PCA-4248, A PAF RECEPTOR ANTAGONIST, INHIBITS PAF-INDUCED PHOSPHOINOSITIDE TURNOVER

The effect of a new PAF (platelet activating factor; -O-alkyl-2-acetyl -sn-glycero-3-phosphoryl-choline) receptor antagonist, PCA-4248 ,4,6-t rimethyl-1,4-dihydropyridine-3-carboxylate), on phosphoinositide turno ver evoked by PAF was investigated. PAF treatment resulted in an incre ased P-32 incorporation into phosphoinositides and phosphatidic acid i n rabbit platelets. Treatment with PCA-4248 abolished both effects in a dose-dependent manner, 10 mu M being the most effective dose. In thr ombin stimulated platelets, phosphoinositide turnover was not influenc ed by PCA-4248. In addition, PAF caused a rapid and significant increa se in protein phosphorylation. Thus, PAF treatment resulted in a marke d phosphorylation of two proteins of 47 kDa and 20 kDa. Treatment with PCA-4248 resulted in an inhibition of these actions. Serotonin secret ion evoked by PAF was also inhibited by PCA-4248. It is concluded that PCA-4248 antagonizes the PAF effects by acting as a competitive antag onist at the PAF receptor level as evidenced from binding studies.