title: Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids.
abstract: The cytochrome P450-derived epoxyeicosatrienoic acids (EETs) have potent effects on renal vascular reactivity and tubular sodium and water transport; however, the role of these eicosanoids in the pathogenesis of hypertension is controversial. The current study examined the hydrolysis of the EETs to the corresponding dihydroxyeicosatrienoic acids (DHETs) as a mechanism for regulation of EET activity and blood pressure. EET hydrolysis was increased 5- to 54-fold in renal cortical S9 fractions from the spontaneously hypertensive rat (SHR) relative to the normotensive Wistar-Kyoto (WKY) rat. This increase was most significant for the 14,15-EET regioisomer, and there was a clear preference for hydrolysis of 14, 15-EET over the 8,9- and 11,12-EETs. Increased EET hydrolysis was consistent with increased expression of soluble epoxide hydrolase (sEH) in the SHR renal microsomes and cytosol relative to the WKY samples. The urinary excretion of 14,15-DHET was 2.6-fold higher in the SHR than in the WKY rat, confirming increased EET hydrolysis in the SHR in vivo. Blood pressure was decreased 22+/-4 mm Hg (P:<0.01) 6 hours after treatment of SHRs with the selective sEH inhibitor N:, N:'-dicyclohexylurea; this treatment had no effect on blood pressure in the WKY rat. These studies identify sEH as a novel therapeutic target for control of blood pressure. The identification of a potent and selective inhibitor of EET hydrolysis will be invaluable in separating the vascular effects of the EET and DHET eicosanoids.
authors.affiliation: Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, CA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Yu
authors.forename: F
authors.initials: F
authors.lastname: Xu
authors.forename: L M
authors.initials: LM
authors.lastname: Huse
authors.forename: C
authors.initials: C
authors.lastname: Morisseau
authors.forename: A J
authors.initials: AJ
authors.lastname: Draper
authors.forename: J W
authors.initials: JW
authors.lastname: Newman
authors.forename: C
authors.initials: C
authors.lastname: Parker
authors.forename: L
authors.initials: L
authors.lastname: Graham
authors.forename: M M
authors.initials: MM
authors.lastname: Engler
authors.forename: B D
authors.initials: BD
authors.lastname: Hammock
authors.forename: D C
authors.initials: DC
authors.lastname: Zeldin
authors.forename: D L
authors.initials: DL
authors.lastname: Kroetz
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000652:urine; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D004852:Epoxy Compounds / Q000378:metabolism*; D006868:Hydrolysis / Q000187:drug effects; D006973:Hypertension / Q000209:etiology / Q000378:metabolism*; D007672:Kidney Cortex / Q000201:enzymology; D008297:Male; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D001095:Arachidonic Acids; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C050715:8,9-epoxyeicosatrienoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D014508:Urea; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid; C000948:1,3-dicyclohexylurea