Abstract P425: Ras Blockade Alone or Combined With Inhibition of Soluble Epoxide Hydrolase: Effects on the Course of Congestive Heart Failure in Ren-2 Transgenic Hypertensive Rats With Aorto-caval Fistula

Abstract

Rationale and Objective: We recently showed that increasing epoxyeicosatrienoic acids (EETs) in kidney by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, markedly attenuated the development of renal dysfunction and progression of aorto-caval (ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). Therefore, in this study we examined if additional inhibition of sEH to RAS blockade could further improve the course of ACF-induced CHF in TGR. Methods: The treatment regimens were started from one week after creation of ACF and the follow-up period was 60 weeks. RAS blockade was achieved by administration of angiotensin-converting enzyme inhibitor (ACEi, trandolapril, 3 mg/L in drinking water) and sEH was blocked using a sEH inhibitor (sEHi, c -AUCB, 3 mg/L in drinking water). The following experimental groups were investigated: 1) Sham-operated TGR; 2) Untreated ACF TGR; 3) ACF TGR + ACEi; 4) ACF TGR + ACEi + sEHi (n = 36 in each ACF group). In separate groups renal hemodynamics and excretory function were evaluated two weeks post-ACF, just before the onset the decompensated phase of CHF. Results: After 29 weeks post-ACF, no animal survived. ACEi treatment greatly improved the survival rate (87%) at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53%, p < 0.05). After 2 weeks post-ACF, untreated TGR group showed lower mean arterial pressure (MAP) (124 ± 3 vs. 146 ± 4 mmHg, p < 0.05), renal blood flow (7.6 ± 0.3 vs. 10.5 ± 0.3 mL.min -1 .g -1 , p < 0.05) and absolute sodium excretion (0.18 ± 0.06 vs. 1.09 ± 0.19 μmol.min -1 .g -1 , p<0.05) than sham-operated TGR group, respectively. The treatment with ACEi alone or combination treatment with sEHi did not prevent the changes in renal hemodynamics and sodium excretion. Conclusion: We found that addition of sEHi to ACEi treatment did not provide better protection against CHF progression and the survival rate, indeed, decreased significantly. Thus, increasing bioavailability of tissue EETs in individuals with pharmacologically-induced suppression of the RAS is not a promising approach to further attenuate renal dysfunction and progression of CHF.