title: 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.
abstract: The detailed mechanisms determining the course of congestive heart failure (CHF) and associated renal dysfunction remain unclear. In a volume overload model of CHF induced by creation of aorto-caval fistula (ACF) in Hannover Sprague-Dawley (HanSD) rats we explored the putative pathogenetic contribution of epoxyeicosatrienoic acids (EETs), active products of CYP-450 dependent epoxygenase pathway of arachidonic acid metabolism, and compared it with the role of the renin-angiotensin system (RAS). Chronic treatment 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 to levels observed in sham-operated HanSD rats, but did not improve the survival or renal function impairment. In contrast, chronic angiotensin-converting enzyme inhibition (ACEi, trandolapril, 6 mg/l in drinking water) increased renal blood flow, fractional sodium excretion and markedly improved survival, without affecting left ventricular structure and performance. Hence, renal dysfunction rather than cardiac remodeling determines long-term mortality in advanced stage of CHF due to volume overload. Strong protective actions of ACEi were associated with suppression of the vasoconstrictor/sodium retaining axis and activation of vasodilatory/natriuretic axis of the renin-angiotensin system in the circulating blood and kidney tissue.
authors.affiliation: Department of Pathophysiology, Second Faculty of Medicine, Charles University, Prague, Czech Republic. luce@medicon.cz.
authors.forename: L
authors.initials: L
authors.lastname: Červenka
authors.forename: V
authors.initials: V
authors.lastname: Melenovský
authors.forename: Z
authors.initials: Z
authors.lastname: Husková
authors.forename: A
authors.initials: A
authors.lastname: Sporková
authors.forename: M
authors.initials: M
authors.lastname: Bürgelová
authors.forename: P
authors.initials: P
authors.lastname: Škaroupková
authors.forename: S H
authors.initials: SH
authors.lastname: Hwang
authors.forename: B D
authors.initials: BD
authors.lastname: Hammock
authors.forename: J D
authors.initials: JD
authors.lastname: Imig
authors.forename: J
authors.initials: J
authors.lastname: Sadowski
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D004852:Epoxy Compounds / Q000378:metabolism; D006333:Heart Failure / Q000097:blood / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D007668:Kidney / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood; D011897:Random Allocation; D051381:Rats; D051437:Renal Insufficiency / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D012084:Renin-Angiotensin System / Q000187:drug effects; D014463:Ultrasonography; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D000806:Angiotensin-Converting Enzyme Inhibitors; D001565:Benzoates; D004852:Epoxy Compounds; D010446:Peptide Fragments; D000804:Angiotensin II; D014508:Urea; D000803:Angiotensin I; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid; C118790:angiotensin I (1-7)