Protein phosphatase 2A and Ca2+-activated K+ channels contribute to 11,12-epoxyeicosatrienoic acid analog mediated mesenteric arterial relaxation

Dimitropoulou, Christiana; West, Lindsey; Field, Mary; White, Richard E.; Reddy, L. Manmohan; Falck, John R.; Imig, John D.

doi:10.1016/j.prostaglandins.2006.09.008

Cited by 45 publications

(62 citation statements)

References 46 publications

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“…These compounds are metabolized to less active dihydroxy eicosanoids by sEH (20,28,33). There is strong evidence that, among their varied biochemical effects, EETs are endothelial-derived hyperpolarizing factors and produce vasodilation in many organs, including heart, brain, and skeletal muscle either directly or indirectly through NO (2,16,17,23,25,33). Recently, it has been shown that interventions that increase EETs improve insulin sensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence that EETs are endothelial-derived hyperpolarizing factors (EDHFs) and produce vasodilation directly through calcium-activated potassium channels or the TRPV 4 channel and indirectly through NO production (16,17,23,33). This knowledge has led to the development of inhibitors of soluble epoxide hydrolase (sEH), an enzyme responsible for breakdown of EETs to less active dihydroxyeicosatrienoic acids, for a variety of purposes, including as antihypertensive therapy (12,20).…”

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confidence: 99%

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Epoxyeicosatrienoic acids mediate insulin-mediated augmentation in skeletal muscle perfusion and blood volume

Shim¹,

Kim²,

Chadderdon³

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Skeletal muscle microvascular blood flow (MBF) increases in response to physiological hyperinsulinemia. This vascular action of insulin may facilitate glucose uptake. We hypothesized that epoxyeicosatrienoic acids (EETs), a family of arachadonic, acid-derived, endothelium-derived hyperpolarizing factors, are mediators of insulin's microvascular effects. Contrast-enhanced ultrasound (CEU) was performed to quantify skeletal muscle capillary blood volume (CBV) and MBF in wild-type and obese insulin-resistant (db/db) mice after administration of vehicle or trans-4- [4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid (t-AUCB), an inhibitor of soluble epoxide hydrolase that converts EETs to less active dihydroxyeicosatrienoic acids. Similar studies were performed in rats pretreated with L-NAME. CEU was also performed in rats undergoing a euglycemic hyperinsulinemic clamp, half of which were pretreated with the epoxygenase inhibitor MS-PPOH to inhibit EET synthesis. In both wild-type and db/db mice, intravenous t-AUCB produced an increase in CBV (65-100% increase at 30 min, P Ͻ 0.05) and in MBF. In db/db mice, t-AUCB also reduced plasma glucose by ϳ15%. In rats pretreated with L-NAME, t-AUCB after produced a significant Ϸ20% increase in CBV, indicating a component of vascular response independent of nitric oxide (NO) production. Hyperinsulinemic clamp produced a time-dependent increase in MBF (19 Ϯ 36 and 76 Ϯ 49% at 90 min, P ϭ 0.026) that was mediated in part by an increase in CBV. Insulin-mediated changes in both CBV and MBF during the clamp were blocked entirely by MS-PPOH. We conclude that EETs are a mediator of insulinmediated augmentation in skeletal muscle perfusion and are involved in regulating changes in CBV during hyperinsulinemia.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Epoxyeicosatrienoic acids mediate insulin-mediated augmentation in skeletal muscle perfusion and blood volume

Shim¹,

Kim²,

Chadderdon³

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…The parent EET analog 11-(nonyloxy)undec-8(Z)-enoic acid (NUDA) acts as a potent vasorelaxant in mesenteric and renal arteries (Dimitropoulou et al, 2007;Imig et al, 2008). For the in vivo studies described here, NUDA was conjugated to L-aspartic acid to give (S)-2-(11-(nonyloxy)undec-8(Z)-enamido)succinic acid (NUDSA) to minimize ␤-oxidation and to improve its solubility in aqueous milieu.…”

Section: Methodsmentioning

confidence: 99%

Epoxyeicosatrienoic Acid Agonist Rescues the Metabolic Syndrome Phenotype of HO-2-Null Mice

Sodhi

Inoue

Gotlinger

et al. 2009

J Pharmacol Exp Ther

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130

158

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Heme oxygenase (HO) and cytochrome P450 (P450)-derived epoxyeicosatrienoic acids (EETs) participate in vascular protection, and recent studies suggest these two systems are functionally linked. We examined the consequences of HO deficiency on P450-derived EETs with regard to body weight, adiposity, insulin resistance, blood pressure, and vascular function in HO-2-null mice. The HO-2-null mice were obese, displayed insulin resistance, and had high blood pressure. HO-2 deficiency was associated with decreases in cyp2c expression, EET levels, HO-1 expression, and HO activity and with an increase in superoxide production and an impairment in the relaxing response to acetylcholine. In addition, HO-2-null mice exhibited increases in serum levels of tumor necrosis factor (TNF)-␣ and macrophage chemoattractant protein (MCP)-1 and a decrease in serum adiponectin levels. Treatment of HO-2-null mice with a dual-activity EET agonist/soluble epoxide hydrolase inhibitor increased renal and vascular EET levels and HO-1 expression, lowered blood pressure, prevented body weight gain, increased insulin sensitivity, reduced subcutaneous and visceral fat, and decreased serum TNF-␣ and MCP-1, while increasing adiponectin and restoring the relaxing responses to acetylcholine. The decrease in cyp2c expression and EETs levels in HO-2-null mice underscores the importance of the HO system in the regulation of epoxygenase levels and suggests that protection against obesityinduced cardiovascular complications requires interplay between these two systems. A deficiency in one of these protective systems may contribute to the adverse manifestations associated with the clinical progression of the metabolic syndrome.

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“…Activation of large‐conductance calcium‐activated K + channels (BK ca ) has been suggested to play a role in vasodilation induced by EETs 31, 32. Iberiotoxin, a selective and reversible inhibitor of high‐conductance calcium‐activated potassium channel (BK ca inhibitor), could not block the vasodilator effect produced by 11, 12‐EET in the mesenteric vasculature.…”

Section: Discussionmentioning

confidence: 99%

11,12-Epoxyeicosatrienoic acid induces vasodilator response in the rat perfused mesenteric vasculature

Bihzad

Yousif

2017

Auton Autacoid Pharmacol

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Summary Epoxyeicosatrienoic acids (EETs) are endogenous ligands that undergo hydrolysis by soluble epoxide hydrolase (sEH). The responses of 11, 12‐EET in comparison with other vasodilator agonists including carbachol and sodium nitroprusside (SNP) were investigated. The effect of 1‐cyclohexyl‐3‐dodecyl urea (CDU), a sEH, was tested on the vasodilator effect induced by 11, 12‐EET in the perfused mesenteric beds isolated from normo‐glycaemic and type‐1 STZ‐diabetic rats.In the perfused mesenteric beds of control and diabetic animals, 11, 12‐EET produced vasodilation in a dose‐dependent manner. The vasodilator response induced by 11, 12‐EET was significantly decreased in tissues obtained from diabetic animals, but this was significantly corrected through inhibition of sEH.The effects of nitric oxide synthase inhibitor, cyclo‐oxygenase inhibitor, specific potassium channel inhibitors, soluble guanylyl cyclase inhibitor and transient receptor potential channel V4 inhibitor, on vasodilator response to 11, 12‐EET were investigated.In tissues isolated from control animals, vasodilator responses to 11, 12‐EET were not inhibited by acute incubation with l‐NAME, l‐NAME with indomethacin, glibenclamide, iberiotoxin, charybdotoxin, apamin or ODQ.Incubation with the transient receptor potential channel V4 inhibitor ruthenium red caused significantly reduced vasodilator responses induced by 11, 12‐EET.In conclusion, results from this study indicate that 11, 12‐EET has a vasodilator effect in the perfused mesenteric bed, partly through activation of vanilloid receptor. A strategy to elevate the levels of EETs may have a significant impact in correcting microvascular abnormality associated with diabetes.

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Protein phosphatase 2A and Ca2+-activated K+ channels contribute to 11,12-epoxyeicosatrienoic acid analog mediated mesenteric arterial relaxation

Cited by 45 publications

References 46 publications

Epoxyeicosatrienoic acids mediate insulin-mediated augmentation in skeletal muscle perfusion and blood volume

Epoxyeicosatrienoic acids mediate insulin-mediated augmentation in skeletal muscle perfusion and blood volume

Epoxyeicosatrienoic Acid Agonist Rescues the Metabolic Syndrome Phenotype of HO-2-Null Mice

11,12-Epoxyeicosatrienoic acid induces vasodilator response in the rat perfused mesenteric vasculature

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