PS-B12-2: ENDOTHELIN TYPE A RECEPTOR BLOCKADE ATTENUATES HEART FAILURE IN RATS WITH ANGIOTENSIN II-DEPENDENT HYPERTENSION.

Abstract

Objective: Evaluation of the effects of endothelin type A (ETA) receptor blockade on the echocardiography, hemodynamic cardiac and renal parameters, and the course of high-output heart failure (HF) in rats with angiotensin II-dependent hypertension. Design and Methods: Eight-week-old male Ren-2 transgenic rats (TGR) were used as a model of angiotensin II-dependent hypertension. HF was induced by creating an aorto-caval fistula (ACF). Two weeks later, rats were divided into four groups: placebo (water) or three therapeutic groups (initial n minimum of 31 rats), and the treatment was initiated: in the first group, selective ETA receptor blockade was achieved by atrasentan, the second group received trandolapril, an angiotensin-converting enzyme inhibitor (ACEi), and the third was treated by combinational therapy (atrasentan + trandolapril), all in drinking water. The follow-up period was twenty weeks, then echocardiography, renal hemodynamics and albuminuria, invasive pressure-volume (P-V) analysis of left ventricle (LV), and organ weight measurement were done. Results: Eighteen days after creating ACF, untreated TGR began to die, and none was alive by day 79. Both atrasentan and trandolapril treatment improved the survival rate, ultimately to 56% (18 of 31 animals) and 69% (22 of 32 animals), respectively. Combined ACE and ETA receptor blockade improved the final survival rate to 52% (17 of 33 animals). The effects of the three treatment regimens on the survival rate did not significantly differ (Log-rank (Mantel-Cox) p = 0.345) (Figure 1, A). Untreated ACF TGR displayed marked renal dysfunction, cardiac hypertrophy, lung congestion, and impairment of LV contractility. None of the treatment regimens affected the progress of renal dysfunction, but they suppressed the albuminuria (Figure 1, B), development of cardiac hypertrophy and lung congestion and improved LV systolic function. Conclusion: The treatment with ETA receptor antagonist delays the onset of decompensation of volume-overload HF and improves the survival rate in hypertensive TGR similar to ACE inhibition.