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.

摘要

We showed recently that increasing kidney epoxyeicosatrienoicacids (EETs) by blocking soluble epoxide hydrolase (sEH),an enzyme responsible for EETs degradation, retarded thedevelopment of renal dysfunction and progression of aorto-cavalfistula(ACF)-induced congestive heart failure (CHF) in Ren-2transgenic hypertensive rats (TGR). In that study the final survivalrate of untreated ACF TGR was only 14 % but increased to 41 %after sEH blockade. Here we examined if sEH inhibition added torenin-angiotensin system (RAS) blockade would further enhanceprotection against ACF-induced CHF in TGR. The treatmentregimens were started one week after ACF creation and the followupperiod was 50 weeks. RAS was blocked using angiotensinconvertingenzyme inhibitor (ACEi, trandolapril, 6 mg/l) and sEHwith an sEH inhibitor (sEHi, c -AUCB, 3 mg/l). Renal hemodynamicsand excretory function were determined two weeks post-ACF, justbefore the onset of decompensated phase of CHF. 29 weeks post-ACF no untreated animal survived. ACEi treatment greatlyimproved the survival rate, to 84 % at the end of study.Surprisingly, combined treatment with ACEi and sEHi worsened therate (53 %). Untreated ACF TGR exhibited marked impairment ofrenal function and the treatment with ACEi alone or combined withsEH inhibition did not prevent it. In conclusion, addition of sEHi toACEi treatment does not provide better protection against CHFprogression and does not increase the survival rate in ACF TGR:indeed, the rate decreases significantly. Thus, combined treatmentwith sEHi and ACEi is not a promising approach to furtherattenuate renal dysfunction and retard progression of CHF.