title: 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.
abstract: The detailed mechanisms determining the course of congestive heart failure (CHF) in hypertensive subjects with associated renal dysfunction remain unclear. In Ren-2 transgenic rats (TGR), a model of angiotensin II (ANG II)-dependent hypertension, CHF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). In these rats we investigated the putative pathophysiological contribution of epoxyeicosatrienoic acids (EETs) and compared it with the role of the renin-angiotensin system (RAS). We found that untreated ACF TGR exhibited marked intrarenal and myocardial deficiency of EETs and impairment of renal function. Chronic treatment of these rats with cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB, 3 mg/L in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs, markedly improved survival rate, and increased renal blood flow, glomerular filtration rate and fractional sodium excretion, without altering RAS activity. Chronic angiotensin-converting enzyme inhibition (ACEi) with trandolapril, (6 mg/L in drinking water) improved survival rate even more, and also inhibited the development of renal dysfunction; these beneficial actions were associated with significant suppression of the vasoconstrictor/sodium retaining axis and further activation of the vasodilatory/natriuretic axis of the systemic and intrarenal RAS, without modifying tissue availability of biologically active fatty acid epoxides. In conclusion, these findings strongly suggest that chronic sEH inhibition and chronic treatment with ACEi, each of them altering a different vasoactive system, delay or even prevent the onset of decompensation of CHF in ACF TGR, probably by preventing the development of renal dysfunction.
authors.affiliation: Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.|Department of Pathophysiology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Luděk
authors.initials: L
authors.lastname: Červenka
authors.affiliation: Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Vojtěch
authors.initials: V
authors.lastname: Melenovský
authors.affiliation: Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Husková
authors.affiliation: Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Škaroupková
authors.affiliation: Department of Pharmacology, Kagawa University, Kagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Department of Renal and Body Fluid Physiology, M. Mossakowski Medical Research Centre, Polish Academy of Science, Warsaw, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Sadowski
mesh_terms: D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001011:Aorta; D001794:Blood Pressure / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D005260:Female; D005402:Fistula / Q000150:complications*; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000187:drug effects; D012995:Solubility; D013997:Time Factors; D014682:Vena Cava, Inferior
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D010446:Peptide Fragments; D000804:Angiotensin II; D003577:Cytochrome P-450 Enzyme System; D000803:Angiotensin I; D004851:Epoxide Hydrolases; D012083:Renin; C118790:angiotensin I (1-7); C572289:eicosenoic acid
keywords: aorto-caval fistula; congestive heart failure; epoxyeicosatrienoic acids; hypertension; renal dysfunction; renin-angiotensin system; soluble epoxide hydrolase