrophil influx. 5 The pre‐incubation of rat peritoneal eosinophils for 10 min with BN 50730 (30nM‐1 μ m ) dose‐dependently inhibited the chemotaxis induced by PAF (0.1 μ m ) in vitro . The IC 50 values for BN 52021, WEB 2086 and BN 50730 in this system were 5, 5 and 0.05 μ m respectively. 6 In separate assays, rat peritoneal eosinophils and rabbit washed platelets were preincubated with BN 50730 or WEB 2086 (1 μ m ) then subjected to a series of at least two consecutive washings in order to remove the antagonist from the receptor environment. Under such conditions, only the cells pretreated with WEB 2086 recovered the sensitivity to the lipid. 7 We conclude that BN 50730 is a potent, specific and long‐acting PAF antagonist and its effect seems to result from a high affinity and non‐competitive interaction of the drug with the PAF receptor.