NONSELECTIVE ET(A) ET(B) RECEPTOR ANTAGONIST BLOCKS PROLIFERATION OF RAT VASCULAR SMOOTH-MUSCLE CELLS AFTER BALLOON ANGIOPLASTY/

To elucidate the role of endothelin receptor subtypes in the abnormal proliferation of vascular smooth muscle cells (VSMC) associated with v ascular injury, we have investigated the effects of a novel and potent nonselective ET(A)/ET(B) receptor antagonist (TAK-044) on the prolife ration of rat VSMC in vitro and in vivo. TAK-044 dose-dependently inhi bited DNA synthesis stimulated by 10(-7) M ET-1 in cultured rat VSMC f rom the late passage with the approximate IC50 of 6 x 10(-8) M. After balloon angioplasty, the neointimal lesion in the injured carotid arte ries in the TAK-044-treated group (0.052 +/- 0.014 mm(2)) was signific antly (p < 0.05) decreased compared to that in control group (0.26 +/- 0.045 mm(2)), while the medial surface area was not affected. The int ima/media ratio in the TAK-044 group (31 +/- 6%) also significantly (p < 0.05) decreased from that of the control group (148 +/- 25%). Our d ata suggest that nonselective ET(A)/ET(B) receptor antagonists may be therapeutic potential for prevention against the intimal thickening as sociated with vascular injury.