Cytochrome P450 metabolites of arachidonic acid are potent inhibitors of vasopressin action on rabbit cortical collecting duct.

Hirt, Déborah; Capdevila, Jorge H.; Falck, John R.; Breyer, Matthew D.; Jacobson, Howard

doi:10.1172/jci114365

Cited by 61 publications

(44 citation statements)

References 31 publications

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“…4,31 EETs have also been reported to inhibit Na ϩ /K ϩ -ATPase activity, 32 inhibit Na ϩ transport in the proximal tubule 33 and rabbit cortical collecting duct, 7 and inhibit vasopressin-stimulated water reabsorption in the collecting duct. 6 20-HETE also plays a critical role in the regulation of Cl Ϫ transport in the TALH 3,5 and inhibits Na ϩ /K ϩ /2Cl -transport by blocking K ϩ channels in the apical membrane of TALH cells, 34 thereby limiting the availability of K ϩ for transport via Na ϩ /K ϩ /2Cl Ϫ transporters. This reduces the lumen positive transepithelial potential and reduces passive reabsorption of Na ϩ in this nephron segment.…”

Section: Discussionmentioning

confidence: 99%

“…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][3][4][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.…”

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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: Discussionmentioning

confidence: 99%

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confidence: 99%

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

2003

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“…The demonstrated abilities of EETs to directly activate smooth muscle K ϩ channels (21) and to inhibit the renal Na ϩ -K ϩ -ATPase (22,23) are potential mechanisms by which the vasodilatory and antihypertensive actions of EETs may be achieved. In the rabbit cortical collecting duct, 14,15-DHET is a potent inhibitor of vasopressin-stimulated water reabsorption (24) and inhibits osmotic water flow in the toad urinary bladder (25). Dietary salt loading of rats causes increased urinary excretion of EETs and DHETs concomitant with induction of renal CYP-dependent epoxygenase activity (9,26).…”

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

Sinal¹,

Miyata²,

Tohkin³

et al. 2000

Journal of Biological Chemistry

314

272

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Renal microsomal cytochrome P-450 monooxygenasedependent metabolism of arachidonic acid generates a series of regioisomeric epoxyeicosatrienoic acids that can be further metabolized by soluble epoxide hydrolase to the corresponding dihydroxyeicosatrienoic acids. Evidence exists that these metabolites affect renal function and, in particular, blood pressure regulation. To examine this possibility, blood pressure and renal arachidonic acid metabolism were examined in mice with a targeted disruption of the soluble epoxide hydrolase gene. Systolic blood pressure of male soluble epoxide hydrolase-null mice was lower compared with wild-type mice in both the absence and presence of dietary salt loading. Both female soluble epoxide hydrolase-null and wild-type female mice also had significantly lower systolic blood pressure than male wild-type mice. Renal formation of epoxyeicosatrienoic and dihydroxyeicosatrienoic acids was markedly lower for soluble epoxide hydrolase-null versus wild-type mice of both sexes. Although disruption of soluble epoxide hydrolase in female mice had minimal effects on blood pressure, deletion of this gene feminized male mice by lowering systolic blood pressure and altering arachidonic acid metabolism. These data provide the first direct evidence for a role for soluble epoxide hydrolase in blood pressure regulation and identify this enzyme as a novel and attractive target for therapeutic intervention in hypertension. Mammalian soluble epoxide hydrolase (sEH)1 is a cytosolic enzyme expressed in multiple tissues that catalyzes the conversion of a diverse group of epoxides to their corresponding diols (1, 2). The broad spectrum of xenobiotic epoxides metabolized by this enzyme suggests a role in the protection of cells against the potentially harmful effects of these compounds (3). However, sEH hydrates fatty acid epoxides most effectively, with epoxides of arachidonic acid (AA) being among the best substrates (4 -6). This metabolism may result in the formation of metabolites with greater or less biological activity, indicating that sEH may have important physiological functions. Intracellular metabolism of AA by prostaglandin H2 synthase, lipoxygenases, and the cytochrome P-450 (CYP) monooxygenase system generates a number of metabolites, collectively termed eicosanoids, with important biological and cell signaling roles (7-12). CYP-dependent metabolism of AA (Fig. 1) generates three primary classes of metabolites: mid-chain cis-trans-conjugated dienols (5-, 8-, 9-, 11-, 12-and 15-hydroxyeicosatetraenoic acids (HETEs)); -terminal alcohols (16-through 20-hydroxyeicosatetraenoic acids); and, cis-epoxyeicosatrienoic acids (6-, 8,9-, 11,12-, and 14,15 epoxyeicosatrienoic acids (EETs)) (13). EETs have been shown in vitro to be efficiently hydrated to their corresponding dihydroxyeicosatrienoic acids (DHETs) by sEH (5).Evidence exists for a variety of renal functions attributable to EETs and DHETs generated by CYP-dependent epoxygenase activity and sEH, respectively. Most notably, evidence exists for ...

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“…Indomethacin, A23187, and L-ascorbic acid were purchased from Sigma (St. Louis, MO). C 18 Bond Elut solid-phase extraction (SPE) columns were purchased from Varian (Harbor City, CA). Acetonitrile was HPLC grade.…”

Section: Methodsmentioning

confidence: 99%

“…Cytochrome P450 epoxygenases metabolize AA to 4 regioisomeric epoxyeicosatrienoic acids (EETs), and soluble epoxide hydrolase (sEH) enzymes subsequently convert EETs to the corresponding DHETs [15][16][17]. EETs have various biological functions, including inhibiting the hydro-osmotic action of arginine vasopressin in the kidney, calcium mobilization, and prostaglandin formation [18,19]. EETs stimulate relaxation in coronary rings and coronary arterioles [20 -25].…”

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Structural characterization of monohydroxyeicosatetraenoic acids and dihydroxy- and trihydroxyeicosatrienoic acids by ESI-FTICR

Cui

Isbell

Chawengsub

et al. 2008

J. Am. Soc. Mass Spectrom.

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The fragmentation characteristics of monohydroxyeicosatetraenoic acids and dihydroxy-and trihydroxyeicosatrienoic acids were investigated by electrospray ionization Fourier transform ion cyclotron resonance (FTICR) mass spectrometry using sustained off-resonance irradiation collision-induced dissociation (SORI-CID) and infrared multiphoton dissociation (IRMPD). The fragmentation patterns of these compounds were associated with the number and positions of the hydroxyl substituents. The fragmentation is more complicated with increasing number of the hydroxyl groups of the compounds. In general, the major carbon-carbon cleavage of [M Ϫ H] Ϫ ions occurred at the ␣-position to the hydroxyl group, and the ␣ carbon-carbon cleavage occurred when there was a double-bond at the ␤-position to the ␤ hydroxyl group. SORI-CID and IRMPD produced some common fragmentation patterns; however, each technique provided some unique patterns that are useful for structural identification of these compounds. This study demonstrated the application of FTICR via the identification of regioisomers of trihydroxyeicosatrienoic acids in rabbit aorta samples. (J Am

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Cytochrome P450 metabolites of arachidonic acid are potent inhibitors of vasopressin action on rabbit cortical collecting duct.

Cited by 61 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

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

Structural characterization of monohydroxyeicosatetraenoic acids and dihydroxy- and trihydroxyeicosatrienoic acids by ESI-FTICR

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