Alterations in renal function contribute to Goldblatt two-kidney, one-clip (2K1C) hypertension. A previous study indicated that bioavailability of cytochrome P-450 metabolites epoxyeicosatrienoic acids (EETs) is decreased while that of 20-hydroxyeicosatetraenoic acids (20-HETE) is increased in this model. We utilized the inhibitor of soluble epoxide hydrolase cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB) and HET-0016, the inhibitor of 20-HETE production, to study the role of EETs and 20-HETE in the regulation of renal function. Chronic c-AUCB treatment significantly decreased systolic blood pressure (SBP) (133 ± 1 vs. 163 ± 3 mmHg) and increased sodium excretion (1.23 ± 0.10 vs. 0.59 ± 0.03 mmol/day) in 2K1C rats. HET-0016 did not affect SBP and sodium excretion. In acute experiments, renal blood flow (RBF) was decreased in 2K1C rats (5.0 ± 0.2 vs. 6.9 ± 0.2 ml·min(-1)·g(-1)). c-AUCB normalized RBF in 2K1C rats (6.5 ± 0.6 ml·min(-1)·g(-1)). HET-0016 also increased RBF in 2K1C rats (5.8 ± 0.2 ml·min(-1)·g(-1)). Although RBF and glomerular filtration rate (GFR) remained stable in normotensive rats during renal arterial pressure (RAP) reductions, both were significantly reduced at 100 mmHg RAP in 2K1C rats. c-AUCB did not improve autoregulation but increased RBF at all RAPs and shifted the pressure-natriuresis curve to the left. HET-0016-treated 2K1C rats exhibited impaired autoregulation of RBF and GFR. Our data indicate that c-AUCB displays antihypertensive properties in 2K1C hypertension that are mediated by an improvement of RBF and pressure natriuresis. While HET-0016 enhanced RBF, its anti-natriuretic effect likely prevented it from producing a blood pressure-lowering effect in the 2K1C model.

Department of Experimental Medicine Institute for Clinical and Experimental Medicine Prague Czech Republic

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Campbell WB, Falck JR. Arachidonic acid metabolites as endothelium-derived hyperpolarizing factors. Hypertension 49: 590–596, 2007 PubMed

Campbell WB, Gebremedhin D, Pratt PF, Harder DR. Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ Res 78: 415–423, 1996 PubMed

Capdevila JH, Falck JR, Imig JD. Role of the cytochrome P450 arachidonic acid monooxygenases in the control of systemic blood pressure and experimental hypertension. Kidney Int 72: 683–689, 2007 PubMed

CertíkováChábová V, Kramer HJ, Vaněčková I, Thumová M, Škaroupková P, Tesař V. The roles of intrarenal 20-hydroxyeicosatetraenoic and epoxyeicosatrienoic acids in the regulation of renal function in hypertensive Ren-2 transgenic rats. Kidney Blood Press Res 30: 335–346, 2007 PubMed

Cervenka L, Vaněčková I, Husková Z, Vaǒurková Z, Erbanová M, Thumová M. Pivotal role of AT1A receptors in the development of two-kidney, one-clip hypertension: study in AT1A receptor knockout mice. J Hypertens 26: 1379–1389, 2008 PubMed PMC

Cervenka L, Wang CT, Mitchell KD, Navar LG. Proximal tubular angiotensin II levels and renal functional responses to AT1 receptor blockade in nonclipped kidneys of Goldblatt hypertensive rats. Hypertension 33: 102–107, 1999 PubMed

Cervenka L, Wang CT, Navar LG. Effects of acute AT1 receptor blockade by candesartan on arterial pressure and renal function in rats. Am J Physiol Renal Physiol 274: F940–F945, 1998 PubMed

El-Dahr SS, Dipp S, Guan S, Navar LG. Renin, angiotensinogen, and kallikrein gene expression in two-kidney Goldblatt hypertensive rats. Am J Hypertens 6: 914–919, 1993 PubMed

Erbanová M, Thumová M, Husková Z, Vaněčková I, Vaǒurková Z, Mullins JJ, Kramer HJ, Bürgelová M, Rakušan D, Červenka L. Impairment of the autoregulation of renal hemodynamics and of the pressure-natriuresis relationship precedes the development of hypertension in Cyp1a1-Ren-2 transgenic rats. J Hypertens 27: 575–586, 2009 PubMed

Fleming I. Vascular cytochrome P450 enzymes: physiology and pathophysiology. Trends Cardiovascular Med 18: 20–25, 2008 PubMed

Guan S, Fox K, Mitchell Navar LG. Angiotensin and angiotensin converting enzyme tissue levels in two-kidney, one-clip hypertensive rats. Hypertension 20: 763–767, 1992 PubMed

Hercule HC, Schunck WH, Gross V, Seringer J, Leung FP, Weldon SM, da Costa Goncalves Ach Huang, Huang Y, Luft FC, Gollasch M. Interaction between P450 eicosanoids and nitric oxide in the control of arterial tone in mice. Arterioscler Thromb Vasc Biol 29: 54–60, 2009 PubMed

Hercule HC, Wang MH, Oyekan AO. Contribution of cytochrome P450 4A isoforms to renal functional response to inhibition of nitric oxide production in the rat. J Physiol 551: 971–979, 2003 PubMed PMC

Huang H, Morisseau C, Wang J, Yang T, Falck JR, Hammock BD, Wang MH. Increasing or stabilizing renal epoxyeicosatrienoic acid production attenuates abnormal renal function and hypertension in obese rats. Am J Physiol Renal Physiol 293: F342–F349, 2007 PubMed

Huang WC, Ploth DW, Navar LG. Angiotensin-mediated alterations in nephron function in Goldblatt hypertensive rats. Am J Physiol Renal Fluid Electrolyte Physiol 243: F553–F560, 1982 PubMed

Hwang SH, Tsai HJ, Liu Morisseau C JY, Hammock BD. Orally bioavailable potent soluble epoxide hydrolase inhibitors. J Med Chem 50: 3825–3840, 2007 PubMed PMC

Imig JD, Dimitropoulou C, Reddy DS, White RE, Falck JR. Afferent arteriolar dilation to 11,12-EET analogs involves PP2A activity and Ca2+-activated K+channels. Microcirculation 15: 137–150, 2008 PubMed PMC

Imig JD, Falck JR, Inscho EW. Contribution of cytochrome P450 epoxygenase and hydroxylase pathways to afferent arteriolar autoregulatory responsiveness. Br J Pharmacol 127: 1399–1405, 1999 PubMed PMC

Imig JD, Falck JR, Wei S, Capdevila JH. Epoxygenase metabolites contribute to nitric oxide-independent afferent arteriolar vasodilatation in response to bradykinin. J Vasc Res 38: 247–255, 2001 PubMed

Imig JD, Zhao X, Falck JR, Wei S, Capdevila JH. Enhanced renal mircovascular reactivity to angiotensin II in hypertension is ameliorated by the sulfonimide analog of 11,12-epoxyeicosatrienoic acid. J Hypertens 19: 983–992, 2001 PubMed

Imig JD, Zhao X, Zaharis CZ, Olearczyk JJ, Pollock DM, Newman JW, Kim HI, Watanabe T, Hammock BD. An orally active epoxide hydrolase inhibitor lowers blood pressure and provides renal protection in salt-sensitive hypertension. Hypertension 46: 975–981, 2005 PubMed PMC

Imig JD. Targeting epoxides for organ damage in hypertension. J Cardiovasc Pharmacol 56: 326–335, 2010 PubMed PMC

Ito O, Roman RJ. Role of 20-HETE in elevating chloride transport in the thick ascending limb of Dahl SS/Jr rats. Hypertension 33: 419–423, 1999 PubMed

Jung O, Brandes RP, Kim IH, Schweda F, Schmidt R, Hammock BD, Busse R, Fleming I. Soluble epoxide hydrolase is a main effector of angiotensin II-induced hypertension. Hypertension 45: 759–765, 2005 PubMed

Kobori H, Nangaku M, Navar LG, Nishiyama A. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 59: 251–287, 2007 PubMed

Kohagure K, Endo Y, Ito O, Arima S, Omata K, Ito S. Endogenous nitric oxide and epoxyeicosatrienoic acids modulate angiotensin II-induced constriction in the rabbit afferent arteriole. Acta Physiol Scand 168: 107–112, 2000 PubMed

Liu J-Y, Tsai H-J, Hwang SH, Jones PD, Morisseau C, Hammock BD. Pharmacokinetic optimization of four soluble epoxide hydrolase inhibitors for use in a murine model of inflammation. Br J Pharmacol 156: 284–296, 2009 PubMed PMC

Madhun ZT, Goldthwait DA, McKay D, Hopfer U, Douglas JG. An epoxygenase metabolite of arachidonic acid mediates angiotensin II-induced rises in cytosolic calcium in rabbit proximal tubule epithelial cells. J Clin Invest 88: 456–461, 1991 PubMed PMC

Majid DSW, Navar LG. Blockade of distal nephron sodium transport attenuates pressure natriuresis in dongs. Hypertension 23: 1040–1045, 1994 PubMed

Minuz P, Jiang H, Fava C, Turolo L, Tacconelli S, Ricci M, Patrignani P, Morganti A, Lechi A, McGiff JC. Altered release of cytochrome P450 metabolites of arachidonic acid in renovascular disease. Hypertension 51: 1379–1385, 2008 PubMed PMC

Miyata N, Roman RJ. Role of 20-hydroxyeicosatetraenoic acid (20-HETE) in vascular system. J Smooth Muscle Res 41: 175–193, 2005 PubMed

Navar LG, Zou L, Von Thun A, Wang CT, Imig JD, Mitchell KD. Unraveling the mystery of Goldblatt hypertension. News Physiol Sci 13: 170–176, 1998 PubMed

Ploth DW, Roy RN, Huang WC, Navar LG. Impaired renal blood flow and cortical pressure autoregulation in contralateral kidneys of Goldblatt hypertensive rats. Hypertension 3: 67–74, 1981 PubMed

Ploth DW. Angiotensin-dependent renal mechanism in two-kidney, one-clip renal vascular hypertension. Am J Physiol Renal Fluid Electrolyte Physiol 245: F131–F141, 1983 PubMed

Quigley R, Baum M, Reddy KM, Griener JC, Falck JR. Effects of 20-HETE and 19(S)-HETE on rabbit proximal straight tubule volume transport. Am J Physiol Renal Physiol 278: F949–F953, 2000 PubMed PMC

Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev 82: 131–185, 2002 PubMed

Rostand SG, Lewis D, Watkins JB, Huang WC, Navar LG. Attenuated pressure natriuresis in hypertensive rats. Kidney Int 21: 331–338, 1982 PubMed

Sakairi Y, Jacobson HR, Noland DT, Capdevila JH, Falck JR, Breyer MD. 5,6-EET inhibits ion transport in collecting duct by stimulating endogenous prostaglandin synthesis. Am J Physiol Renal Fluid Electrolyte Physiol 268: F931–F939, 1995 PubMed

Schwartzman M, Ferreri NR, Carroll MA, Songu-Mize E, McGiff JC. Renal cytochrome P450-related arachidonate metabolite inhibits (Na+ + K+)ATPase. Nature 314: 620–622, 1985 PubMed

Singh H, Cheng J, Deng H, Kemp R, Ishizuka T, Nasjletti A, Schwartzman ML. Vascular cytochrome P450 4A expression and 20-hydroxyeicosatetraenoic acid synthesis contribute to endothelial dysfunction in androgen-induced hypertension. Hypertension 50: 123–129, 2007 PubMed

Spiecker M, Darius H, Hankeln T, Soufi M, Huesing A, Maisch B, Darryl C, Zeldin J, Liao JK. Risk of coronary artery disease associated with polymorphism of the cytochrome P450 epoxygenase CYP2J2. Circulation 110: 2132–2136, 2004 PubMed PMC

Sudhahar V, Shaw S, Imig JD. Epoxyeicosatrienoic acid analogs and vascular function. Curr Med Chem 17: 1181–1190, 2010 PubMed PMC

Vanourková Z, Kramer HJ, Husková Z, Vanecková I, Opocenský M, Chábová VC, Tesar V, Skaroupková P, Thumová M, Dohnalová M, Mullins JJ, Cervenka L. AT1 receptor blockade is superior to conventional triple therapy in protecting against end-organ damage in Cyp1a1-Ren-2 transgenic rats with inducible hypertension. J Hypertens 24: 2465–2472, 2006 PubMed

Von Thun AM, Vari RC, El-Dahr SS, Navar LG. Augmentation of intrarenal angiotensin II levels by chronic angiotensin II infusion. Am J Physiol Renal Fluid Electrolyte Physiol 266: F120–F128, 1994 PubMed

Walkowska A, Škaroupková P, Husková Z, Vaǒurková Z, Čertíková Chábová V, Tesař V, Kramer HJ, Falck JR, Imig JD, Kompanowska-Jezierska E, Sadowski J, Červenka L. Intrarenal cytochrome P-450 metabolites of arachidonic acid in the regulation of the nonclipped kidney function in two-kidney, one-clip Goldblatt hypertensive rats. J Hypertens 28: 582–593, 2010 PubMed PMC

Wang CT, Chin SY, Navar LG. Impairment of pressure-natriuresis and renal autoregulation in ANG II-infused hypertensive rats. Am J Physiol Renal Physiol 279: F319–F325, 2000 PubMed

Wang D, Borrego-Conde LJ, Falck JR, Sharma KK, Wilcox CS, Umans JG. Contribution of nitric oxide, EDHF, and EETs to endothelium-dependent relaxation in renal afferent arterioles. Kidney Int 63: 2187–2193, 2003 PubMed

Wei Y, Lin DH, Kemp R, Yaddanapudi GS, Nasjletti A, Falck JR, Wang WH. Arachidonic acid inhibits epithelial Na channel via cytochrome P450 (CYP) epoxygenase-dependent metabolic pathways. J Gen Physiol 124: 719–727, 2004 PubMed PMC

Williams JM, Sarkis A, Lopez B, Ryan RP, Flasch AK, Roman RJ. Elevations in renal interstitial hydrostatic pressure and 20-hydroxyeicosatetraenoic acid contribute to pressure natriuresis. Hypertension 49: 687–694, 2007 PubMed

Williams JM, Murphy S, Burke M, Roman RJ. 20-Hydroxyeicosatetraeonic acid: a new target for the treatment of hypertension. J Cardiovasc Pharmacol 56: 336–344, 2010 PubMed PMC

Yang S, Lin L, Chen JX, Lee CR, Seubert JM, Wang Y, Wang H, Chao ZR, Tao DD, Gong JP, Lu ZY, Wang DW, Zeldin DC. Cytochrome P-450 epoxygenases protect endothelial cells from apoptosis induced by tumor necrosis factor alpha via MAPK and PI3K/Akt signaling pathways. Am J Physiol Heart Circ Physiol 293: H142–H151, 2007 PubMed PMC

Yu M, Lopez B, Dos Santos EA, Falck JR, Roman RJ. Effects of 20-HETE on Na+ transport and Na+-K+-ATPase activity in the thick ascending loop of Henle. Am J Physiol Regul Integr Comp Physiol 292: R2400–R2405, 2007 PubMed

Yu Z, Xu F, Huse LM, Morisseau C, Draper AJ, Newman JW, Parker C, Graham L, Engler MM, Hammock BD, Zeldin DC, Kroetz DL. Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circ Res 87: 992–998, 2000 PubMed

Yu Z, Xu F, Huse LM, Morisseau C, Draper AJ, Newman JW, Parker C, Graham L, Engler MM, Hammock BD, Zeldin DC, Kroetz DL. Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circ Res 87: 992–998, 2000 PubMed

Zeldin DC, Kobayashi J, Falck JR, Winder BS, Hammock BD, Snapper JR, Capdevila JH. Regio- and enantiofacial selectivity of epoxyeicosatrienoic acid hydration by cytosolic epoxide hydrolase. J Biol Chem 268: 6402–6407, 1993 PubMed

Zhang F, Wang MH, Krishna UM, Falck JR, Laniado-Schwartzman M, Nasjletti A. Modulation by 20-HETE of phenylephrine-induced mesenteric artery contraction in spontaneously hypertensive and Wistar-Kyoto rats. Hypertension 38: 1311–1315, 2001 PubMed

Zhang Y, Wu JH, Vickers JJ, Ong SL, Temple SE, Mori TA, Croft KD, Whitworth JA. The role of 20-hydroxyeicosatetraenoic acid in adrenocorticotrophic hormone and dexamethasone-induced hypertension. J Hypertens 27: 1609–1616, 2009 PubMed

Zhao X, Yamamoto T, Newman JW, Kim IH, Watanabe T, Hammock BD, Stewart J, Pollock JS, Pollock DM, Imig JD. Soluble epoxide hydrolase inhibition protects the kidney from hypertension-induced damage. J Am Soc Nephrol 15: 1244–1253, 2004 PubMed

Zhao X, Pollock DM, Zeldin DC, Imig JD. Salt-sensitive hypertension after exposure to angiotensin is associated with inability to upregulate renal epoxygenases. Hypertension 42: 775–780, 2003 PubMed

Zou AP, Drummond HA, Roman RJHypertension. Role of 20-HETE in elevating loop chloride reabsorption in Dahl SS/Jr rats. Hypertension 27: 631–635, 1996 PubMed

Zou AP, Imig JD, Kaldunski M, de Mondellano PR, Sui Z, Roman RJ. Inhibition of renal vascular 20-HETE production impairs autoregulation of renal blood flow. Am J Physiol Renal Fluid Electrolyte Physiol 266: F275–F282, 1994 PubMed

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