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

Prostaglandins Other Lipid Mediat. 2013 Jul-Aug:104-105:93-108. doi: 10.1016/j.prostaglandins.2012.08.007. Epub 2012 Sep 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Cytochrome P-450 CYP4A / genetics
  • Cytochrome P-450 CYP4A / metabolism
  • Dinoprostone / antagonists & inhibitors
  • Dinoprostone / metabolism
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endotoxemia / chemically induced
  • Endotoxemia / metabolism
  • Endotoxemia / physiopathology
  • Endotoxemia / prevention & control*
  • Epoprostenol / antagonists & inhibitors
  • Epoprostenol / metabolism
  • Gene Expression
  • Heart / drug effects
  • Heart / physiopathology
  • Hydroxyeicosatetraenoic Acids / metabolism
  • Hypotension / chemically induced
  • Hypotension / metabolism
  • Hypotension / physiopathology
  • Hypotension / prevention & control*
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / physiopathology
  • Lipopolysaccharides
  • Male
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism
  • Nitrobenzenes / pharmacology*
  • Peroxynitrous Acid / antagonists & inhibitors
  • Peroxynitrous Acid / metabolism*
  • Rats
  • Rats, Wistar
  • Shock, Septic / chemically induced
  • Shock, Septic / metabolism
  • Shock, Septic / physiopathology
  • Shock, Septic / prevention & control*
  • Sulfonamides / pharmacology*

Substances

  • 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