A Synthetic Analogue of 20‐HETE, 5,14‐HEDGE, Reverses Endotoxin‐Induced Hypotension via Increased 20‐HETE Levels Associated with Decreased iNOS Protein Expression and Vasodilator Prostanoid Production in Rats

:  Nitric oxide (NO) produced by inducible NO synthase (iNOS) is responsible for endotoxin (ET)‐induced hypotension and vascular hyporeactivity and plays a major contributory role in the multiorgan failure. Endotoxic shock is also associated with an increase in vasodilator prostanoids as well as a d...

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Published in:Basic & clinical pharmacology & toxicology 2010-05, Vol.106 (5), p.378-388
Main Authors: Cuez, Tuba, Korkmaz, Belma, Buharalioglu, C. Kemal, Sahan‐Firat, Seyhan, Falck, John, Malik, Kafait U., Tunctan, Bahar
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blood Pressure - drug effects
Cytochrome P-450 CYP4A - metabolism
Endotoxins
Heart Rate - drug effects
Hydroxyeicosatetraenoic Acids - metabolism
Hypotension - chemically induced
Hypotension - drug therapy
Hypotension - metabolism
Lipopeptides - therapeutic use
Medical sciences
Nitric Oxide Synthase Type II - metabolism
Pharmacology. Drug treatments
Prostaglandins - metabolism
Rats
Rats, Sprague-Dawley
Shock, Septic - chemically induced
Vasodilation
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Summary::  Nitric oxide (NO) produced by inducible NO synthase (iNOS) is responsible for endotoxin (ET)‐induced hypotension and vascular hyporeactivity and plays a major contributory role in the multiorgan failure. Endotoxic shock is also associated with an increase in vasodilator prostanoids as well as a decrease in endothelial NO synthase (eNOS) and cytochrome P450 4A protein expression, and production of a vasoconstrictor arachidonic acid product, 20‐hydroxyeicosatetraenoic acid (20‐HETE). The aim of this study was to investigate the effects of a synthetic analogue of 20‐HETE, N‐[20‐hydroxyeicosa‐5(Z),14(Z)‐dienoyl]glycine (5,14‐HEDGE), on the ET‐induced changes in eNOS, iNOS and heat shock protein 90 (hsp90) expression as well as 20‐HETE and vasodilator prostanoid (6‐keto‐PGF1α and PGE2) production. ET‐induced fall in blood pressure and rise in heart rate were associated with an increase in iNOS protein expression and a decrease in eNOS protein expression in heart, thoracic aorta, kidney and superior mesenteric artery. ET did not change hsp90 protein expression in the tissues. ET‐induced changes in eNOS and iNOS protein expression were associated with increased 6‐keto‐PGF1α and PGE2 levels and a decrease in 20‐HETE levels, in the serum and kidney. These effects of ET on the iNOS protein expression and 6‐keto‐PGF1α, PGE2 and 20‐HETE levels were prevented by 5,14‐HEDGE. Furthermore, a competitive antagonist of vasoconstrictor effects of 20‐HETE, 20‐hydroxyeicosa‐6(Z),15(Z)‐dienoic acid, prevented the effects of 5,14‐HEDGE on the ET‐induced changes in systemic and renal levels of these prostanoids and 20‐HETE. These data are consistent with the view that an increase in systemic and renal 20‐HETE levels associated with a decrease in iNOS protein expression and vasodilator prostanoid production contributes to the effect of 5,14‐HEDGE to prevent the hypotension during rat endotoxemia.
ISSN:1742-7835
1742-7843
DOI:10.1111/j.1742-7843.2009.00501.x