Studies of Platelet Activating Factor (PAF) Antagonists from Microbial Products. III. Pharmacological Studies of FR-900452 in Animal Models

1-Methyl-3-[1-[5-methylthiomethyl-6-oxo-3-(2-oxo-3-cyclopenten-1-ylidene)-2-piperazinyl]-ethyl]-2-indolinone (FR-900452), isolated from the fermentation broth of Streptomyces phaeofaciens No. 7739, is a specific inhibitor of rabbit platelet aggregation induced by platelet activating factor (PAF) in vitro. In order to ascertain the PAF antagonistic activity of FR-900452 in vivo, the effects of this compound on PAF-induced bronchoconstriction in guinea-pigs, hypotension in rats and vascular permeability increase in mice were examined. The compound significantly inhibited the bronchoconstriction, the hypotension and the vascular permeability increase at a dosage of less than 10mg/kg, i.v., and the hypotensive actions induced by i.v. administration of histamine (His, 100μg/kg), acetylcholine (Ach, 1μg/kg), bradykinin (Bk, 10μg/kg) and isoproterenol (Isp, 1μg/kg) were not altered by FR-900452 (10mg/kg, i.v.). Therefore, to determine whether endogenous PAF contributes to the pathogenesis of immunoglobulin E (IgE)-mediated anaphylaxis, the effect of FR-900452 on the hypotension induced by IgE-mediated anaphylaxis in rats was tested. The compound significantly prevented the hypotension at a dose of 10mg/kg, i.v. The results suggest that PAF may play a role in the pathogenesis of the IgE-mediated hypotension in rats.