Recent studies have shown that the long-term antihypertensive action of soluble epoxide hydrolase inhibition (sEH) in angiotensin-II (AngII)-dependent hypertension might be mediated by the suppression of intrarenal AngII levels. To test this hypothesis, we examined the effects of acute (2 days) and chronic (14 days) sEH inhibition on blood pressure (BP) in transgenic rats with inducible AngII-dependent hypertension. AngII-dependent malignant hypertension was induced by 10 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. BP was monitored by radiotelemetry. Acute and chronic sEH inhibition was achieved using cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid, given at doses of 0.3, 3, 13, 26, 60 and 130 mg/L in drinking water. At the end of experiments, renal concentrations of epoxyeicosatrienoic acids, their inactive metabolites dihydroxyeicosatrienoic acids and AngII were measured. Acute BP-lowering effects of sEH inhibition in I3C-induced rats was associated with a marked increase in renal epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids ratio and acute natriuresis. Chronic treatment with cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid in I3C-induced rats elicited dose-dependent persistent BP lowering associated with a significant reduction of plasma and kidney AngII levels. Our findings show that the acute BP-lowering effect of sEH inhibition in I3C-induced Cyp1a1-Ren-2 transgenic rats is mediated by a substantial increase in intrarenal epoxyeicosatrienoic acids and their natriuretic action without altering intrarenal renin-angiotensin system activity. Long-term antihypertensive action of cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid in I3C-induced Cyp1a1-Ren-2 transgenic rats is mediated mostly by suppression of intrarenal AngII concentration.

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

Zobrazit více v 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

Capdevilla J, Wang W. Role of cytochrome P450 epoxygenase in regulating renal membrane transport and hypertension. Curr Opin Nephrol Hypertens. 2013;22:163–169. PubMed PMC

Li J, Carroll MA, Chander PN, Falck JR, Sangras B, Stier CT. Soluble epoxide hydrolase inhibitor, AUDA, prevents early salt-sensitive hypertension. Front Biosci. 2008;13:3480–3487. PubMed

Huang H, Morisseau C, Wang JF, et al. Increasing or stabilizing renal epoxyeicosatrienoic acid production attenuates abnormal renal function and hypertension in obese rats. Am J Physiol. 2007;293:F342–F349. PubMed

Jiang H, Quilley J, Doumad AB, et al. Increases in plasma trans-EETs and blood pressure reduction in spontaneously hypertensive rats. Am J Physiol. 2011;300:H1990–H1996. PubMed PMC

Kompanowska-Jezierska E, Kuczeriszka M. Cytochrome P-450 metabolites in renal circulation and excretion - interaction with the nitric oxide (NO) system. J Physiol Pharmacol. 2008;59(Suppl 9):137–149. PubMed

Sporkova A, Kopkan L, Varcabová A, 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

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

Lee CR, Imig JD, Edin ML, Foley J, 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

Kopkan L, Husková Z, Sporková A, et al. Soluble epoxide hydrolase inhibition exhibits antihypertensive actions independently of nitric oxide in mice with renovascular hypertension. Kidney Blood Press Res. 2012;35:595–607. PubMed PMC

Honetschlägerová Z, Kitada K, Husková Z, et al. Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME. J Hypertens. 2013;31:321–332. PubMed PMC

Elmarakby AA. Reno-protective mechanisms of epoxyeicosatrienoic acids in cardiovascular disease. Am J Physiol. 2012;302:R321–R330. PubMed

Varcabová Š, Husková Z, Kramer HJ, et al. Antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats is mediated by suppression of the intrarenal renin-angiotensin system. Clin Exp Pharmacol Physiol. 2013;40:273–281. PubMed PMC

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

Von Thun, Vari RC, El-Dahr SD, Navar LG. Augmentation of intrarenal angiotensin II levels by chronic angiotensin II infusion. Am J Physiol. 1994;266:F120–F128. 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

Reckelhoff JF, Romero JC. Role of oxidative stress in angiotensin-induced hypertension. Am J Physiol. 2003;284:R893–R912. PubMed

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

Pinto YM, Paul M, Ganten D. Lessons from rat models of hypertension: from Goldblatt to genetic engineering. Cardiovasc Res. 1998;39:77–88. PubMed

Mullins LJ, Mullins J. Current successes and limitations of using genetic modification for blood pressure research. Pflugers Arch. 2003;445:491–494. PubMed

Kantachuvesiri S, Fleming S, Peters J, et al. Controlled hypertension, a transgenic toggle switch reveals differential mechanisms underlying vascular disease. J Biol Chem. 2001;276:36727–36733. PubMed

Vaňourková Z, Kramer HJ, Husková Z, et al. AT1 receptor blockade is superior to conventional triple therapy in protecting against end-organ damage Cyp1a1-Ren-2 transgenic rats with inducible hypertension. J Hypertens. 2006;24:2465–2472. PubMed

Husková Z, Vaňourková Z, Erbanová M, et al. Inappropriately high circulating and intrarenal angiotensin II levels during dietary salt loading exacerbate hypertension in Cyp1a1-Ren-2 transgenic rats. J Hypertens. 2010;28:495–509. PubMed

Mitchell KD, Bagatell SJ, Miller CS, Mouton CR, Seth DM, Mullins JJ. Genetic clamping of renin gene expression induces hypertension and elevation of intrarenal II levels of graded severity in Cyp1a1-Ren2 transgenic rats. JRAAS. 2006;7:74–86. PubMed

Peters B, Grisk O, Becher B, et al. Dose-dependent titration of prorenin and blood pressure in Cyp1a1-Ren-2 transgenic rats: absence of prorenin-induced glomerulosclerosis. J Hypertens. 2008;26:102–109. PubMed

Peters BS, Dornaika R, Hosten N, et al. Regression of cardiac hypertrophy in Cyp1a1-Ren-2 transgenic rat. J Magn Reson Imaging. 2012;36:373–378. PubMed

Navar LG, Prieto MC, Satou R, Kobori H. Intrarenal angiotensin II and its contribution to the genesis of chronic hypertension. Curr Opin Pharmacol. 2011;11:180–186. PubMed PMC

Gonzalez-Vilalobos RA, Janjoulia T, Fletecher NK, et al. The absence of intrarenal ACE protects against hypertension. J Clin Invest. 2013;125:2011–2023. 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. 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

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

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. New York, NY: Raven Press, Publishers; 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

Kujal P, Čertíková Chábová V, Škaroupková P, et al. Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren-2 transgenic hypertensive rats. Clin Exp Pharmacol Physiol. 2014;41:227–237. PubMed PMC

Castrop H, Höcherl K, Kurtz A, Schweda F, Todorov V, Wagner C. Physiology of kidney renin. Physiol Rev. 2010;90:607–673. PubMed

Hall JE, Brands MW. The renin-angiotensin-aldosterone system: renal mechanisms and circulatory homeostasis. In: Seldin DW, Giebisch G, editors. The Kidney: Physiology and Pathophysiology. Lippincott Williams & Wilkins; Philadelphia: 2000. pp. 1009–1046.

Kujal P, Čertíková Chábová V, Vernerova 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

Vaněčková I, Kujal P, Husková Z, et al. Effects of combined endothelin A receptor blockade and renin-angiotensin system blockade on the course end-organ damage in 5/6 nephrectomized Ren-2 hypertensive rats. Kidney Blood Press Res. 2012;35:382–392. PubMed

Kurtz TW, Griffin KA, Bidani AK, Davisson RL, Hall JE. Recommendations for blood pressure measurements in humans and experimental animals. Part 2: Blood pressure measurements in experimental animals. Hypertension. 2005;45:299–310. PubMed

Nogueira EF, Vargas CA, Otis M, Gallo-Payet N, Bollag WB, Rainey WE. Angiotensin-II acute regulation of rapid response genes in human, bovine, and rat adrenocortical cells. J Mol Endocrinol. 2007;39:365–374. PubMed

Characterization of a new model of chemotherapy-induced heart failure with reduced ejection fraction and nephrotic syndrome in Ren-2 transgenic rats

The treatment with sGC stimulator improves survival of hypertensive rats in response to volume-overload induced by aorto-caval fistula

Inappropriate activation of the renin-angiotensin system improves cardiac tolerance to ischemia/reperfusion injury in rats with late angiotensin II-dependent hypertension

Increased Endogenous Activity of the Renin-Angiotensin System Reduces Infarct Size in the Rats with Early Angiotensin II-dependent Hypertension which Survive the Acute Ischemia/Reperfusion Injury

Early Renal Vasodilator and Hypotensive Action of Epoxyeicosatrienoic Acid Analog (EET-A) and 20-HETE Receptor Blocker (AAA) in Spontaneously Hypertensive Rats

Addition of Endothelin A-Receptor Blockade Spoils the Beneficial Effect of Combined Renin-Angiotensin and Soluble Epoxide Hydrolase Inhibition: Studies on the Course of Chronic Kidney Disease in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats

Epoxyeicosanoids in hypertension

Pharmacological Blockade of Soluble Epoxide Hydrolase Attenuates the Progression of Congestive Heart Failure Combined With Chronic Kidney Disease: Insights From Studies With Fawn-Hooded Hypertensive Rats

20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: a study in Cyp1a1-Ren-2 transgenic rats

Effect of angiotensin-converting enzyme blockade, alone or combined with blockade of soluble epoxide hydrolase, on the course of congestive heart failure and occurrence of renal dysfunction in Ren-2 transgenic hypertensive rats with aorto-caval fistula

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

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