Effects of epoxyeicosatrienoic acids on the cardiac sodium channels in isolated rat ventricular myocytes

Lee, Hon Chi; Lü, Tong; Weintraub, Neal L.; VanRollins, Mike; Spector, Arthur A.; Shibata, Erwin F.

doi:10.1111/j.1469-7793.1999.0153o.x

Cited by 93 publications

(94 citation statements)

References 46 publications

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“…In general, the effects of DHETs on these pathways are less pronounced [23,24]. Within the heart, EETs activate cardiac ATP-sensitive K + (K ATP ) channels [28][29][30][31], enhance L-type calcium currents [32,33] and improve postischemic recovery of left ventricular function [31,[34][35][36]. Thus, alteration in the production and/or elimination of EETs may affect steady-state cellular levels of these bioactive eicosanoids in vivo and could potentially influence cardiac function (Fig.…”

Section: Arachidonic Acid Cyp Epoxygenases and Soluble Epoxide Hydromentioning

confidence: 99%

Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury

Seubert¹,

Zeldin²,

Nithipatikom³

et al. 2007

Prostaglandins & Other Lipid Mediators

134

131

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Cardiomyocyte injury following ischemia-reperfusion can lead to cell death and result in cardiac dysfunction. A wide range of cardioprotective factors have been studied to date, but only recently has the cardioprotective role of fatty acids, specifically arachidonic acid (AA), been investigated. This fatty acid can be found in the membranes of cells in an inactive state and can be released by phospholipases in response to several stimuli, such as ischemia. The metabolism of AA involves the cycloxygenase (COX) and lipoxygenase (LOX) pathways, as well as the less well characterized cytochrome P450 (CYP) monooxygenase pathway. Current research suggests important differences with respect to the cardiovascular actions of specific CYP mediated arachidonic acid metabolites. For example, CYP mediated hydroxylation of AA produces 20-hydroxyeicosatetraenoic acid (20-HETE) which has detrimental effects in the heart during ischemia, pro-inflammatory effects during reperfusion and potent vasoconstrictor effects in the coronary circulation. Conversely, epoxidation of AA by CYP enzymes generates 5,6-, 8,9-, 11,12-and 14,15-epoxyeicosatrienoic acids (EETs) that have been shown to reduce ischemia-reperfusion injury, have potent anti-inflammatory effects within the vasculature, and are potent vasodilators in the coronary circulation. This review aims to provide an overview of current data on the role of these CYP pathways in the heart with an emphasis on their involvement as mediators of ischemia-reperfusion injury. A better understanding of these relationships will facilitate identification of novel targets for the prevention and/or treatment of ischemic heart disease, a major worldwide public health problem.

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Section: Arachidonic Acid Cyp Epoxygenases and Soluble Epoxide Hydromentioning

confidence: 99%

Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury

Seubert¹,

Zeldin²,

Nithipatikom³

et al. 2007

Prostaglandins & Other Lipid Mediators

134

131

View full text Add to dashboard Cite

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“…It has been proposed that release of EETs from endothelial cells acts to hyperpolarize arterial smooth muscle by increasing the open probability of largeconductance calcium-activated potassium channels (BK Ca ), there-by causing vasodilation (Campbell et al, 1996;Fisslthaler et al, 1999;Hu and Kim, 1993;Harder et al, 1995). Effects of EETs on other membrane ion channels have also been reported, including inhibition of voltage-activated Na + channels (Lee et al, 1999), and either potentiation or inhibition of Ltype voltage-activated Ca ++ channels (Chen et al, 1999;Fang et al, 1999). The antiinflammatory mechanisms of EETs that may play a role in alleviating inflammatory pain are their ability to inhibit PGE 2 production (Fang et al, 1998;Kozak et al, 2003) as well as NF-κB-mediated gene transcription and cell adhesion molecule 1 expression induced by TNFα, IL-1α, or LPS (Node et al, 1999).…”

Section: Potential Anti-hyperalgesic Mechanisms Of Sehis and Eetsmentioning

confidence: 99%

Inhibition of soluble epoxide hydrolase reduces LPS-induced thermal hyperalgesia and mechanical allodynia in a rat model of inflammatory pain

et al. 2006

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Soluble epoxide hydrolases catalyze the hydrolysis of epoxides in acyclic systems. In man this enzyme is the product of a single copy gene (EPXH-2) present on chromosome 8. The human sEH is of interest due to emerging roles of its endogenous substrates, epoxygenated fatty acids, in inflammation and hypertension. One of the consequences of inhibiting sEH in rodent inflammation models is a profound decrease in the production of pro-inflammatory and proalgesic lipid metabolites including prostaglandins. This prompted us to hypothesize that sEH inhibitors may have antinociceptive properties. Here we tested if sEH inhibitors can reduce inflammatory pain. Hyperalgesia was induced by intraplantar LPS injection and sEH inhibitors were delivered topically. We found that two structurally dissimilar but equally potent sEH inhibitors can be delivered through the transdermal route and that sEH inhibitors effectively attenuate thermal hyperalgesia and mechanical allodynia in rats treated with LPS. In addition we show that epoxydized arachidonic acid metabolites, EETs, are also effective in attenuating thermal hyperalgesia in this model. In parallel with the observed biological activity metabolic analysis of oxylipids showed that inhibition of sEH resulted with a decrease in PGD 2 levels and sEH generated degradation products of linoleic and arachidonic acid metabolites with a concomitant increase in epoxides of linoleic acid. These data show that inhibition of sEH may become a viable therapeutic strategy to attain analgesia.

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“…Certainly, given that EETs affect the open probability of L-type Ca 2ϩ channels 28 and cardiac Na ϩ channels 29 as well as Ca 2ϩ -dependent K ϩ channels and ATP-sensitive K ϩ channels on ventricular myocytes, direct effects of EETs on the sinoatrial node are conceivable. However, we failed to observe any dromotropic or chronotropic effects of 11,12-EET on the isolated perfused mouse heart (R.P.…”

Section: Jung Et Al Epoxide Hydrolase and Hypertension 763mentioning

confidence: 99%

Soluble Epoxide Hydrolase Is a Main Effector of Angiotensin II–Induced Hypertension

et al. 2005

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Abstract-The soluble epoxide hydrolase (sEH) metabolizes vasodilatory epoxyeicosatrienoic acids (EETs) to their di-hydroxy derivatives. We hypothesized that the metabolism of EETs by the sEH contributes to angiotensin II-induced hypertension and tested the effects of a water-soluble sEH inhibitor, 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) on blood pressure. AUDA (130 g/mL in drinking water) did not affect blood pressure in normotensive animals but markedly lowered it in mice with angiotensin II-induced hypertension (1 mg/kg per day). The effect of AUDA was accompanied by an increase in urinary salt and water excretion. Intravenous application of AUDA (8 mg/kg) acutely lowered blood pressure and heart rate in animals with angiotensin II-induced hypertension but failed to affect blood pressure in animals with phenylephrine-induced hypertension (29 mg/kg per day). AUDA (0.1 mol/L) selectively lowered vascular resistance in an isolated perfused kidney preparation from angiotensin II-pretreated mice but not from control mice. In the perfused hind limb and in isolated carotid arteries from angiotensin II-treated mice, AUDA was without effect. The -hydroxylase inhibitor N-methylsulfonyl-12,12-dibromododec-11-enamide, which attenuates formation of the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid, decreased tone in carotid arteries from angiotensin II-treated but not from control mice. These data demonstrate that the decrease in blood pressure observed after sEH inhibition in angiotensin II-induced hypertension can be attributed to an initial reduction in heart rate followed by pressure diuresis resulting from increased perfusion of the kidney. Direct vasodilatation of resistance arteries in skeletal muscles does not appear to contribute to the antihypertensive effects of sEH inhibition in mice. Key Words: angiotensin Ⅲ lipids E poxyeicosatrienoic acids (EETs) are important signaling molecules derived from arachidonic acid by the action of cytochrome P450 (CYP) epoxygenases. 1 Endotheliumderived EETs are potent vasodilators involved in the action of the endothelium-derived hyperpolarizing factor (EDHF), 2 lower blood pressure, and increase renal sodium excretion. 1,3 Consequently, it may be possible to attenuate or prevent the development of hypertension by maintaining high intravascular EET concentrations. The arachidonic acid epoxides are metabolized to their di-hydroxyl derivatives (DHETS) by the soluble epoxide hydrolase (sEH), 4 and this hydrophilic modification facilitates their diffusion out of the cells and renal clearance. 5,6 The activity of the sEH is therefore thought to be a major determinant of EET bioavailability. 4 The expression of the sEH is high in a number of organs, including the kidney and the liver, 7 and several publications have suggested that the sEH plays a role in regulation of blood pressure. For example, male sEH Ϫ/Ϫ mice have a lower blood pressure than their control litter mates, 8 and inhibition of sEH using N,NЈ-dicyclohexylurea lowers blood pressure in spontaneously ...

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Effects of epoxyeicosatrienoic acids on the cardiac sodium channels in isolated rat ventricular myocytes

Cited by 93 publications

References 46 publications

Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury

Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury

Inhibition of soluble epoxide hydrolase reduces LPS-induced thermal hyperalgesia and mechanical allodynia in a rat model of inflammatory pain

Soluble Epoxide Hydrolase Is a Main Effector of Angiotensin II–Induced Hypertension

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