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_1α 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-PGF _1α 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-PGF_1α, 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.