We showed recently that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, retarded the development of renal dysfunction and progression of aorto-caval fistula(ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). In that study the final survival rate of untreated ACF TGR was only 14 % but increased to 41 % after sEH blockade. Here we examined if sEH inhibition added to renin-angiotensin system (RAS) blockade would further enhance protection against ACF-induced CHF in TGR. The treatment regimens were started one week after ACF creation and the follow-up period was 50 weeks. RAS was blocked using angiotensin-converting enzyme inhibitor (ACEi, trandolapril, 6 mg/l) and sEH with an sEH inhibitor (sEHi, c-AUCB, 3 mg/l). Renal hemodynamics and excretory function were determined two weeks post-ACF, just before the onset of decompensated phase of CHF. 29 weeks post-ACF no untreated animal survived. ACEi treatment greatly improved the survival rate, to 84 % at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53 %). Untreated ACF TGR exhibited marked impairment of renal function and the treatment with ACEi alone or combined with sEH inhibition did not prevent it. In conclusion, addition of sEHi to ACEi treatment does not provide better protection against CHF progression and does not increase the survival rate in ACF TGR: indeed, the rate decreases significantly. Thus, combined treatment with sEHi and ACEi is not a promising approach to further attenuate renal dysfunction and retard progression of CHF.
- MeSH
- arteriovenózní píštěl MeSH
- benzoáty farmakologie terapeutické užití MeSH
- epoxid hydrolasy antagonisté a inhibitory MeSH
- indoly terapeutické užití MeSH
- inhibitory ACE terapeutické užití MeSH
- kombinovaná farmakoterapie MeSH
- krysa rodu rattus MeSH
- močovina analogy a deriváty farmakologie terapeutické užití MeSH
- potkani Sprague-Dawley MeSH
- potkani transgenní MeSH
- preklinické hodnocení léčiv MeSH
- renální insuficience etiologie prevence a kontrola MeSH
- srdeční selhání komplikace farmakoterapie mortalita MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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.
- MeSH
- angiotensin I krev MeSH
- angiotensin II krev MeSH
- benzoáty farmakologie terapeutické užití MeSH
- epoxid hydrolasy antagonisté a inhibitory MeSH
- epoxidové sloučeniny metabolismus MeSH
- inhibitory ACE MeSH
- krysa rodu rattus MeSH
- kyselina 8,11,14-eikosatrienová analogy a deriváty krev metabolismus MeSH
- ledviny metabolismus MeSH
- močovina analogy a deriváty farmakologie terapeutické užití MeSH
- modely nemocí na zvířatech MeSH
- myokard metabolismus MeSH
- náhodné rozdělení MeSH
- peptidové fragmenty krev MeSH
- preklinické hodnocení léčiv MeSH
- renální insuficience krev etiologie prevence a kontrola MeSH
- renin-angiotensin systém účinky léků MeSH
- srdeční selhání krev komplikace farmakoterapie ultrasonografie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
