20-HETE and Furosemide-Induced Natriuresis in Salt-Sensitive Essential Hypertension

Laffer, Cheryl L.; Laniado−Schwartzman, Michal; Wang, Mong Heng; Nasjletti, Alberto; Elijovich, Fernando

doi:10.1161/01.hyp.0000051888.91497.47

Cited by 60 publications

(42 citation statements)

References 31 publications

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“…This finding is consistent with previous studies, indicating that a deficiency in the renal formation of 20-HETE 3,22 plays a critical role in elevating loop Cl Ϫ transport, resetting pressure natriuresis and the development of hypertension in DS rats. 3,5 Our findings are also consistent with those of Stec et al, 23 who demonstrated that chronic blockade of the renal formation of 20-HETE with an intrarenal infusion of 17-ODYA induced salt-sensitive hypertension in Lewis rats; it also fits with a recent report by Laffer et al 24 showing that 20-HETE excretion is linked to salt sensitivity of blood pressure in humans.…”

Section: Discussionsupporting

confidence: 92%

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

2003

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Abstract-This study examined whether chronic blockade of epoxyeicosatrienoic acids (EETs) and/or 20-hydroxyeicosatetraenoic acid (20-HETE) formation promotes development of salt-sensitive hypertension. Changes in blood pressure, renal cytochrome P450 metabolism of arachidonic acid, and 20-HETE excretion in response to a high salt diet were measured in rats chronically treated with 1-aminobenzotriazole (ABT, 50 mg/kg per day) to block EETs and 20-HETE formation or N-hydroxy-NЈ-(4-butyl-2 methylphenyl) formamidine (HET0016, 10 mg/kg per day) that selectively reduces 20-HETE formation. ABT reduced blood pressure in rats fed a low salt (0.4% NaCl) diet, but blood pressure rose by 20 mm Hg after these rats were switched to a high salt (8% NaCl) diet for 10 days. HET0016 had no effect on blood pressure in rats fed a low salt diet; however, blood pressure rose by 18 mm Hg after the rats were fed a high salt diet. 20-HETE formation in kidney homogenates rose by 30% and epoxygenase activity doubled when rats were fed a high salt diet. Chronic treatment with ABT and HET0016 inhibited the renal formation of 20-HETE by Ϸ90%. Renal epoxygenase activity decreased by 76% in ABT-treated rats and was not significantly altered in rats treated with HET0016. 20-HETE excretion rose from 470Ϯ21 to 570Ϯ41 ng/d when the rats were switched from the low to the high salt diet. 20-HETE excretion fell by 68% and 85% in rats that were chronically treated with ABT and HET0016. These results suggest that chronic blockade of the formation of 20-HETE promotes the development of salt-sensitive hypertension in rats. Key Words: rats, Dahl Ⅲ metabolism Ⅲ arachidonic acids Ⅲ blood pressure Ⅲ hypertension, sodium-dependent T he role of the cytochrome P450 (P450) metabolites of arachidonic acid (AA) in the development and maintenance of hypertension remains uncertain in part because this pathway has both prohypertensive and antihypertensive actions. 1 20-Hydroxyeicosatetraenoic acid (20-HETE) inhibits Na ϩ transport in the proximal tubule and thick ascending limb of the loop of Henle (TALH), 2-5 and compounds that induce the renal formation of 20-HETE lower blood pressure in Dahl salt-sensitive (DS) rats. 1 Similarly, epoxyeicosatrienoic acids (EETs) inhibit Na ϩ transport in the proximal tubule and collecting duct, 6,7 and increasing the renal levels of EETs with inhibitors of soluble epoxide hydrolase (sEH) reduces blood pressure in spontaneously hypertensive rats (SHRs) 8 and angiotensin II-induced hypertensive rats. 9 However, 20-HETE is also a potent vasoconstrictor, 1 and many investigators have reported that blocking the vascular effects of 20-HETE may contribute to its antihypertensive effect in SHR and other experimental models of hypertension. 10,11 Part of the problem in defining the role of the P450 metabolites of AA in the control of blood pressure has been the lack of selective inhibitors of the pathway that chronically block the formation of 20-HETE and EETs in vivo. Inhibitors that are commonly used to inhibit the formation of EETs and ...

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Section: Discussionsupporting

confidence: 92%

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

2003

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“…The administration of furosemide was found associated with increased excretion of 20-HETE, correlated with changes in urinary sodium, in salt resistant and sensitive hypertensive subjects. Both sodium and 20-HETE excretion were altered in salt senisitve subjects, thus suggesting that 20-HETE modulates the natriuretic response to furosemide and that impaired natriuretic response in salt sensitive subjects implicates a mechanism controlling 20-HETE release [45]. In all these study correlation was found between urinary 20-HETE and BMI of hypertensive subect [45].…”

Section: Human Studies Exploring the Patophysological Role Of 20-hetementioning

confidence: 74%

“…Both sodium and 20-HETE excretion were altered in salt senisitve subjects, thus suggesting that 20-HETE modulates the natriuretic response to furosemide and that impaired natriuretic response in salt sensitive subjects implicates a mechanism controlling 20-HETE release [45]. In all these study correlation was found between urinary 20-HETE and BMI of hypertensive subect [45]. When obese hypertensive subjects were studied, not only correlation with BMI was confirmed, but also correlation between increased circulating insulin, not insulin resistance per se, and reduced urinary excretion of 20-HETE was found.…”

Section: Human Studies Exploring the Patophysological Role Of 20-hetementioning

confidence: 99%

Hypertension, cardiovascular risk and polymorphisms in genes controlling the cytochrome P450 pathway of arachidonic acid: A sex-specific relation?

Fava

Ricci

Melander

et al. 2012

Prostaglandins & Other Lipid Mediators

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“…4,5 Similar observations between urinary levels of 20-HETE and sodium excretion have recently been reported in salt-sensitive versus salt-resistant patients. 18,19 These studies suggest that alterations in renal 20-HETE production may be involved in the development of saltsensitive hypertension; nonetheless, it should be noted that at this point in time, specific deficits in tubular 20-HETE production have not been identified in salt-sensitive hypertensive populations.…”

Section: Discussionmentioning

confidence: 99%

Fenofibrate Prevents the Development of Angiotensin II–Dependent Hypertension in Mice

et al. 2005

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Abstract-Previous studies have indicated that the production of 20-hydroxyecisatatraenoic acid (20-HETE) is similar in the liver of C57/B6 mice and rats, but the renal production of 20-HETE is very low in this strain of mice. The present study examined the effects of induction of the renal production of 20-HETE with fenofibrate (FF) on the development of angiotensin II (Ang II)-dependent hypertension in C57BL/6J mice. The mice were divided into 4 groups and treated with vehicle (control), FF (90 mg/kg per day, IP), Ang II (1000 ng/kg per minute, SC), and Ang II plus FF. Mean arterial blood pressure (MAP) averaged 109Ϯ4 and 106Ϯ2 mm Hg in control and FF-treated mice (nϭ7). MAP was significantly increased in the Ang II-treated mice to 144Ϯ4 mm Hg (nϭ7). However, FF treatment prevented the development of Ang II-dependent hypertension, with MAP averaging 115Ϯ5 mm Hg in mice treated with both Ang II plus FF (nϭ7). Renal production of 20-HETE was very low in control (nϭ7) and Ang II-treated (nϭ7) mice and was increased by Ͼ2-fold in FF-treated (nϭ7) and Ang II plus FF-treated (nϭ7) mice. The levels of Cyp4A proteins were markedly increased in the kidneys of mice treated with FF and Ang II plus FF but not in the renal vasculature. These results suggest that upregulation of the production of 20-HETE in renal tubules may contribute to the blood pressure-lowering effects of FF treatment in Ang II-dependent hypertension in C57BL/6J mice. 1 Of these metabolites, 20-hydroxyecisatatraenoic acid (20-HETE) has been reported to inhibit sodium transport and promote natriuresis. 2,3 Studies in Dahl salt-sensitive (Dahl S) rats indicate that production of 20-HETE in the outer medulla is reduced and that this defect contributes to the development of salt-sensitive hypertension in this model. 4,5 Induction of the renal expression of Cyp4a enzymes in the kidney using fibrate compounds has been reported to lower blood pressure in spontaneously hypertensive rats (SHR) and stroke-prone SHR and Dahl S rats. 6,7 The reduction of blood pressure with clofibrate in Dahl S rats was also associated with the normalization of the pressurenatruretic response in this model. 8 In mice, the expression of Cyp4A proteins and renal 20-HETE production is reduced during the development of deoxycorticosterone acetate-salt hypertension. 9 Induction of the renal production of 20-HETE with bezafibrate lowered the blood pressure and improved renal hemodynamics in this model. 10 These studies suggest that a deficiency in the renal production of 20-HETE may promote the development of hypertension. More recently, we have reported that the renal production of 20-HETE is also very low in the kidney of C57BL/6J mice, 11 indicating that they may be a good model to determine the role of CYP metabolites of AA in the regulation of renal function and blood pressure. Thus, the present study examined the effects of induction of the renal production of 20-HETE with FF on the development of Ang II-dependent hypertension in C57BL/6J mice.

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20-HETE and Furosemide-Induced Natriuresis in Salt-Sensitive Essential Hypertension

Cited by 60 publications

References 31 publications

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

Hypertension, cardiovascular risk and polymorphisms in genes controlling the cytochrome P450 pathway of arachidonic acid: A sex-specific relation?

Fenofibrate Prevents the Development of Angiotensin II–Dependent Hypertension in Mice

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