The aim of the present study was to evaluate the hypothesis that the antihypertensive effects of inhibition of soluble epoxide hydrolase (sEH) are mediated by increased intrarenal availability of epoxyeicosatrienoic acids (EETs), with consequent improvement in renal haemodynamic autoregulatory efficiency and the pressure-natriuresis relationship. Ren-2 transgenic rats (TGR), a model of angiotensin (Ang) II-dependent hypertension, and normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats were treated with the sEH inhibitor cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy)benzoic acid (c-AUCB; 26 mg/L) for 48 h. Then, the effects on blood pressure (BP), autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR), and on the pressure-natriuresis relationship in response to stepwise reductions in renal arterial pressure (RAP) were determined. Treatment with c-AUCB did not significantly change BP, renal autoregulation or pressure-natriuresis in normotensive HanSD rats. In contrast, c-AUCB treatment significantly reduced BP, increased intrarenal bioavailability of EETs and significantly suppressed AngII levels in TGR. However, treatment with c-AUCB did not significantly improve the autoregulatory efficiency of RBF and GFR in response to reductions of RAP and to restore the blunted pressure-natriuresis relationship in TGR. Together, the data indicate that the antihypertensive actions of sEH inhibition in TGR are predominantly mediated via significant suppression of intrarenal renin-angiotensin system activity.

Center for Experimental Medicine Institute for Clinical and Experimental Medicine Prague Czech Republic

See more in PubMed

Mullins JJ, Peters J, Ganten D. Fulminant hypertension in transgenic rats harboring the mouse Ren-2 gene. Nature. 1990;344:541–544. PubMed

Husková Z, Kramer HJ, Vaňourková Z, Červenka L. Effects of changes in sodium balance on plasma and kidney angiotensin II levels in anesthetized and conscious Ren-2 transgenic rats. J. Hypertens. 2006;24:517–527. PubMed

Kujal P, Čertíková Chábová V, Vernerová Z, et al. Similar renoprotection after renin-angiotensin-dependent and –independent antihypertensive therapy in 5/6-nephrectomized Ren-2 transgenic rats: are there blood pressure-independent effects? Clin. Exp. Pharmacol. Physiol. 2010;37:1159–1169. PubMed

Hartner A, Porst M, Klanke B, Cordasic N, Veelken R, Hilgers KF. Angiotensin II formation in the kidney and nephrosclerosis in Ren-2 hypertensive rats. Nephrol. Dial. Transplant. 2006;21:1778–1785. PubMed

Jacinto SM, Mullins JJ, Mitchell KD. Enhanced renal vascular responsiveness to angiotensin II in hypertensive ren-2 transgenic rats. Am. J. Physiol. 1999;276:F315–F322. PubMed

Kopkan L, Kramer HJ, Huskova Z, Vaňourková Z, Škaroupková P, Thumová M, Červenka L. The role of intrarenal angiotensin II in the development of hypertension in Ren-2 transgenic rats. J. Hypertens. 2005;23:1531–1539. PubMed

Lee MA, Böhm M, Paul M, Bader M, Ganten U, Ganten D. Physiological characterization of the hypertensive transgenic rat TGR(mRen2)27. Am. J. Physiol. 1990;270:E919–E929. PubMed

Kopkan L, Husková Z, Vaňourková Z, et al. Reduction of oxidative stress does not attenuate the development of angiotensin II-dependent hypertension in Ren-2 transgenic rats. Vascular. Pharmacol. 2009;51:175–181. PubMed

Kopkan L, Husková Z, Vanourková Z, Thumová M, Skaroupková P, Cervenka L, Majid DS. Superoxide and its interaction with nitric oxide modulates renal function in prehypertensive Ren-2 transgenic rats. J Hypertens. 2007;25:2257–2265. 2007. PubMed

Vernerová Z, Kujal P, Kramer HJ, Bäcker A, Červenka L, Vaněčková I. End-organ damage in hypertensive transgenic Ren-2 rats: influence of early and late endothelin receptor blockade. Physiol. Res. 2009;58(Suppl 2):S69–S78. PubMed

Campbell WB, Fleming I. Epoxyeicosatrienoic acids and endothelium-dependent response. Pfugers. Arch. 2010;459:881–895. PubMed PMC

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

Imig JD. Epoxides and soluble epoxide hydrolase in cardiovascular physiology. Physiol. Rev. 2012;92:101–130. PubMed PMC

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. 2001;19:983–992. PubMed

Lee CR, Imig JD, Edin ML, et al. Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice. FASEB. J. 2010;24:3770–3781. PubMed PMC

Honetschlägerová Z, Husková Z, Vaňourková Z, et al. Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats with inducible hypertension. J. Physiol. 2011;589:207–219. PubMed PMC

Honetschlägerová Z, Sporková A, Kopkan L, et al. Inhibition of soluble epoxide hydrolyse improves the impaired pressure-natriuresis relationship and attenuates the development of hypertension and hypertension-associated end-organ damage in Cyp1a1-Ren-2 transgenic rats. J. Hypertens. 2011;29:1590–1601. PubMed PMC

Sporková A, Kopkan L, Varcabová Š, et al. Role of cytochrome P450 metabolites in the regulation of renal function and blood pressure in 2-kidney, 1-clip hypertensive rats. Am. J. Physiol. 2011;300:R1468–R1475. PubMed PMC

Springate J, Van Liew J, Ganten D. Enalapril and pressure-diuresis in hypertensive rats transgenic for mouse renin gene. Kidney. Blood. Press. Res. 1997;20:1–5. PubMed

Lippoldt A, Gross V, Bohlender J, Ganten U, Luft FC. Lifelong angiotensin-converting enzyme inhibition, pressure natriuresis, and renin-angiotensin system gene expression in transgenic (mRen-2)27 rats. J. Am. Soc. Nephrol. 1996;7:2119–2129. PubMed

Neckář J, Kopkan L, Husková Z, et al. Inhibition of soluble epoxide hydrolase by cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid exhibits antihypertensive and cardioprotective actions in transgenic rats with angiotensin II-dependent hypertension. Clin. Sci. 2012;122:513–525. PubMed PMC

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

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

Erbanová M, Thumová M, Husková Z, et al. 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. 2009;27:575–586. PubMed

Semple SJ, de Wardener HE. Effect of increased renal venous pressure on circulatory autoregulation of isolated dog kidneys. Circ. Res. 1959;7:643–648. PubMed

Husková Z, Kramer HJ, Thumová M, Vaňourková Z, Bürgelová M, Teplan V, Červenka L. Effects of anaesthesia on plasma and kidney ANG II levels in normotensive and ANG II-dependent hypertensive rats. Kidney Blood Press Res. 2006;29:74–83. PubMed

Walkowska A, Škaroupková P, Husková Z, et al. 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. 2010;28:582–593. PubMed PMC

Li PL, Campbell WB. Regulation of potassium channels in coronary smooth muscle through a guanine nucleotide binding protein. Circ. Res. 1997;80:877–884. 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. 2003;63:2187–2193. PubMed

Campbell WB, Gebremedhin D, Pratt PF, Harder DR. Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ. Res. 1996;78:415–423. 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. 2000;168:107–112. PubMed

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. 1991;88:456–461. PubMed PMC

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. 1995;268:F931–F939. PubMed

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

Guyton AC, Hall JE, Coleman TG, Manning RD., Jr. The dominant role of the kidneys in the long term regulation of arterial pressure in normal and hypertensive states. In: Laragh JH, Brenner BM, editors. Hypertension: Pathophysiology, Diagnosis and Management. Raven Press, Publishers; New York, NY: 1990. pp. 1029–1052.

Roman RJ, Cowley AW., Jr. Abnormal pressure-diuresis-natriuresis response in spontaneously hypertensive rats. Am J Physiol. 1985;248:F199–F205. PubMed

Miao CY, Liu KL, Benzoni D, Sassard J. Acute pressure-natriuresis function shows early impairment in Lyon hypertensive rats. J. Hypertens. 2005;23:1225–1231. PubMed

Van der Mark J, Kline RL. Altered pressure natriuresis in chronic angiotensin II hypertension in rats. Am. J. Physiol. 1994;266:F739–F748. PubMed

Hall JE, Mizelle HL, Brands MV, Hildebrandt DA. Pressure natriuresis and angiotensin II in reduced kidney mass, salt-induced hypertension. Am. J. Physiol. 1992;262:R61–R71. 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. 2007;59:251–287. PubMed

Kline RL, Liu F. Modification of pressure natriuresis by long-term losartan in spontaneously hypertensive rats. Hypertension. 1994;24:467–473. PubMed

Vaněčková I, Dobešová Z, Kuneš J, Zicha J. The effects of repeated delivery of angiotensin II AT1 receptor antisense on distinct vasoactive systems in Ren-2 transgenic rats: young vs. adult animals. Hypertens. Res. 2012 doi: 10.1038/hr2012.39. PubMed

Henrich WL, Falck JR, Campbell WB. Inhibition of renin release by 14,15-epoxyeicosatrienoic acid in renal cortical slices. Am. J. Physiol. 1990;258:E269–E274. PubMed

Bohlender J, Ménard J, Edling O, Ganten D, Luft FC. Mouse and rat plasma renin concentration and gene expression in (mRen2)27 transgenic rats. Am. J. Physiol. 1998;274:H1450–H1456. PubMed

Červenka L, Vaněčková I, Husková Z, Vaňourková Z, Erbanová M, Thumová M, Škaroupková P, Opočenský M, Malý J, Čertíková Chábová V, Tesař V, Burgelova M, Viklický O, Teplan V, Želízko M, Kramer HJ, Navar LG. Pivotal role of angiotensin II receptor subtype 1A in the development of two-kidney, one-clip hypertension: study in angiotensin II receptor subtype 1A knockout mice. J. Hypertens. 2008;26:1379–1389. PubMed PMC

Welch WJ. Angiotensin II-dependent superoxide. Effects on hypertension and vascular dysfunction. Hypertension. 2008;52:51–56. PubMed PMC

Renal sympathetic denervation improves pressure-natriuresis relationship in cardiorenal syndrome: insight from studies with Ren-2 transgenic hypertensive rats with volume overload induced using aorto-caval fistula

Impaired renal autoregulation and pressure-natriuresis: any role in the development of heart failure in normotensive and angiotensin II-dependent hypertensive rats?

Epoxyeicosanoids in hypertension

Two pharmacological epoxyeicosatrienoic acid-enhancing therapies are effectively antihypertensive and reduce the severity of ischemic arrhythmias in rats with angiotensin II-dependent hypertension

Combined Inhibition of Soluble Epoxide Hydrolase and Renin-Angiotensin System Exhibits Superior Renoprotection to Renin-Angiotensin System Blockade in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats with Established Chronic Kidney Disease

Epoxyeicosatrienoic acid analog attenuates the development of malignant hypertension, but does not reverse it once established: a study in Cyp1a1-Ren-2 transgenic rats

Different mechanisms of acute versus long-term antihypertensive effects of soluble epoxide hydrolase inhibition: studies in Cyp1a1-Ren-2 transgenic rats

Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren-2 transgenic hypertensive rats