Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids.
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.
Yu
Z
Z
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, CA, USA.
Xu
F
F
Huse
L M
LM
Morisseau
C
C
Draper
A J
AJ
Newman
J W
JW
Parker
C
C
Graham
L
L
Engler
M M
MM
Hammock
B D
BD
Zeldin
D C
DC
Kroetz
D L
DL
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
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