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-1 (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-1 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-1 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-I levels 12 weeks after operation were similarly lower in both sham (105+/-7.4 pg/g tissue) and shunt rabbits (126+/-9.2 pg/g tissue) than in those with saline administration; however, the plasma ET-1 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-1 does not play a major role in the compensatory stage of cardiovascular remodeling in the present volume-overload model.
Tojo
T
T
The First Department of Internal Medicine, Yamagata University School of Medicine, Japan.
Tsunoda
Y
Y
Nakada
S
S
Tomoike
H
H
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy* / Q000503:physiopathology; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D011180:Postmortem Changes; D011817:Rabbits; D017466:Receptors, Endothelin / Q000502:physiology*; D020257:Ventricular Remodeling / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C088196:TAK 044