Abstract 531: Regulation of Plasma 20-HETE and Soluble Epoxide Hydrolase by Salt Balance in Normotensive Subjects

The tissue sources of circulating and urinary 20-HETE and EETs are not well known. We have previously shown urine 20-HETE abnormalities in salt-sensitive (SS) hypertension. We studied plasma 20-HETE and EETs in normotensive volunteers classified as SS or salt resistant (SR) with an acute protocol of salt loading (HS, 460 mmol diet and iv) and depletion (LS, 10 mmol and furosemide). Plasma 20-HETE and total (EET+DHET) or active EET did not differ between SR and SS during baseline (B, UNaV 146±17 mmol/24hr), HS (422±20) or LS (24±6). In normal SR subjects, HS did not affect the levels of either eicosanoid but reduced degradation of EETs into DHETs by decreasing the activity of soluble epoxide hydrolase (sEH or DHET/[EET+DHET]). No major clinical or biochemical correlates for plasma 20-HETE were identified in B, HS or LS. In SR but not SS, EET+DHET (r=0.57, p<0.003) and DHET (r=0.45, p<0.03) correlated with aldosterone during B and HS. LS stimulated 20-HETE in both SS and SR and also unexpectedly increased EET+DHET in SR subjects. This did not lead to increased EETs because of concomitant stimulation of sEH with increased degradation into DHETs. In SR, stimulation of 20-HETE by LS correlated with greater natriuresis (r=0.71, p<0.02), greater reduction of MAP (r=0.66, p<0.03) and lesser stimulation of aldosterone (r=0.64, p<0.04), relationships not observed in SS. Finally, in SR subjects only, during B and HS, plasma 20-HETE correlated with the activity of sEH (r=0.56, p<0.005) and levels of DHET (r=0.63, p<0.001), but not with total or active EETs. Our data on stimulation of plasma 20-HETE by LS and its correlates (markers of severity of sodium depletion) suggest recruitment of systemic vasoconstrictor 20-HETE for maintenance of BP. Plasma EET responses to HS and LS are not consistent with its renal natriuretic role but correlate with aldosterone responses to salt balance, perhaps reflecting modulation of aldosterone actions on extrarenal ENaC. Although no significant correlations were detected between blood pressure and EETs, there was a direct relationship between plasma 20-HETE, sEH activity and degradation of EETs into DHETs. This suggests coordinated vasoconstriction and vasodilation by these eicosanoids in normal SR humans, which is disrupted in normotensive SS.

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Targeted Disruption of Soluble Epoxide Hydrolase Reveals a Role in Blood Pressure Regulation

Journal of Biological Chemistry ◽

10.1074/jbc.m008106200 ◽

2000 ◽

Vol 275 (51) ◽

pp. 40504-40510 ◽

Cited By ~ 251

Author(s):

Christopher J. Sinal ◽

Masaaki Miyata ◽

Masahiro Tohkin ◽

Kiyoshi Nagata ◽

John R. Bend ◽

...

Keyword(s):

Blood Pressure ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Blood Pressure Regulation ◽

Pressure Regulation ◽

Targeted Disruption

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Polymorphism in Soluble Epoxide Hydrolase and Blood Pressure in Spontaneously Hypertensive Rats

Hypertension ◽

10.1161/01.hyp.0000032278.75806.68 ◽

2002 ◽

Vol 40 (4) ◽

pp. 485-490 ◽

Cited By ~ 49

Author(s):

Myriam Fornage ◽

Cruz A. Hinojos ◽

Barbara W. Nurowska ◽

Eric Boerwinkle ◽

Bruce D. Hammock ◽

...

Keyword(s):

Blood Pressure ◽

Spontaneously Hypertensive Rats ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

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Inhibition of Soluble Epoxide Hydrolase Attenuates Bosutinib-Induced Blood Pressure Elevation

Hypertension ◽

10.1161/hypertensionaha.121.17548 ◽

2021 ◽

Author(s):

Zhen Cui ◽

Bochuan Li ◽

Yanhong Zhang ◽

Jinlong He ◽

Xuelian Shi ◽

...

Keyword(s):

Blood Pressure ◽

Endothelial Cells ◽

Endothelial Cell ◽

Side Effects ◽

Epoxide Hydrolase ◽

Endothelial Activation ◽

Soluble Epoxide Hydrolase ◽

Mesenteric Arteries ◽

Arterial Blood ◽

Soluble Epoxide Hydrolase Inhibitor

Endothelial cells play a critical role in maintaining homeostasis of vascular function, and endothelial activation is involved in the initial step of atherogenesis. Previously, we reported that Abl kinase mediates shear stress–induced endothelial activation. Bosutinib, a dual inhibitor of Src and Abl kinases, exerts an atheroprotective effect; however, recent studies have demonstrated an increase in the incidence of side effects associated with bosutinib, including increased arterial blood pressure (BP). To understand the effects of bosutinib on BP regulation and the mechanistic basis for novel treatment strategies against vascular dysfunction, we generated a line of mice conditionally lacking c-Abl in endothelial cells (endothelial cell- Abl KO ). Knockout mice and their wild-type littermates ( Abl f/f ) were orally administered a clinical dose of bosutinib, and their BP was monitored. Bosutinib treatment increased BP in both endothelial cell- Abl KO and Abl f/f mice. Furthermore, acetylcholine-evoked endothelium-dependent relaxation of the mesenteric arteries was impaired by bosutinib treatment. RNA sequencing of mesenteric arteries revealed that the CYP (cytochrome P450)-dependent metabolic pathway was involved in regulating BP after bosutinib treatment. Additionally, bosutinib treatment led to an upregulation of soluble epoxide hydrolase in the arteries and a lower plasma content of eicosanoid metabolites in the CYP pathway in mice. Treatment with 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea, a soluble epoxide hydrolase inhibitor, reversed the bosutinib-induced changes to the eicosanoid metabolite profile, endothelium-dependent vasorelaxation, and BP. Thus, the present study demonstrates that upregulation of soluble epoxide hydrolase mediates bosutinib-induced elevation of BP, independent of c-Abl. The addition of soluble epoxide hydrolase inhibitor in patients treated with bosutinib may aid in preventing vascular side effects.

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Abstract P642: Two Pools of Eicosatrienoic Acids in Humans: Alterations in Salt Sensitive Normotensive Subjects

Hypertension ◽

10.1161/hyp.68.suppl_1.p642 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Fernando Elijovich ◽

Ginger L Milne ◽

Nancy J Brown ◽

Michal Laniado-Schwartzman ◽

Cheryl L Laffer

Keyword(s):

Epoxide Hydrolase ◽

Fractional Excretion ◽

Eicosatrienoic Acid ◽

Distributed Data ◽

Indiana University ◽

System P ◽

Low Salt ◽

Total Pool ◽

Normotensive Subjects ◽

Stimulation Of

We measured eicosatrienoic acids in 21 normotensive subjects classified as salt-resistant (SR=13) or salt-sensitive (SS=8) with the rapid protocol of Indiana University (high salt, HS=460 mEq Na/24 hrs, low-salt, LS=10 mEq Na/24 hrs + furosemide 40 mg x 3). No EETs were detected in urine; hence, ELISA 14-15 DHETs were taken to represent the total pool of this urine isoform (U-TP). Plasma total pools (8-9,11-12,14-15 and 14-15 P-TP) are the sum of EETs+DHETs (HPLC-MS), and their results were similar, so the former are reported. Analyses required log-transformation of not normally distributed data. U-TP was not changed by HS but decreased with LS (Δlog -0.47±0.19, p<0.01), consistent with the response of a natriuretic system. Further, in the baseline, HS and LS periods combined, U-TP correlated positively with UNaV (r=0.35, p<0.005), fractional excretion of Na (r=0.37, p<0.003) and Na/K ratio (r=0.39, p<0.002), indicating inhibition of ENaC. P-TP was not changed by HS (due to inhibited soluble epoxide hydrolase with reduction in DHETs and increase in EETs) but was increased by LS (Δlog 0.05±0.02, p<0.01), including EETs (0.04±0.02, p<0.03), inconsistent with a natriuretic system. P-TP did not correlate with urine parameters. Instead, plasma DHETs correlated with aldosterone (r=0.34, p<0.005) and plasma EETs with catecholamines (r=0.45, p<0.001). Differences between SR and SS subjects included: a) lower levels of U-TP and P-TP in SS than SR, significant in some stages of the experiment, b) lack of response of U-TP to changes in salt balance in SS, c) lack of the correlations between U-TP and natriuresis/ENaC activity and between DHET/aldosterone in SS, all observed only in SR. We conclude that: 1. Urine eicosatrienoic acids reflect a renal pool involved in regulation of natriuresis whereas plasma ones are probably of systemic origin and uninvolved in Na excretion, 2. There may be a feed-forward mechanism for the systemic, non-renal effects of aldosterone, by stimulation of inactive DHETs, 3. Catecholamines may stimulate epoxygenases or EETs may produce neuronal release of catecholamines, which remains to be investigated, and 4. Differences between SS and SR suggest abnormalities of eicosatrienoic acid regulation of natriuresis in SS subjects.

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GSK2256294 Decreases sEH (Soluble Epoxide Hydrolase) Activity in Plasma, Muscle, and Adipose and Reduces F2-Isoprostanes but Does Not Alter Insulin Sensitivity in Humans

Hypertension ◽

10.1161/hypertensionaha.121.17659 ◽

2021 ◽

Author(s):

James M. Luther ◽

Justina Ray ◽

Dawei Wei ◽

John R. Koethe ◽

Latoya Hannah ◽

...

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Epoxide Hydrolase ◽

Renal Plasma Flow ◽

Soluble Epoxide Hydrolase ◽

Improve Insulin Sensitivity ◽

Double Blind ◽

Phosphorylated Akt

Epoxyeicosatrienoic acids (EETs) reduce blood pressure by acting in the vasculature and kidney, and interventions to increase circulating EETs improve insulin sensitivity and prevent diabetes in animal models. Inhibition of EET hydrolysis with a sEH (soluble epoxide hydrolase) inhibitor is an attractive approach for hypertension and diabetes. We tested the hypothesis that sEH inhibition increases circulating EETs, reduces blood pressure, and improves insulin sensitivity, blood flow, and inflammation in a randomized, double-blind, placebo-controlled crossover study. Sixteen participants with obesity and prediabetes were randomized to GSK2256294 10 mg QD or placebo for 7 days, insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and adipose and muscle tissues biopsies were performed to assess insulin-stimulated Akt phosphorylation. We assessed tissue and plasma EETs and their respective diol concentrations and sEH activity within plasma, muscle, and adipose tissues. GSK2256294 reduced circulating and adipose tissue sEH activity, but blood pressure, circulating EET, and tissue EETs were unchanged. Plasma sEH activity correlated with muscle and adipose tissue sEH activity. Insulin sensitivity assessed during hyperinsulinemic clamps, as well as adipose and muscle phosphorylated-Akt/Akt expression were similar during GSK2256294 and placebo. sEH inhibition with GSK2256294 reduced plasma F2-isoprostanes (50.7±15.8 versus 37.2±17.3 pg/mL; P =0.03) but not IL (interleukin)-6. Resting blood pressure, forearm blood flow, and renal plasma flow were similar during GSK2256294 and placebo. We demonstrate that GSK2256294 administration for 7 days effectively inhibits sEH activity in plasma, muscle, and adipose tissue and reduces F2-isoprostanes—a marker of oxidative stress—but does not improve insulin sensitivity or blood pressure.

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SGK1 as a determinant of kidney function and salt intake in response to mineralocorticoid excess

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00731.2004 ◽

2005 ◽

Vol 289 (2) ◽

pp. R395-R401 ◽

Cited By ~ 47

Author(s):

Volker Vallon ◽

Dan Yang Huang ◽

Florian Grahammer ◽

Amanda W. Wyatt ◽

Hartmut Osswald ◽

...

Keyword(s):

Blood Pressure ◽

Renal Function ◽

Salt Intake ◽

Salt Appetite ◽

Salt Balance ◽

Wild Type ◽

Similar Extent ◽

Kidney Weight ◽

Pronounced Increase ◽

Stimulation Of

Mineralocorticoids modify salt balance by both stimulating salt intake and inhibiting salt loss. Renal salt retention is accomplished by upregulation of reabsorption, an effect partially mediated by serum- and glucocorticoid-inducible kinase 1 (SGK1). The present study explored the contribution of SGK1 to the regulation of renal function, salt intake, and blood pressure during mineralocorticoid excess. DOCA/1% NaCl treatment increased blood pressure and creatinine clearance to a similar extent in SGK1-deficient sgk1−/− and wild-type sgk1+/+ mice but led to more pronounced increase of proteinuria in sgk1+/+ mice (by 474 ± 89%) than in sgk1−/− mice (by 154 ± 31%). DOCA/1% NaCl treatment led to significant increase of kidney weight (by 24%) and to hypokalemia (from 3.9 ± 0.1 to 2.7 ± 0.1 mmol/l) only in sgk1+/+ mice. The treatment enhanced renal Na+ excretion significantly more in sgk1+/+ mice (from 3 ± 1 to 134 ± 32 μmol·24 h−1·g body wt−1) than in sgk1−/− mice (from 4 ± 1 to 49 ± 8 μmol·24 h−1·g body wt−1), pointing to SGK1-dependent stimulation of salt intake. With access to two drinking bottles containing 1% NaCl or water, DOCA treatment did not significantly affect water intake in either genotype but increased 1% NaCl intake in sgk1+/+ mice (within 9 days from 3.5 ± 0.9 to 16.5 ± 2.4 ml/day) consistent with DOCA-induced salt appetite. This response was significantly attenuated in sgk1−/− mice (from 2.6 ± 0.6 to 5.9 ± 0.9 ml/day). Thus SGK1 contributes to the stimulation of salt intake, kidney growth, proteinuria, and renal K+ excretion during mineralocorticoid excess.

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Soluble epoxide hydrolase gene deletion attenuates renal injury and inflammation with DOCA-salt hypertension

AJP Renal Physiology ◽

10.1152/ajprenal.00098.2009 ◽

2009 ◽

Vol 297 (3) ◽

pp. F740-F748 ◽

Cited By ~ 91

Author(s):

Marlina Manhiani ◽

Jeffrey E. Quigley ◽

Sarah F. Knight ◽

Shiva Tasoobshirazi ◽

TarRhonda Moore ◽

...

Keyword(s):

Blood Pressure ◽

Epoxide Hydrolase ◽

Gene Deletion ◽

Soluble Epoxide Hydrolase ◽

Glomerular Injury ◽

Renal Protection ◽

Renal Inflammation ◽

Arterial Blood ◽

Salt Hypertension ◽

Salt Sensitive Hypertension

Inhibition of soluble epoxide hydrolase (sEH) has been shown to be renal protective in rat models of salt-sensitive hypertension. Here, we hypothesize that targeted disruption of the sEH gene (Ephx2) prevents both renal inflammation and injury in deoxycorticosterone acetate plus high salt (DOCA-salt) hypertensive mice. Mean arterial blood pressure (MAP) increased significantly in the DOCA-salt groups, and MAP was lower in Ephx2−/− DOCA-salt (129 ± 3 mmHg) compared with wild-type (WT) DOCA-salt (145 ± 2 mmHg) mice. Following 21 days of treatment, WT DOCA-salt urinary MCP-1 excretion increased from control and was attenuated in the Ephx2−/− DOCA-salt group. Macrophage infiltration was reduced in Ephx2−/− DOCA-salt compared with WT DOCA-salt mice. Albuminuria increased in WT DOCA-salt (278 ± 55 μg/day) compared with control (17 ± 1 μg/day) and was blunted in the Ephx2−/− DOCA-salt mice (97 ± 23 μg/day). Glomerular nephrin expression demonstrated an inverse relationship with albuminuria. Nephrin immunofluorescence was greater in the Ephx2−/− DOCA-salt group (3.4 ± 0.3 RFU) compared with WT DOCA-salt group (1.1 ± 0.07 RFU). Reduction in renal inflammation and injury was also seen in WT DOCA-salt mice treated with a sEH inhibitor { trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid; tAUCB}, demonstrating that the C-terminal hydrolase domain of the sEH enzyme is responsible for renal protection with DOCA-salt hypertension. These data demonstrate that Ephx2 gene deletion decreases blood pressure, attenuates renal inflammation, and ameliorates glomerular injury in DOCA-salt hypertension.

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Soluble epoxide hydrolase in the generation and maintenance of high blood pressure in spontaneously hypertensive rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00710.2010 ◽

2011 ◽

Vol 300 (4) ◽

pp. E691-E698 ◽

Cited By ~ 35

Author(s):

Maarten P. Koeners ◽

Sebastiaan Wesseling ◽

Arzu Ulu ◽

Rocío López Sepúlveda ◽

Christophe Morisseau ◽

...

Keyword(s):

Blood Pressure ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Female Offspring ◽

Reduce Blood Pressure ◽

Dodecanoic Acid ◽

Dynamic Interactions ◽

Spontaneously Hypertensive ◽

Perinatal Treatment ◽

Orally Active

We hypothesized that perinatal inhibition of soluble epoxide hydrolase (SEH), which metabolizes epoxyeicosatrienoic acids in the arachidonic acid (AA) cascade, with an orally active SEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), would persistently reduce blood pressure (BP) in adult SHR despite discontinuation of AUDA at 4 wk of age. Renal cytoplasmic epoxide hydrolase-2 (Ephx2) gene expression was enhanced in SHR vs. WKY from 2 days to 24 wk. Effects of perinatal treatment with AUDA, supplied to SHR dams until 4 wk after birth, on BP in female and male offspring and renal oxylipin metabolome in female offspring were observed and contrasted to female SHR for direct effects of AUDA (8–12 wk). Briefly, inhibition of SEH was effective in persistently reducing BP in female SHR when applied during the perinatal phase. This was accompanied by marked increases in major renal AA epoxides and decreases in renal lipoxygenase products of AA. Early inhibition of SEH induced a delayed increase in renal 5-HETE at 24 wk, in contrast to a decrease at 2 wk. Inhibition of SEH in female SHR from 8 to 12 wk did not reduce BP but caused profound decreases in renal 15( S)-HETrE, LTB4, TBX2, 5-HETE, and 20-HETE and increases in TriHOMEs. In male SHR, BP reduction after perinatal AUDA was transient. Thus, Ephx2 transcription and SEH activity in early life may initiate mechanisms that eventually contribute to high BP in adult female SHR. However, programmed BP-lowering effects of perinatal SEH inhibition in female SHR cannot be simply explained by persistent reduction in renal SEH activity but rather by more complex and temporally dynamic interactions between the renal SEH, lipoxygenase, and cyclooxygenase pathways.

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