Raloxifene and estrogen inhibit neointimal thickening after balloon injuryin the carotid artery of male and ovariectomized female rats

The effects of raloxifene and 17 alpha-ethinyl estradiol (EE2) on intimal t hickening in response to balloon injury were tested in male and ovariectomi zed female rats. In male rats, oral raloxifene and EE2, administered either by gavage or in the diet, inhibited arterial intimal thickening in respons e to balloon injury to a maximum of similar to 60 and 50%, respectively. Th e effect of oral raloxifene to decrease cholesterol was observed at doses ( greater than or equal to 3 mg/kg/day) higher than those required to inhibit intimal thickening (greater than or equal to 0.03 mg/kg/day). Coadministra tion of the estrogen receptor antagonist, ICI 182,780 (5 mg/kg/day, s.c.), blocked the inhibition of balloon injury by raloxifene and EE2. Direct adve ntitial delivery of raloxifene (0.03 mg/kg/day) and EE2 (0.001 mg/kg/day) t o the vascular wall inhibited intimal thickening by 63 and 53%, respectivel y. In ovariectomized fe male rats, oral raloxifene (0.01-3.0 mg/kg/day) and EE2 (0.08 mg/kg/day) inhibited intimal thickening to a maximum of 32 and 6 0%, respectively. Together, these data suggest that raloxifene and EE2 inhi bit balloon arterial injury in the rat through direct effects on the vascul ar wall that involve the estrogen receptor and are at least partially indep endent of serum cholesterol.