EFFECTS OF PLATELET-ACTIVATING-FACTOR RECEPTOR ANTAGONISTS ON INTRACELLULAR PLATELET-ACTIVATING-FACTOR FUNCTION IN NEUTROPHILS

We investigated the effects of the platelet activating factor (PAF) re ceptor antagonists, SM-12502 (+)-cis-3,5-dimethyl-2-(pyridyl)-thiazoli din-4-one hydrochloride), WEB-2086 )(1,4)diazepin-2-yl)-1-(4-morpholin yl)-1-propanone and RP-48740 ridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-car boxamide) on the PAF-mediated activation of rat neutrophils. These ant agonists inhibited PAF-induced degranulation and chemotaxis in neutrop hils at a dose that correlated well with PAF-induced platelet aggregat ion based on the statistical analyses. N-formyl-L-methionyl-L-leucyl-L -phenylalanin (fMLP)-induced cellular responses were also inhibited by the PAF receptor antagonists, but their inhibitory potencies did not correlate with those for PAF-induced platelet aggregation. In addition , the doses required for inhibition were higher than those required ag ainst PAF-induced responses (i.e. IC(50)of WEB-2086, SM-12502 and RP-4 8740 in fMLP-induced/PAF-induced degranulation was 40.0, 2.8 and 5.6, respectively). PAF receptor antagonists inhibited inositol 1,4,5-triph osphate production and the release of Ca2+ from the intracellular stor e site after stimulation with PAF. In the fMLP-induced responses, PAF receptor antagonists did not inhibit IF, production and Ca2+ release, but did inhibit transmembrane Ca2+ influx. These results suggest the p resence of distinct PAF receptor subtype, to which exogenously added P AF binds, while endogenously produced PAF binds to the other. Intracel lular PAF, which was produced by fMLP-stimulation, may play an importa nt role in the late phase of signal transduction, and may participate in the transmembrane Ca2+ influx.