Basic & clinical pharmacology & toxicology
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Basic Clin. Pharmacol. Toxicol. · May 2010
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 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-PGF(1alpha) and PGE(2)) production. ⋯ These effects of ET on the iNOS protein expression and 6-keto-PGF(1alpha), PGE(2) 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.