Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids

The cytochrome P450-derived epoxyeicosatrienoic acids (EETs) have potent ef fects 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 hypert ensive 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 solu ble epoxide hydrolase (sEH) in the SHR renal microsomes and cytosol relativ e to the WKY samples. The urinary excretion of 14,15-DHET was 2.6-fold high er in the SHR than in the WKY rat, confirming increased EET hydrolysis in t he 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'-dicyclohexylu rea; this treatment had no effect on blood pressure in the WKY rat. These s tudies identify sEH as a novel therapeutic target for control of blood pres sure. The identification of a potent and selective inhibitor of EET hydroly sis will be invaluable in separating the vascular effects of the EET and DH ET eicosanoids.