Soluble Epoxide Hydrolase Regulates Hydrolysis of Vasoactive Epoxyeicosatrienoic Acids

TLDR

Cytochrome P450–derived epoxyeicosatrienoic acids (EETs) influence renal vascular reactivity and sodium handling, but their role in hypertension remains controversial. The study aimed to investigate EET hydrolysis to DHETs as a regulatory mechanism of blood pressure and to identify a potent, selective inhibitor to distinguish the vascular effects of EETs and DHETs. The authors measured EET hydrolysis in renal cortical S9 fractions and assessed the effect of a selective soluble epoxide hydrolase inhibitor on blood pressure in spontaneously hypertensive rats. EET hydrolysis was markedly increased in SHR renal fractions, with a 14,15‑EET preference, higher sEH expression and urinary DHET excretion, and treatment with a selective sEH inhibitor lowered blood pressure by.

Abstract

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.