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 journalArticle

14 Scopus citations

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 (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
Volume104-105
DOIs
StatePublished - Jul 1 2013

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Pharmacology
  • Cell Biology

Fingerprint Dive into the research topics of 'NS-398 reverses hypotension in endotoxemic rats: Contribution of eicosanoids, NO, and peroxynitrite'. Together they form a unique fingerprint.

  • Cite this

    Tunctan, B., Sari, A. N., Kacan, M., Unsal, D., Buharalioglu, C. K., Sahan-Firat, S., Korkmaz, B., Falck, J. R., & Malik, K. U. (2013). NS-398 reverses hypotension in endotoxemic rats: Contribution of eicosanoids, NO, and peroxynitrite. Prostaglandins and Other Lipid Mediators, 104-105, 93-108. https://doi.org/10.1016/j.prostaglandins.2012.08.007