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

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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

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Keywords

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

ASJC Scopus subject areas

  • Medicine(all)
  • Physiology

Cite this

Červenka, L., Melenovský, V., Husková, Z., Sporková, A., Bürgelová, M., Škaroupková, P., Hwang, S. H., Hammock, B. D., Imig, J. D., & 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, 64(6), 857-873.