NS-398 reverses hypotension in endotoxemic rats: contribution of eicosanoids, NO, and peroxynitrite.

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.
AuthorsBahar Tunctan, Ayse Nihal Sari, Meltem Kacan, Demet Unsal, C Kemal Buharalioglu, Seyhan Sahan-Firat, Belma Korkmaz, John R Falck, Kafait U Malik
JournalProstaglandins & other lipid mediators (Prostaglandins Other Lipid Mediat) 2013 Jul-Aug Vol. 104-105 Pg. 93-108 ISSN: 1098-8823 [Print] United States
PMID22975359 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Inc. All rights reserved.
Chemical References
  • Cyclooxygenase 2 Inhibitors
  • Hydroxyeicosatetraenoic Acids
  • Lipopolysaccharides
  • Nitrobenzenes
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Peroxynitrous Acid
  • Nitric Oxide
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Epoprostenol
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Cytochrome P-450 CYP4A
  • Cyclooxygenase 2
  • Ptgs2 protein, rat
  • Dinoprostone
  • Animals
  • Cyclooxygenase 2 (genetics, metabolism)
  • Cyclooxygenase 2 Inhibitors (pharmacology)
  • Cytochrome P-450 CYP4A (genetics, metabolism)
  • Dinoprostone (antagonists & inhibitors, metabolism)
  • Endothelial Cells (drug effects, metabolism)
  • Endotoxemia (chemically induced, metabolism, physiopathology, prevention & control)
  • Epoprostenol (antagonists & inhibitors, metabolism)
  • Gene Expression
  • Heart (drug effects, physiopathology)
  • Hydroxyeicosatetraenoic Acids (metabolism)
  • Hypotension (chemically induced, metabolism, physiopathology, prevention & control)
  • Kidney (drug effects, metabolism, physiopathology)
  • Lipopolysaccharides
  • Male
  • Nitric Oxide (antagonists & inhibitors, metabolism)
  • Nitric Oxide Synthase Type III (antagonists & inhibitors, genetics, metabolism)
  • Nitrobenzenes (pharmacology)
  • Peroxynitrous Acid (antagonists & inhibitors, metabolism)
  • Rats
  • Rats, Wistar
  • Shock, Septic (chemically induced, metabolism, physiopathology, prevention & control)
  • Sulfonamides (pharmacology)

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