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

Bahar Tunctan, Ayse Nihal Sari, Meltem Kacan, Demet Unsal, C. Kemal Buharalioglu, Seyhan Sahan-Firat, Belma Korkmaz, J R Falck, Kafait U. Malik

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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 (10 mg/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, PGE 2, 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 1 h 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.

Original languageEnglish (US)
Pages (from-to)93-108
Number of pages16
JournalProstaglandins and Other Lipid Mediators
StatePublished - Jul 2013


  • 20-HETE
  • Blood pressure
  • Cyclooxygenase-2
  • Endotoxin
  • Nitric oxide
  • Peroxynitrite
  • Prostaglandins

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Pharmacology
  • Cell Biology


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