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

Tuba Cuez, Belma Korkmaz, C. Kemal Buharalioglu, Seyhan Sahan-Firat, John Falck, Kafait Malik, Bahar Tunctan

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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 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 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, 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.

Original languageEnglish (US)
Pages (from-to)378-388
Number of pages11
JournalBasic and Clinical Pharmacology and Toxicology
Volume106
Issue number5
DOIs
StatePublished - May 1 2010

Fingerprint

Controlled Hypotension
Vasodilator Agents
Endotoxins
Nitric Oxide Synthase
Prostaglandins
Rats
Proteins
Dinoprostone
Kidney
HSP90 Heat-Shock Proteins
Vasoconstrictor Agents
HSP20 Heat-Shock Proteins
Endotoxemia
Superior Mesenteric Artery
N-(20-hydroxyeicosa-5,14-dienoyl)glycine
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Nitric Oxide Synthase Type III
Blood pressure
Prostaglandins F
Nitric Oxide Synthase Type II

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Toxicology

Cite this

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. / Cuez, Tuba; Korkmaz, Belma; Buharalioglu, C. Kemal; Sahan-Firat, Seyhan; Falck, John; Malik, Kafait; Tunctan, Bahar.

In: Basic and Clinical Pharmacology and Toxicology, Vol. 106, No. 5, 01.05.2010, p. 378-388.

Research output: Contribution to journalArticle

@article{14d74515ba1a43cf83b4fef0c11a5c3c,
title = "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",
abstract = "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-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-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.",
author = "Tuba Cuez and Belma Korkmaz and Buharalioglu, {C. Kemal} and Seyhan Sahan-Firat and John Falck and Kafait Malik and Bahar Tunctan",
year = "2010",
month = "5",
day = "1",
doi = "10.1111/j.1742-7843.2009.00501.x",
language = "English (US)",
volume = "106",
pages = "378--388",
journal = "Basic and Clinical Pharmacology and Toxicology",
issn = "1742-7835",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - 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

AU - Cuez, Tuba

AU - Korkmaz, Belma

AU - Buharalioglu, C. Kemal

AU - Sahan-Firat, Seyhan

AU - Falck, John

AU - Malik, Kafait

AU - Tunctan, Bahar

PY - 2010/5/1

Y1 - 2010/5/1

N2 - 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-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-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.

AB - 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-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-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.

UR - http://www.scopus.com/inward/record.url?scp=77951074203&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951074203&partnerID=8YFLogxK

U2 - 10.1111/j.1742-7843.2009.00501.x

DO - 10.1111/j.1742-7843.2009.00501.x

M3 - Article

VL - 106

SP - 378

EP - 388

JO - Basic and Clinical Pharmacology and Toxicology

JF - Basic and Clinical Pharmacology and Toxicology

SN - 1742-7835

IS - 5

ER -