Orally active endothelin receptor antagonist BMS-182874 suppresses neointimal development in balloon-injured rat carotid arteries

Vascular smooth muscle cell (SMC) proliferation is an important component in the development of restenosis. Because endothelin (ET) has been reported to act as an SMC mitogen, we postulated that the orally active ET_A receptor antagonist BMS-182874 would suppress the development of the intimal lesion that develops in rat carotid arteries after balloon injury. Using cultured rat aortic SMC. we noted that ET-l-stimulated increases in pHJthymidine incorporation were blocked by BMS-182874. To determine the effect of the drug on intimal lesion formation, we treated rats with BMS-182874 (100 mg/kg orally, p.o.) or vehicle once daily for 3 weeks, beginning 1 week before balloon injury. Two weeks after injury, drug-treated rats had a 35% decrease in lesion area and a 34% decrease in the lesion/media ratio as compared with the vehicle-treated rats. In situ hybridization (ISH) analysis of balloon-injured rat carotid arteries showed an increase in ET_A receptor mRNA. These data support the concept that ET_A receptor activation contributes to intimal lesion formation by promotion of SMC proliferation and suggest a potential use for ET_A receptor antagonists in the amelioration of hyperproliferative vascular diseases, including restenosis.