Why the study?
Does soluble epoxide hydrolase inhibition with c-AUCB improve survival and renal function in rats with volume overload-induced congestive heart failure?
Does soluble epoxide hydrolase inhibition with c-AUCB improve survival and renal function in rats with volume overload-induced congestive heart failure?
In a rat model of volume overload-induced heart failure, ACE inhibition improved survival and renal function, whereas soluble epoxide hydrolase inhibition did not, suggesting that renal dysfunction rather than cardiac remodeling determines long-term mortality.
sEHi confers no survival benefit in this rat volume-overload model; leaves open whether EET modulation merits testing in other HF etiologies or species.
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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Červenka et al. (2015) studied this question.
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