Effect of 14,15-epoxyeicosatrienoic acid infusion on blood pressure in normal and hypertensive rats

Lin, Wei; Falck, John R.; Wong, Patrick Y.-K.

doi:10.1016/0006-291x(90)90619-x

Cited by 29 publications

(17 citation statements)

References 6 publications

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“…Studies in other laboratories have established that various EET regioisomers cause either vasodilatation or vasoconstriction in a variety of vascular beds (8)(9)(10) and that they possess antiinflammatory properties (11). Based on these findings, sEH inhibition is a potentially attractive pharmacological approach to human hypertension.…”

mentioning

confidence: 99%

Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation

Davis

Thompson

Howard

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

112

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Atherosclerosis, in its myriad incarnations the foremost killer disease in the industrialized world, is characterized by aberrant proliferation of vascular smooth muscle (VSM) cells in part as a result of the recruitment of inflammatory cells to the blood vessel wall. The epoxyeicosatrienoic acids are synthesized from arachidonic acid in a reaction catalyzed by the cytochrome P450 system and are vasoactive substances. Metabolism of these compounds by epoxide hydrolases results in the formation of compounds that affect the vasculature in a pleiotropic manner. As an outgrowth of our observations that urea inhibitors of the soluble epoxide hydrolase (sEH) reduce blood pressure in spontaneously hypertensive rats as well as the findings of other investigators that these compounds possess antiinflammatory actions, we have examined the effect of sEH inhibitors on VSM cell proliferation. We now show that the sEH inhibitor 1-cyclohexyl-3-dodecyl urea (CDU) inhibits human VSM cell proliferation in a dose-dependent manner and is associated with a decrease in the level of cyclin D1. In addition, cis-epoxyeicosatrienoic acid mimics the growth-suppressive activity of CDU; there is no evidence of cellular toxicity or apoptosis in CDU-treated cells when incubated with 20 μM CDU for up to 48 h. These results, in light of the antiinflammatory and antihypertensive properties of these compounds that have been demonstrated already, suggest that the urea class of sEH inhibitors may be useful for therapy for diseases such as hypertension and atherosclerosis characterized by exuberant VSM cell proliferation and vascular inflammation

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mentioning

confidence: 99%

Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation

Davis

Thompson

Howard

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

112

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“…Four DHETs (5, 6 ; 8, 9 ; 11,12 ; 14,15 DHET) were reported to inhibit AVP-stimulated hydraulic conductivity in rabbit cortical collecting ducts (flirt et al 1989). In addition, 14, 15 EET was found to inhibit renin secretion in rat renal cortical slices (Henrich et al 1990) and it decreases blood pressure in SHR and WKY rats by intravenous and intraarterial infusion (Lin et al 1990). Since EETs and their corresponding diols have a wide spectrum of renal effects, their broad distribution pattern along the entire nephron segments are suitable to reveal their biological effects.…”

Section: Anatomical and Physiological Relationshipmentioning

confidence: 99%

Roles of Renal Cytochrome P450-Dependent Arachidonic Acid Metabolites in Hypertension.

Omata

Abe

Sheu

et al. 1992

Tohoku J. Exp. Med.

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“…Epoxyeicosatrienoic acids (EETs) and hydroxyeicosatrienoic acids, chiefly 20-HETE, are metabolites of arachidonic acid catalysed by the enzymes P450 epoxygenases and P450 ω -hydoxylases. Researchers have reported that decreased renal epoxygenases levels are associated with the development of hypertension [1,[6][7][8].Epoxyeicosatrienoic acids are considered as endothelialderived hyperpolarizing factors (EDHF) [9][10][11][12] possessing vasodilatory properties in some vascular beds [9,10,[13][14][15][16] independent of the nitric oxide or PGI2 driven vasorelaxation. EETs are released from the endothelial cells that activates the vascular smooth muscle cell G s α leading to the opening of Ca 2 + -activated K + channels.…”

mentioning

confidence: 99%

“…Epoxyeicosatrienoic acids are considered as endothelialderived hyperpolarizing factors (EDHF) [9][10][11][12] possessing vasodilatory properties in some vascular beds [9,10,[13][14][15][16] independent of the nitric oxide or PGI2 driven vasorelaxation. EETs are released from the endothelial cells that activates the vascular smooth muscle cell G s α leading to the opening of Ca 2 + -activated K + channels.…”

mentioning

confidence: 99%

Oral Delivery of 1,3‐Dicyclohexylurea Nanosuspension Enhances Exposure and Lowers Blood Pressure in Hypertensive Rats

Ghosh¹,

Chiang²,

Wahlstrom³

et al. 2008

Basic Clin Pharma Tox

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Cytochrome P450-derived epoxyeicosatrienoic acids (EET) are biologically active metabolites of arachidonic acid that have potent effects on renal vascular reactivity and tubular ion transport and have been implicated in the control of blood pressure. EETs are hydrolyzed to their less active diols, dihydroxyeicosatrienoic acids (DHET), by the enzyme soluble epoxide hydrolase (sEH). 1,3-Dicyclohexylurea (DCU), a potent sEH inhibitor, lowers systemic blood pressure in spontaneously hypertensive rats when dosed intraperitoneally. However, DCU has poor aqueous solubility, posing a challenge for in vivo oral delivery. To overcome this limitation, we formulated DCU in a nanosuspension using wet milling. Milling reduced particle size, increasing the total surface area by approximately 40-fold. In rats chronically infused with angiotensin II, the DCU nanosuspension administered orally twice daily for 4 days produced plasma exposures an order of magnitude greater than unmilled DCU and lowered blood pressure by nearly 30 mmHg. Consistent with the mechanism of sEH inhibition, DCU increased plasma 14,15-EET and decreased plasma 14,15-DHET levels. These data confirm the antihypertensive effect of sEH inhibition and demonstrate that greatly enhanced exposure of a low-solubility compound is achievable by oral delivery using a nanoparticle drug delivery system.It is now well established that cytochrome P450 metabolites are major regulators of cardiovascular and renal functions particularly in the maintenance of vascular tone and ion transport [1]. Recently, these metabolites have also been implicated in anti-inflammatory roles [2][3][4][5]. Epoxyeicosatrienoic acids (EETs) and hydroxyeicosatrienoic acids, chiefly 20-HETE, are metabolites of arachidonic acid catalysed by the enzymes P450 epoxygenases and P450 ω -hydoxylases. Researchers have reported that decreased renal epoxygenases levels are associated with the development of hypertension [1,[6][7][8].Epoxyeicosatrienoic acids are considered as endothelialderived hyperpolarizing factors (EDHF) [9][10][11][12] possessing vasodilatory properties in some vascular beds [9,10,[13][14][15][16] independent of the nitric oxide or PGI2 driven vasorelaxation. EETs are released from the endothelial cells that activates the vascular smooth muscle cell G s α leading to the opening of Ca 2 + -activated K + channels. This effect may or may not involve cAMP or PKA in some cell types, but may involve ADP ribosylation [17][18][19] hyperpolarizing the vascular smooth muscle cells leading to vasorelaxation particularly in the resistant arteries such as the renal [19], coronary [16] and mesenteric arteries [20].Epoxyeicosatrienoic acid formed by the P450 epoxygenases enzyme from arachidonic acid is hydrolyzed to its less active diol, dihydroxyeicosatrienoic acids (DHET) by the enzyme soluble epoxide hydrolase [21,22]. The role of soluble epoxide hydrolase in the long-term control of arterial blood pressure and the pathogenesis of experimental hypertension has already been proposed [6,15,...

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Effect of 14,15-epoxyeicosatrienoic acid infusion on blood pressure in normal and hypertensive rats

Cited by 29 publications

References 6 publications

Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation

Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation

Roles of Renal Cytochrome P450-Dependent Arachidonic Acid Metabolites in Hypertension.

Oral Delivery of 1,3‐Dicyclohexylurea Nanosuspension Enhances Exposure and Lowers Blood Pressure in Hypertensive Rats

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