Nonselective ETA/ETB 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 vascular injury, we have investigated the effects of a novel and potent nonselective ETA/ETB receptor antagonist (TAK-044) on the proliferation of rat VSMC in vitro and in vivo. TAK-044 dose-dependently inhibited DNA synthesis stimulated by 10(-7) M ET-1 in cultured rat VSMC from the late passage with the approximate IC50 of 6 x 10(-8) M. After balloon angioplasty, the neointimal lesion in the injured carotid arteries in the TAK-044-treated group (0.052 +/- 0.014 mm2) was significantly (p < 0.05) decreased compared to that in control group (0.26 +/- 0.045 mm2), while the medial surface area was not affected. The intima/media ratio in the TAK-044 group (31 +/- 6%) also significantly (p < 0.05) decreased from that of the control group (148 +/- 25%). Our data suggest that nonselective ETA/ETB receptor antagonists may be therapeutic potential for prevention against the intimal thickening associated with vascular injury.