Inhibition of soluble epoxide hydrolase by trans-4- [4-(3-adamantan-1-yl- ureido)-cyclohexyloxy]-benzoic acid is protective against ischemia-repefusion injury

Ketul R. Chaudhary, Mohamed Abukhashim, Sung Hee Hwang, Bruce D. Hammock, John M. Seubert

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Arachidonic acid, a polyunsaturated fatty acid, can be metabolized to cardioprotective epoxyeicosatrienoic acids (EETs) by cytochrome P450 epoxygenases, which are subsequently hydrolyzed to less bioactive dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). To study the effects of pharmacological inhibitor of sEH (sEHi), C57BL6 mice hearts were perfused in Langendorff mode for 40 minutes of baseline and subjected to 30 minutes of global no-flow ischemia followed by 40 minutes of reperfusion. Hearts were perfused with the sEHi, trans-4-[4-(3-adamantan-1-yl-ureido)- cyclohexyloxy]-benzoic acid (t-AUCB; 0.05, 0.1, 0.5, and 1 μM). To study the mechanism(s), hearts were perfused with 0.1 μM t-AUCB in the presence or absence of putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (10 μM) or phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin (200 nM) or LY294002 (5 μM). Infarct size was determined at the end of 2-hour reperfusion by 2,3,5-triphenyltetrazolium chloride staining. Inhibition of sEH by t-AUCB significantly improved postischemic left ventricular developed pressure (LVDP) recovery and reduced the infarct size after ischemia and reperfusion, as compared with control hearts. Perfusion with 14,15-epoxyeicosa-5(Z)-enoic acid, wortmannin or LY294002 before ischemia abolished the cardioprotective phenotype; however, coperfusion of both t-AUCB and 11,12-EET did not result in an additive effect on improved LVDP recovery. Together, our data suggest that pharmacological inhibition of sEH by t-AUCB is cardioprotective.

Original languageEnglish (US)
Pages (from-to)67-73
Number of pages7
JournalJournal of Cardiovascular Pharmacology
Volume55
Issue number1
DOIs
StatePublished - Jan 2010

Fingerprint

Epoxide Hydrolases
Benzoic Acid
Ischemia
Wounds and Injuries
Reperfusion
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Ventricular Pressure
Phosphatidylinositol 3-Kinase
Pharmacology
Acids
Unsaturated Fatty Acids
Arachidonic Acid
Cytochrome P-450 Enzyme System
Perfusion
4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid
Staining and Labeling
Phenotype

Keywords

  • Cardioprotection
  • Epoxyeicosatrienoic acid
  • Ischemia and reperfusion
  • SEH inhibitors

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Inhibition of soluble epoxide hydrolase by trans-4- [4-(3-adamantan-1-yl- ureido)-cyclohexyloxy]-benzoic acid is protective against ischemia-repefusion injury. / Chaudhary, Ketul R.; Abukhashim, Mohamed; Hwang, Sung Hee; Hammock, Bruce D.; Seubert, John M.

In: Journal of Cardiovascular Pharmacology, Vol. 55, No. 1, 01.2010, p. 67-73.

Research output: Contribution to journalArticle

Chaudhary, Ketul R. ; Abukhashim, Mohamed ; Hwang, Sung Hee ; Hammock, Bruce D. ; Seubert, John M. / Inhibition of soluble epoxide hydrolase by trans-4- [4-(3-adamantan-1-yl- ureido)-cyclohexyloxy]-benzoic acid is protective against ischemia-repefusion injury. In: Journal of Cardiovascular Pharmacology. 2010 ; Vol. 55, No. 1. pp. 67-73.
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