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. 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.
Cuez
Tuba
T
Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey.
Korkmaz
Belma
B
Buharalioglu
C Kemal
CK
Sahan-Firat
Seyhan
S
Falck
John
J
Malik
Kafait U
KU
Tunctan
Bahar
B
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism; D004731:Endotoxins; D006339:Heart Rate / Q000187:drug effects; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D007022:Hypotension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D055666:Lipopeptides / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000139:chemically induced; D014664:Vasodilation
D004731:Endotoxins; D006893:Hydroxyeicosatetraenoic Acids; D055666:Lipopeptides; C533498:N-(20-hydroxyeicosa-5,14-dienoyl)glycine; D011453:Prostaglandins; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D052247:Nitric Oxide Synthase Type II; D042926:Cytochrome P-450 CYP4A