HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

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.
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
Topics
  • 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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: