Anti-Atherosclerotic Effects of Tamoxifen in Cholesterol-fed Ovariectomized Rabbits.

Abstract

SUMMARYIt has been indicated that the anti-estrogen agent, tamoxifen, developed for the treatment of breast cancer, may act on the vascular system as an estrogen agonist. However, to our knowledge few reports suggest that tamoxifen exerts anti-atherogenic actions. In the present study, we evaluated the anti-atherosclerotic effects of tamoxifen in ovariectomized cholesterol-fed rabbits. Ovariectomized rabbits were fed a 1% cholesterol diet and divided into 4 groups: control group (C, n=5); estrogen treatment (E, n=6); low-dose tamoxifen treatment (0.5 mg/kg) (LT, n=6); and high-dose tamoxifen (1.0 mg/kg) (HT, n=7). After 6 weeks, both Oil red O-positive areas on the intimal surfaces of aortae and the ratios of intimal to medial areas (I/M ratios) measured from cross-sections of aortae were significantly lower in groups E, LT and HT compared with group C. Although there were no significant differences in serum NOx (NO 2 and NO 3 ) levels among the 4 groups, NOx levels were slightly higher in groups E, LT and HT than group C. Acetylcholine (ACh) was administered to all animals, and the responses of ear arteriole diameters were compared among the 4 groups. While ear arteriole diameters were significantly decreased in group C, no significant changes were observed in groups E, LT or HT following ACh administration. Ratios of ear arteriole diameters after to before ACh administration were significantly greater in groups E, LT and HT compared to group C. These findings suggest that tamoxifen exerts anti-atherosclerotic effects, and that these effects are attributed to the maintenance of vascular endothelial function. (Jpn Heart J 2002; 43: 545-558) Key words: Tamoxifen, Estrogen, Atherosclerosis, Vascular endothelial function, NO WHILE the incidence of cardiovascular disease in premenopausal women is less than half that in men of similar age, its rate of occurrence markedly increases following menopause, with the coronary heart disease incidence in women over the age of 75 approaching the rates of men. 1) In vitro studies demonstrate that estrogen exerts anti-atherogenic actions by inducing LDL receptor activity, 2)From the