title: Inhibition by nitric oxide-releasing compounds of prostacyclin production in human endothelial cells.
abstract: 1. The effects of two chemically unrelated nitric oxide (NO)-releasing compounds were studied on prostacyclin production in lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs). The cells expressed cyclooxygenase-2 (COX-2) protein and produced prostacyclin by NS-398-sensitive manner suggesting that prostacyclin production derives principally by COX-2 pathway. 2. A novel NO-releasing oxatriazole derivative GEA 3175 (1-30 microm) inhibited LPS-induced production of prostacyclin in HUVECs in a dose-dependent manner being more potent than the earlier known NO-donor S-nitroso-N-acetylpenicillamine (SNAP). 3. The effects of the two NO-donors on prostacyclin synthesis were reversed when red blood cells were added into the culture indicating that the effects are due to NO released from the compounds. 4. Addition of exogenous arachidonic acid into the culture did not alter the inhibitory action of NO-donors suggesting that phospholipases are not the target of action of NO. 5. The NO-donors did not inhibit prostacyclin production in the presence of a selective COX-2 inhibitor NS-398. These data suggest that NO affects COX-2 pathway rather than has an overall effect on cyclooxygenases. 6. NO-releasing compounds did not alter the level of COX-2 protein expression in LPS-treated HUVECs as measured by Western blot analysis. 7. The results suggest that NO-donors inhibit the activity of COX-2 in human endothelial cells. A link between NO and the regulation of eicosanoid synthesis could represent an important mechanism in controlling vascular and inflammatory responses in pathophysiological states and during treatment with nitrovasodilators.
authors.affiliation: University of Tampere, Medical School, Finland.
authors.forename: O
authors.initials: O
authors.lastname: Kosonen
authors.forename: H
authors.initials: H
authors.lastname: Kankaanranta
authors.forename: U
authors.initials: U
authors.lastname: Malo-Ranta
authors.forename: A
authors.initials: A
authors.lastname: Ristimäki
authors.forename: E
authors.initials: E
authors.lastname: Moilanen
mesh_terms: D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; C093084:GEA 3175; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D014230:Triazoles; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010396:Penicillamine