Effect of angiotensin-converting enzyme blockade, alone or combined with blockade of soluble epoxide hydrolase, on the course of congestive heart failure and occurrence of renal dysfunction in Ren-2 transgenic hypertensive rats with aorto-caval fistula. Physiol Res 2018 Jul 17;67(3):401-415
Date
03/13/2018Pubmed ID
29527914Pubmed Central ID
PMC6056335DOI
10.33549/physiolres.933757Scopus ID
2-s2.0-85050353397 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
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.
Author List
Kala P, Sedláková L, Škaroupková P, Kopkan L, Vaňourková Z, Táborský M, Nishiyama A, Hwang SH, Hammock BD, Sadowski J, Melenovský V, Imig JD, Červenka LMESH terms used to index this publication - Major topics in bold
Angiotensin-Converting Enzyme InhibitorsAnimals
Arteriovenous Fistula
Benzoates
Drug Evaluation, Preclinical
Drug Therapy, Combination
Epoxide Hydrolases
Female
Heart Failure
Indoles
Male
Rats
Rats, Sprague-Dawley
Rats, Transgenic
Renal Insufficiency
Urea
