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. 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(1alpha) and
PGE(2) 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(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.