Role of 20-Hydroxyeicosatetraenoic and Epoxyeicosatrienoic Acids in the Regulation of Vascular Function in a Model of Hypertension and Endothelial Dysfunction

Abstract

The objective of this study was to determine if acute inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis or reduced inactivation of epoxyeicosatrienoic acids (EETs) can correct L-N^G-nitro-arginine-methyl-ester (L-NAME)-induced abnormal vascular reactivity in the perfused mesenteric bed and the carotid artery of spontaneously hypertensive rats (SHR). Administration of L-NAME in drinking water (80 mg/l) to SHR for 3 weeks resulted in abnormal vascular reactivity to norepinephrine and carbachol in the perfused mesenteric vascular bed and carotid artery, and significantly elevated mean arterial blood pressure (244 ± 9 mm Hg) as compared to SHR controls drinking regular water (176 ± 3 mm Hg). In the perfused mesenteric vascular bed, the impaired vascular responsiveness to norepinephrine was corrected by acute treatment with N-hydroxy-N′-(4-butyl-2-methylphenyl)formamidine (HET0016), an inhibitor of 20-HETE formation, but not by 1-cyclohexyl-3-dodecyl urea (CDU), an inhibitor of soluble epoxide hydrolase. Treatment with either HET0016 or CDU did not improve impaired carbachol-induced vasodilation in the perfused mesenteric vascular bed. In the isolated carotid artery, treatment with HET0016 corrected the L-NAME-induced increase in norepinephrine-induced vasoconstriction, whereas only CDU treatment could improve impaired carbachol-induced vasodilation. Results of this study indicate that vascular function in a state of compromised nitric oxide formation is differentially modulated by 20-HETE and EETs, and that treatment with HET0016 or CDU may improve vascular function in a state of high blood pressure and endothelial dysfunction.

Intake of n-3 Polyunsaturated Fatty Acids Increases Omega-3 Index in Aged Male and Female Spontaneously Hypertensive Rats

“…Indeed, AA stimulates production of prostacyclin (PGI 2 ) by vascular tissue, a compound that exhibits antithrombotic effects and intake of n-3 PUFA enhanced it [22]. Moreover, AA is converted to epoxyeicosatrienoic acids (EETs) by epoxygenases or to 20-hydroxyeicosatetraeonic acid (20-HETE) by omega-hydrolases [23]. 20-HETE, a vasoconstrictor associated with endothelial dysfunction, is higher in hypertensive individuals as well as SHR and androgens increase its synthesis [24].…”

Whole rat DNA array survey for candidate genes related to hypertension in kidneys from three spontaneously hypertensive rat substrains at two stages of age and with hypotensive induction caused by hydralazine hydrochloride

“…fornage et al reported lower expression of this gene in the kidney of 4-to 5-week-old SHRs compared to WKY rats (35), and Corenblum et al observed lower expression of Ephx2 in the brain of SHRSPs compared to stroke-resistant SHRs (36). Although a number of studies have reported that soluble epoxide hydrolase elevates blood pressure by degrading vasodilative epoxyeicosatrienoic acids by means of an inhibitor (37)(38)(39), the role of Ephx2 in hypertension remains controversial. Considering our data and several other reports, Ephx2 may not be a candidate gene for hypertension as the expression of Ephx2 was elevated or decreased in some SHR substrains at some ages and, thus, results were not consistent.…”

20-HETE in the regulation of vascular and cardiac function

“…In animals treated with NO inhibitor, the resulted hypertension and end organ damage in the kidney is associated with increased CYP4A expression and 20-HETE bio-synthesis (Benter et al, 2005; Hercule, Wang, & Oyekan, 2003; A. O. Oyekan et al, 1999; Yousif & Benter, 2010). Superoxide has also been shown to affect 20-HETE levels.…”