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

L. Červenka, V. Melenovský, Z. Husková, A. Sporková, M. Bürgelová, P. Škaroupková, S. H. Hwang, B. D. Hammock, J. D. Imig, J. Sadowski

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)857-873
Number of pages17
JournalPhysiological Research
Volume64
Issue number6
StatePublished - 2015

Fingerprint

Epoxide Hydrolases
Venae Cavae
Fistula
Heart Failure
Kidney
trandolapril
Renin-Angiotensin System
Drinking Water
Sprague Dawley Rats
Sodium
Benzoic Acid
Renal Circulation
Vasoconstrictor Agents
Peptidyl-Dipeptidase A
Acids
Mortality

Keywords

  • Aorto-caval fistula
  • Congestive heart failure
  • Epoxyeicosatrienoic acids
  • Renin-angiotensin system
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Medicine(all)
  • Physiology

Cite this

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. / Červenka, L.; Melenovský, V.; Husková, Z.; Sporková, A.; Bürgelová, M.; Škaroupková, P.; Hwang, S. H.; Hammock, B. D.; Imig, J. D.; Sadowski, J.

In: Physiological Research, Vol. 64, No. 6, 2015, p. 857-873.

Research output: Contribution to journalArticle

Červenka, L, Melenovský, V, Husková, Z, Sporková, A, Bürgelová, M, Škaroupková, P, Hwang, SH, Hammock, BD, Imig, JD & Sadowski, J 2015, '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', Physiological Research, vol. 64, no. 6, pp. 857-873.
Červenka, L. ; Melenovský, V. ; Husková, Z. ; Sporková, A. ; Bürgelová, M. ; Škaroupková, P. ; Hwang, S. H. ; Hammock, B. D. ; Imig, J. D. ; Sadowski, J. / 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. In: Physiological Research. 2015 ; Vol. 64, No. 6. pp. 857-873.
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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.",
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AU - Červenka, L.

AU - Melenovský, V.

AU - Husková, Z.

AU - Sporková, A.

AU - Bürgelová, M.

AU - Škaroupková, P.

AU - Hwang, S. H.

AU - Hammock, B. D.

AU - Imig, J. D.

AU - Sadowski, J.

PY - 2015

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N2 - 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.

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KW - Renin-angiotensin system

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