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, John R. Falck, Kafait Malik

Research output: Contribution to journalArticle

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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

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Peroxynitrous Acid
Eicosanoids
Cyclooxygenase 2
Hypotension
Lipopolysaccharides
Rats
Nitric Oxide
Kidney
Epoprostenol
Vasodilator Agents
Nitric Oxide Synthase
Cytochrome P-450 Enzyme System
Prostaglandins
Blood Vessels
Blood pressure
Tissue
Proteins
Dinoprostone
Blood Pressure
Endotoxemia

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Pharmacology
  • Cell Biology

Cite this

NS-398 reverses hypotension in endotoxemic rats : Contribution of eicosanoids, NO, and peroxynitrite. / Tunctan, Bahar; Sari, Ayse Nihal; Kacan, Meltem; Unsal, Demet; Buharalioglu, C. Kemal; Sahan-Firat, Seyhan; Korkmaz, Belma; Falck, John R.; Malik, Kafait.

In: Prostaglandins and Other Lipid Mediators, Vol. 104-105, 01.07.2013, p. 93-108.

Research output: Contribution to journalArticle

Tunctan, B, Sari, AN, Kacan, M, Unsal, D, Buharalioglu, CK, Sahan-Firat, S, Korkmaz, B, Falck, JR & Malik, K 2013, 'NS-398 reverses hypotension in endotoxemic rats: Contribution of eicosanoids, NO, and peroxynitrite', Prostaglandins and Other Lipid Mediators, vol. 104-105, pp. 93-108. https://doi.org/10.1016/j.prostaglandins.2012.08.007
Tunctan, Bahar ; Sari, Ayse Nihal ; Kacan, Meltem ; Unsal, Demet ; Buharalioglu, C. Kemal ; Sahan-Firat, Seyhan ; Korkmaz, Belma ; Falck, John R. ; Malik, Kafait. / NS-398 reverses hypotension in endotoxemic rats : Contribution of eicosanoids, NO, and peroxynitrite. In: Prostaglandins and Other Lipid Mediators. 2013 ; Vol. 104-105. pp. 93-108.
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AU - Unsal, Demet

AU - Buharalioglu, C. Kemal

AU - Sahan-Firat, Seyhan

AU - Korkmaz, Belma

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