EFFECTS OF SELECTIVE ENDOTHELIN TYPE A RECEPTOR BLOCKADE IN EXPERIMENTAL HEART AND RENAL FAILURE: STUDIES ON RATS WITH AORTO-CAVAL FISTULA AND 5/6 NEPHRECTOMY

Purpose: Evaluation of the effect of selective endothelin type A (ETA) receptor blockade on the course of (1) volume-overload heart failure (HF) and (2) volume-overload HF combined with chronic kidney disease (CKD).

Methods: (1) HF was induced by aorto-caval fistula (ACF) in hypertensive Ren-2 renin transgenic rats (TGR). (2) ACF-induced HF was combined with CKD induced by 5/6 nephrectomy (5/6 Nx) in HanSD normotensive rats. Selective ETA receptor blockade was achieved by atrasentan. Other groups received trandolapril (ACEi), a combination of atrasentan and trandolapril, or a placebo (water). The follow-up period was 20 weeks. Cardiac functions were assesed by echocardiography and invasive pressure / volume analysis of LV. Albuminuria and histological indexes of tubulosclerosis and glomerulosclerosis were measured as parameters of renal impairment.

Results: (1) None from untreated ACF TGR was alive after day 79. Both atrasentan and trandolapril treatment improved the survival rate, to 56% and 69%, combined ACEi and ETA receptor blockade to 52% (not significant difference) and they suppressed the development of LV remodeling, lung congestion, and improved LV systolic contractility compared to their untreated counterparts. (2) - The final survival in the untreated group was 15%. The treatment with atrasentan or trandolapril alone and the combined treatment improved the survival rate to 64%, 71%, and 75%, (not significant difference). The combined treatment exerted the best renoprotection (albuminuria, renal glomerular and tubulointerstitial injury).

Conclusion: The treatment with selective ETA receptor antagonist improves cardiac functions, delays the onset of decompensation, and increases the survival rate of volume-overload HF in TGR and in HanSD with ACF-induced HF combined with 5/6 Nx-induced CKD, in which it also enhanced renoprotective action.