LONG-LASTING INHIBITORY ACTIVITY OF THE HETRAZEPINIC BN-50730 ON EXUDATION AND CELLULAR ALTERATIONS EVOKED BY PAF AND LPS

1 Inhibitory effects of the hetrazepinic derivative BN 50730 on the ra t pleural inflammatory response, triggered by PAF or lipopolysaccharid es (LPS), were examined. The type of pharmacological blockade exerted by this antagonist in in vitro assays of eosinophil chemotaxis and pla telet aggregation were also investigated. 2 Intrathoracic injection of PAF (1 mu g per cavity) caused a 4 fold increase in the extravasated protein within 15 min and led to a marked eosinophil accumulation 24 h post-challenge. BN 50730 (0.5-10 mu g per cavity) inhibited exudation by PAF dose-dependently without modifying the response induced by his tamine, bradykinin or 5-hydroxytryptamine (5-HT). 3 The kinetics of th e inhibitory effect on exudation revealed that the actions of WEB 2086 and BN 52021 (10 mu g per cavity) were over within 2 and 4 h respecti vely, whereas BN 50730 (10 mu g per cavity) retained 80% of its inhibi tory activity for 4 days. 4 Oral treatment with BN 50730 (10-20 mg kg( -1), 1 h beforehand) suppressed the leucocyte accumulation and late eo sinophilia observed 6 and 24 h after PAF respectively, but did not mod ify the eosinophilia induced by leukotriene B-4 (LTB(4)) or bradykinin . BN 50730 also failed to reduce the eosinophil accumulation induced b y LPS but drastically inhibited the neutrophil influx. 5 The pre-incub ation of rat peritoneal eosinophils for 10 min with BN 50730 (30 nM-1 mu M) dose-dependently inhibited the chemotaxis induced by PAF (0.1 mu M) in vitro. The IC50 values for BN 52021, WEB 2086 and BN 50730 in t his system were 5, 5 and 0.05 mu M respectively. 6 In separate assays, rat peritoneal eosinophils and rabbit washed platelets were preincuba ted with BN 50730 or WEB 2086 (1 mu M) then subjected to a series of a t least two consecutive washings in order to remove the antagonist fro m the receptor environment. Under such conditions, only the cells pret reated with WEB 2086 recovered the sensitivity to the lipid. 7 We conc lude that BN 50730 is a potent, specific and long-acting PAF antagonis t and its effect seems to result from a high affinity and non-competit ive interaction of the drug with the PAF receptor.