S35B, A NEW PHENYLSULFONYLFUROXAN COMPOUND, INHIBITS THROMBIN-INDUCEDSYNTHESIS OF PLATELET-ACTIVATING-FACTOR AND PROSTACYCLIN IN HUMAN ENDOTHELIAL-CELLS

Endothelial cells (EC) produce platelet activating factor (PAF) and pr ostacyclin (PGI(2)) in response to inflammatory agents such as thrombi n. Upon cell stimulation a calcium-dependent phospholipase Az (PLA(2)) is activated which hydrolyzes a membrane phospholipid to yield 1-0-al kyl-2-lyso-sn-glycero-3-phospho-choline (lyso-PAF) and free arachidoni c acid. Lyso-PAF is in turn converted into PAF by a specific acetyltra nsferase and arachidonic acid is metabolized via cyclic endoperoxides to PGI(2). In the present study we report that S35b (4-methyl-3-phenyl sulfonylfuroxan), a new phenyl-sulfonylfuroxan compound with potent an tiaggregatory effect, inhibits thrombin-induced PAF synthesis and acet yltransferase activation as well as PGI(2) production in human umbilic al vein endothelial cells (HUVEC) in a concentration-dependent way. Ad ditionally, we show that S35b stimulates the production of cyclic GMP (cGMP) in HUVEC in a concentration- and time-dependent manner. At high concentration, S35b potentiates the cAMP increase induced by iloprost or forskolin without having a significant influence on cAMP level its elf. Potentiation of cAMP increase during agonist-induced EC stimulati on seems not to be important for the effect of S35b on cellular functi on as the compound is active in inhibiting PAF production when endothe lial cells are pretreated with indomethacin to block PGI(2) synthesis. The increase of cGMP evoked by S35b may account for the effect on end othelial cell function.