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

Abstract

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.

Pharmacological Blockade of Soluble Epoxide Hydrolase Attenuates the Progression of Congestive Heart Failure Combined With Chronic Kidney Disease: Insights From Studies With Fawn-Hooded Hypertensive Rats

“…The beneficial effects of the treatment, particularly on the survival rate, were more pronounced in ACF FHH rats. In addition, our results show that, in accordance with previous findings (Oliver-Dussault et al, 2010; Melenovsky et al, 2012, 2018; Červenka et al, 2015, 2016; Kala et al, 2018), after creation of ACF the animals displayed signs of pronounced cardiac hypertrophy, involving both ventricles. Remarkably, this was associated with distinct lung congestion, indicating LV failure without signs of RV failure (no liver congestion).…”

“…Animals underwent either sham-operation or ACF creation as described above (at the week labeled -4) and were left without treatment for 4 weeks. Previous studies have shown that after this time CHF features are fully developed but the animals are still in the compensation phase (Oliver-Dussault et al, 2010; Melenovsky et al, 2012, 2018; Červenka et al, 2015, 2016; Kala et al, 2018). At this time point (week 0) the rats were divided into the following experimental groups:…”

“…Rats were anesthetized (tiletamine + zolazepam, Virbac SA, Carros Cedex, France, 8 mg/kg; and xylasine, Spofa, Czechia, 4 mg/kg intramuscularly) and CHF was induced by volume overload caused by ACF created using needle technique as employed and validated by many investigators including our own group (Oliver-Dussault et al, 2010; Abassi et al, 2011; Melenovsky et al, 2012, 2018; Cohen-Segev et al, 2014; Brower et al, 2015; Červenka et al, 2015, 2016; Kala et al, 2018). Briefly, after exposure of the abdominal aorta and inferior vena cava between the renal arteries and iliac bifurcation, the aorta was temporarily occluded at this segment for about 40 s. An 18-gauge needle (diameter 1.2 mm) was inserted into the abdominal aorta and advanced across its wall into the inferior vena cava to create ACF.…”

“…The appropriate amount of c -AUCB was dissolved under gentle warming in polyethylene glycol and added with rapid stirring to warm drinking water to obtain 0.1% aqueous solution of polyethylene glycol. The dose of c -AUCB was selected based on our recent studies where it elicited substantial increases in tissue concentration of EETs without altering RAS activity (Sporková et al, 2014; Červenka et al, 2015; Kala et al, 2018).…”

Epoxyeicosatrienoic Acid-Based Therapy Attenuates the Progression of Postischemic Heart Failure in Normotensive Sprague-Dawley but Not in Hypertensive Ren-2 Transgenic Rats

“…With respect to the heart function, TGR exhibited unchanged (Habibi et al, 2011; Ma et al, 2012; Neckář et al, 2012; Červenka et al, 2015a; Kovács et al, 2016) or slightly lower LV systolic function (Whaley-Connell et al, 2007; De Mello et al, 2013), depending on measured heart parameters and used methods. Further, it has been shown that TGR have increased mortality compared to normotensive HanSD rats when subjected to volume overload (Červenka et al, 2015a,b; Kala et al, 2018). Finally, there is a single paper dealing with the progression of post-MI CHF in TGR (Connelly et al, 2013).…”