PCA-4248, a PAF receptor antagonist, inhibits PAF-induced phosphoinositide turnover.
The effect of a new PAF (platelet activating factor; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphoryl-choline) receptor antagonist, PCA-4248 (2-phenylthio)ethyl-5-metoxycarbonyl-2,4,6-trimethyl-1, 4-dihydropyridine-3-carboxylate), on phosphoinositide turnover evoked by PAF was investigated. PAF treatment resulted in an increased 32P incorporation into phosphoinositides and phosphatidic acid in rabbit platelets. Treatment with PCA-4248 abolished both effects in a dose-dependent manner, 10 microM being the most effective dose. In thrombin stimulated platelets, phosphoinositide turnover was not influenced by PCA-4248. In addition, PAF caused a rapid and significant increase in protein phosphorylation. Thus, PAF treatment resulted in a marked phosphorylation of two proteins of 47 kDa and 20 kDa. Treatment with PCA-4248 resulted in an inhibition of these actions. Serotonin secretion evoked by PAF was also inhibited by PCA-4248. It is concluded that PCA-4248 antagonizes the PAF effects by acting as a competitive antagonist at the PAF receptor level as evidenced from binding studies.
Catalán
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RE
Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Spain.
Martínez
A M
AM
Aragonés
M D
MD
Lombardía
M
M
Garde
E
E
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D010716:Phosphatidylinositols / Q000378:metabolism*; D010761:Phosphorus Radioisotopes; D010766:Phosphorylation; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011817:Rabbits; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012701:Serotonin / Q000097:blood
D004095:Dihydropyridines; D010716:Phosphatidylinositols; D010761:Phosphorus Radioisotopes; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C066024:PCA 4248; D012701:Serotonin