S35b, a new phenylsulfonylfuroxan compound, inhibits thrombin-induced synthesis of platelet-activating factor and prostacyclin in human endothelial cells

Abstract

Endothelial cells (EC) produce platelet activating factor (PAF) and prostacyclin (PGI₂) in response to inflammatory agents such as thrombin. Upon cell stimulation a calcium-dependent phospholipase A₂ (PLA₂) is activated which hydrolyzes a membrane phospholipid to yield 1-0-alkyl-2-lyso-sn-glycero-3-phospho-choline (lyso-PAF) and free arachidonic acid. Lyso-PAF is in turn converted into PAF by a specific acetyltransferase and arachidonic acid is metabolized via cyclic endoperoxides to PGI₂. In the present study we report that S35b (4-methyl-3-phenylsulfonylfuroxan), an new phenyl-sulfonylfuroxan compound with potent antiaggregatory effect, inhibits thrombin-induced PAF synthesis and acetyltransferase activation as well as PGI₂ production in human umbilical vein endothelial cells (HUVEC) in a concentration dependent way. Additionally, 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 itself. Potentiation of cAMP increase during agonist-induced EC stimulation seems not to be important for the effect of S35b on cellular function as the compound is active in inhibiting PAF production when endothelial cells are pretreated with indomethacin to block PGI₂ synthesis. The increase of cGMP evoked by S35b may account for the effect on endothelial cell function.