title: 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), a 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.
authors.affiliation: Department of Pathological Biochemistry, Medical Academy, Erfurt, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Heller
authors.forename: F
authors.initials: F
authors.lastname: Bussolino
authors.forename: R
authors.initials: R
authors.lastname: Calvino
authors.forename: D
authors.initials: D
authors.lastname: Ghigo
authors.forename: P
authors.initials: P
authors.lastname: Alessio
authors.forename: R
authors.initials: R
authors.lastname: Todde
authors.forename: R
authors.initials: R
authors.lastname: Fruttero
authors.forename: G
authors.initials: G
authors.lastname: Pescarmona
authors.forename: A
authors.initials: A
authors.lastname: Gasco
authors.forename: U
authors.initials: U
authors.lastname: Till
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000123:Acetyltransferases / Q000378:metabolism; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D006152:Cyclic GMP / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D011464:Epoprostenol / Q000096:biosynthesis*; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000096:biosynthesis*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014471:Umbilical Veins / Q000378:metabolism
chemical_list: D010069:Oxadiazoles; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D005576:Colforsin; C074047:4-methyl-3-(phenylsulfonyl)furoxan; D011464:Epoprostenol; D000242:Cyclic AMP; D000123:Acetyltransferases; C046035:1-alkylglycerophosphocholine acetyltransferase; D013917:Thrombin; D006152:Cyclic GMP; D016285:Iloprost; D015056:1-Methyl-3-isobutylxanthine