title: NS-398 reverses hypotension in endotoxemic rats: contribution of eicosanoids, NO, and peroxynitrite.
abstract: We have previously demonstrated that inhibition of vasodilator prostanoids, PGI2 and PGE2, and nitric oxide (NO) synthesis by a selective cyclooxygenase-2 (COX-2) inhibitor, NS-398, restores blood pressure as a result of increased systemic and renal levels of 20-hydroxyeicosatetraenoic acid (20-HETE) in endotoxemic rats. The aim of this study was to further investigate the effects of NS-398 on the changes in expression and/or activity of COX-2, cytochrome P450 4A1 (CYP4A1), inducible NO synthase (iNOS), and peroxynitrite formation in serum, renal, cardiac, and/or vascular tissues of lipopolysaccharide (LPS)-treated rats. LPS (10mg/kg, i.p.)-induced decrease in blood pressure was associated with increased protein levels of COX-2, iNOS, and nitrotyrosine in kidney, heart, thoracic aorta, and superior mesenteric artery. The activities of COX-2 and iNOS as well as levels of PGI2, PGE2, and nitrotyrosine were also increased in the systemic circulation and renal, cardiac, and vascular tissues of LPS-treated rats. In contrast, renal, cardiac, and vascular CYP4A1 protein expression as well as systemic and tissue levels of 20-HETE were decreased in endotoxemic rats. These effects of LPS, except COX-2 protein expression, were prevented by NS-398 (10 mg/kg, i.p.), given 1h after injection of LPS. These data suggest that COX-2-derived vasodilator prostanoids, PGI2 and PGE2, produced during endotoxemia increase iNOS protein expression and activity as well as peroxynitrite formation resulting in decreased CYP4A1 protein expression and 20-HETE synthesis. Taken together, we concluded that an increase in 20-HETE levels associated with a decrease in the production of vasodilator prostanoids and NO participates in the effect of NS-398 to prevent hypotension in the rat model of septic shock.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey. tunctanb@yahoo.com
authors.forename: Bahar
authors.initials: B
authors.lastname: Tunctan
authors.forename: Ayse Nihal
authors.initials: AN
authors.lastname: Sari
authors.forename: Meltem
authors.initials: M
authors.lastname: Kacan
authors.forename: Demet
authors.initials: D
authors.lastname: Unsal
authors.forename: C Kemal
authors.initials: CK
authors.lastname: Buharalioglu
authors.forename: Seyhan
authors.initials: S
authors.lastname: Sahan-Firat
authors.forename: Belma
authors.initials: B
authors.lastname: Korkmaz
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Kafait U
authors.initials: KU
authors.lastname: Malik
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D042926:Cytochrome P-450 CYP4A / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D011464:Epoprostenol / Q000037:antagonists & inhibitors / Q000378:metabolism; D015870:Gene Expression; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007022:Hypotension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008070:Lipopolysaccharides; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology*; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D011464:Epoprostenol; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D042926:Cytochrome P-450 CYP4A; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D015232:Dinoprostone