Effects of long-term treatment with nonselective endothelin receptor antagonist, TAK-044, on remodeling of cardiovascular system with sustained volume overload

To assess the role of endothelin-l (ET-1) on cardiovascular remodeling, nonselective endothelin-receptor antagonist TAK-044 was administered for the long term to rabbits with or without arteriovenous (A-V) shunt formation. Six weeks after sham operation (n = 12) or carotid-jugular shunt formation (n = 21), TAK-044 (30 mg/day) or saline was infused subcutaneously using osmotic mini pumps for another 6 weeks. Twelve weeks after operation, left ventricular (LV) diameter was enlarged with the presence of an A-V shunt; however, the levels of LV diameter and arterial pressure or the postmortem weight of LVs of shunt rabbits were similar between saline and TAK-044 groups. A linear relation of the luminal diameter and the medial cross-sectional area of the left and right carotid arteries was similar between shunt + saline and shunt + TAK-044 groups. In saline groups, myocardial ET-I levels were higher in shunt than in sham rabbits (217 +/- 22 vs. 136 +/- 19 pg/g tissue; p < 0.01 between rabbit groups) without changes in plasma ET-I concentrations during saline infusion for 6 weeks. Differences in plasma ET-1 levels before and 6 weeks after the administration of TAK-044 were 0.32 +/- 0.78 and 0.16 +/- 0.28 pg/ml (NS between periods) in shunt and sham groups, respectively. In TAK-044 groups, myocardial ET-1 levels 12 weeks after operation were similarly lower in both sham (105 +/- 76 pg/g tissue) and shunt rabbits (126 +/- 9.2 i pg/g tissue) than in those with saline administration; however: the plasma ET-I concentrations were increased significantly 6 weeks after TAK-044 administration by 5.0 +/- 0.6-fold and 3.5 +/- 0.3-fold (p < 0.01) of the levels 6 weeks after operation in shunt and sham groups (NS between groups), respectively. Accordingly, myocardial but not plasma ET-1 levels were increased by a long-term burden of volume overload and were attenuated by a long-term administration of TAK-044 without altering drastically the hemodynamics or vascular remodeling. These results suggest that endogenous ET-l does not play a major role in the compensatory stage of cardiovascular remodeling in the present volume-overload model.