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.

• Authors: Bahar Tunctan, Ayse Nihal Sari, Meltem Kacan, Demet Unsal, C Kemal Buharalioglu, Seyhan Sahan-Firat, Belma Korkmaz, John R Falck, Kafait U Malik
• Journal: Prostaglandins & other lipid mediators (Prostaglandins Other Lipid Mediat) 2013 Jul-Aug Vol. 104-105 Pg. 93-108 ISSN: 1098-8823 [Print] United States
• PMID: 22975359 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 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)