We showed recently that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, retarded the development of renal dysfunction and progression of aorto-caval fistula(ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). In that study the final survival rate of untreated ACF TGR was only 14 % but increased to 41 % after sEH blockade. Here we examined if sEH inhibition added to renin-angiotensin system (RAS) blockade would further enhance protection against ACF-induced CHF in TGR. The treatment regimens were started one week after ACF creation and the follow-up period was 50 weeks. RAS was blocked using angiotensin-converting enzyme inhibitor (ACEi, trandolapril, 6 mg/l) and sEH with an sEH inhibitor (sEHi, c-AUCB, 3 mg/l). Renal hemodynamics and excretory function were determined two weeks post-ACF, just before the onset of decompensated phase of CHF. 29 weeks post-ACF no untreated animal survived. ACEi treatment greatly improved the survival rate, to 84 % at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53 %). Untreated ACF TGR exhibited marked impairment of renal function and the treatment with ACEi alone or combined with sEH inhibition did not prevent it. In conclusion, addition of sEHi to ACEi treatment does not provide better protection against CHF progression and does not increase the survival rate in ACF TGR: indeed, the rate decreases significantly. Thus, combined treatment with sEHi and ACEi is not a promising approach to further attenuate renal dysfunction and retard progression of CHF.

Center for Experimental Medicine Institute for Clinical and Experimental Medicine Prague 4 Czech Republic

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Roger VL. Epidemiology of heart failure. Circ. Res. 2013;113:646–659. PubMed PMC

Ambrosy AP, Fonarow GC, Butler J, et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol. 2014;63:1123–1133. PubMed

Braunwald E. The war against heart failure. Lancet. 2015;385:812–824. PubMed

Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135:e146–e603. PubMed PMC

Ronco C, Haapio M, House AA, Avavekar N, Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52:1527–1539. PubMed

Giamouzis G, Kalogeroupoulos AP, Butler J, et al. Epidemiology and importance of renal dysfunction in heart failure patients. Curr Heart Fail. Rep. 2013;10:411–420. PubMed

Stewart S, MacIntyre K, Hole DJ, Capewell S, McMurray JJV. More “malignant” than cancer? Five year survival following a first admission for heart failure. Eur J Heart Fail. 2001;3:315–322. PubMed

Ichikawa I, Pfeffer JM, Pfeffer MA, Hostetter TH, Brenner BM. Role of angiotensin II in the altered renal function of congestive heart failure. Circ. Res. 1984;55:669–675. PubMed

Moayedi Y, Ross HJ. Advances in heart failure: a review of biomarkers, emerging pharmacological therapies, durable mechanical support and telemonitoring. Clin. Sci. 2017;131:553–566. PubMed

Braam B, Joles JA, Daniswar AH, Gaillard CA. Cardiorenal syndrome – current understanding and future perspectives. Nat Rev Nephrol. 2014;10:48–55. PubMed

Re RN. A reassessment of the pathophysiology of progressive cardiorenal disorders. Med Clin North. Am. 2017;101:103–115. PubMed

Dube P, Weber KT. Congestive heart failure: pathophysiologic consequences of neurohormonal activation and the potential for recovery: part I. Am J. Med Sci. 2011;342:348–351. PubMed

Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/angiotensin 1–7 axis of the renin-angiotensin system in heart failure. Circ. Res. 2016;118:1313–1326. PubMed PMC

Rossi F, Mascolo A, Mollace V. The pathophysiological role of natriuretic peptide-RAAS cross talk in heart failure. Int J Cardiol. 2017;226:121–125. PubMed

Packer M, McMurray JJV. Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin-angiotensin system for the treatment of heart failure. Lancet. 2017;389:1831–1840. 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

Hall JE, Granger JP, Hall ME. Physiology and pathophysiology of hypertension. In: Albeprn RJ, Caplan MJ, Moe OW, editors. Seldin and Giebisch´s The Kidney physiology and pathophysiology. fifth. Academic Press; 2013. pp. 1319–1352.

Ferrario CM, Mullick AE. Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease. Pharmacol Res. 2017 doi: 10.1016/j.phrs.2017.05.020. PubMed DOI PMC

Pfeffer MA, Pfeffer JM, Steinberg C, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circulation. 1985;2:406–412. PubMed

Brands MW, Alonso-Galicia M, Mizelle HL, Montani JP, Hildebrandt DA, Hall JE. Chronic angiotensin-converting-enzyme inhibition improves cardiac output and fluid balance during heart failure. Am J Physiol. 1993;264:R414–R422. PubMed

Ruzicka M, Yuan B, Leenen FHH. Effects of enalapril versus losartan on regression of volume overload-induced cardiac hypertrophy in rats. Circulation. 1994;90:484–491. PubMed

Brower GL, Levick SP, Janicki JS. Differential effects of prevention and reversal treatment with Lisinopril on left ventricular remodeling in a rat model of heart failure. Heart Lung Circ. 2015;24:919–924. PubMed PMC

Červenka L, Melenovský V, Husková Z, Škaroupková P, Nishiyama A, Sadowski J. Inhibition of soluble epoxide hydrolase counteracts the development of renal dysfunction and progression of congestive heart failure in Ren-2 transgenic hypertensive rats with aorto-caval fistula. Clin Exp Pharmacol Physiol. 2015;42:795–807. PubMed

Červenka L, Melenovský V, Husková Z, et al. Inhibition of soluble epoxide hydrolase does not improve the course of congestive heart failure and the development of renal dysfunction in rats with volume overload induced by aorto-caval fistula. Physiol. Res. 2015;64:857–873. PubMed PMC

Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J. Med. 1987;316:1429–1435. PubMed

Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigators. N Engl J. Med. 1992;327:658–691. PubMed

McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J. Med. 2014;371:993–1004. PubMed

Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guideliness for the diagnois and treatment of acute and chronic heart failure: The Task Force of the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardioloy (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–21200. PubMed

Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused updatae of the 2013 ACCF/AHA Guideline for the management of heart failure. Circulation. 2017;136:e137–e161. PubMed

Cohen-Segev R, Francis B, Abu-Saleh N, et al. Cardiac and renal distribution of ACE and ACE-2 in rats with heart failure. Acta Histiochem. 2014;116:1342–1349. PubMed

Oliver-Dussault C, Ascah A, Marcil M, et al. Early predictors of cardiac decompensation in experimental volume overload. Mol Cell Biochem. 2010;338:271–281. PubMed

Abassi Z, Goltsmna I, Karram T, Winaver J, Horrman A. Aortocaval fistula in rat: a unique model of volume-overload congestive heart failure and cardiac hypertrophy. J Biomed Biotechnol. 2011:729497. doi: 10.1155/2011/729497. PubMed DOI PMC

Melenovsky V, Skaroupkova P, Benes J, Torresova V, Kopkan L, Cervenka L. The course of heart failure development and mortality in rats with volume overload due to aorto-caval fistula. Kidney Blood Press. Res. 2012;35:167–173. PubMed

Melenovský V, Benes J, Skaroupkova P, et al. Metabolic characterization of volume overload heart failure due to aorto-caval fistula in rats. Mol Cell Biochem. 2011;354:83–96. PubMed

Červenka L, Škaroupková P, Kompanowska-Jezierska E, Sadowski J. Sex-linked differences in the course of chronic kidney disease and congestive heart failure: a study in 5/6 nephrectomized Ren-2 transgenic hypertensive rats with volume overload using aorto-caval fistula. Clin Exp Pharmacol Physiol. 2016;43:883–895. PubMed

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

Kujal P, Certíková 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

Beneš J, Kazdová L, Drahota Z, et al. Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats. Clin Sci. 2011;121:29–41. PubMed

Hutchinson KR, Guggilam A, Cismowski MJ, et al. Temporal pattern of left ventricle structural and functional remodeling following reversal of volume overload heart failure. J App Physiol. 2011;111:1778–1788. PubMed PMC

Brower GL, Henegar JR, Janicki JS. Temporal evaluation of left ventricular remodeling and function in rats with chronic volume overload. Am J Physiol. 1996;40:H2071–H2078. PubMed

Wang XI, Ren B, Liu S, et al. Characterization of cardiac hypertrophy and heart failure due to volume overload in the rat. J App Physiol. 2003;94:752–763. PubMed

Brower GL, Janicki JS. Contribution of ventricular remodeling to the pathogenesis of heart failure in rats. Am J Physiol. 2001;280:H674–H683. PubMed

Fleming I. The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease. Pharmacol Rev. 2014;66:1106–1140. PubMed

El-Sherbeni AA, Aboutabl ME, Zordoky BNM, Anwar-Mohamed A, El-Kadi AOS. Determination of the dominant arachidonic acid cytochrome P450 monooxygenase in rat heart, lung, kidney, and liver: protein expression and metabolite kinetics. AAPS J. 2013;15:112–122. PubMed PMC

Imig JD. Epoxyeicosatrienoic acids, hypertension, and kidney injury. Hypertension. 2015;65:476–482. PubMed PMC

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

Fan F, Roman RJ. Effect of cytochrome P450 metabolites of arachidonic acid in Nephrology. J Am Soc Nephrol. 2017;28 doi: 10.1681/ASN.2017030252. PubMed DOI PMC

Gonzalez-Villalobos RA, Janjoulia T, Fletcher NK, et al. The absence of intrarenal ACE protects against hypertension. J Clin Invest. 2013;123:2011–2023. PubMed PMC

Carlstrom M, Wilcox CS, Arendshorst WJ. Renal autoregulation in health and disease. Physiol. Rev. 2015;95:405–511. PubMed PMC

Garcia R, Diebold S. Simple, rapid, and effective method of producing aortocaval shunts in the rat. Cardiovasc. Res. 1990;24:430–432. PubMed

Sporková A, Jíchová Š, Husková Z, et al. Different mechanism of acute versus long-term antihypertensive effects of soluble epoxide hydrolase inhibition: studies in Cyp1a1-Ren-2 transgenic rats. Clin Exp Pharmacol Physiol. 2014;41:1003–1013. 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

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