Contrasting Effects of Conjugated Estrogens and Tamoxifen on Dilator Responses of Atherosclerotic Epicardial Coronary Arteries in Nonhuman Primates

Abstract

Background Estrogens have been shown to improve dilator responses of atherosclerotic coronary arteries. Tamoxifen is a mixed estrogen agonist/antagonist with as yet unexplored effects on vascular function. Therefore, the goal of this study was to compare the effects of conjugated equine estrogens (CEEs) with those of tamoxifen on epicardial coronary artery dilator responses in atherosclerotic, ovariectomized monkeys. Methods and Results Fifty ovariectomized cynomolgus monkeys were fed an atherogenic diet for 34 months. During this time, monkeys were assigned to one of three treatment groups: (1) control, no hormone replacement (n=15); (2) CEEs mixed in the diet at a dose of 0.043 mg · kg −1 · d −1 (n=14); or (3) tamoxifen mixed in the diet at a dose of 1.3 mg · kg −1 · d −1 (n=21). Quantitative angiography was used to measure coronary artery dilator responses to intracoronary infusions of acetylcholine (10 −8 , 10 −7 , and 10 −6 mol/L) and nitroglycerin (15 μg/min). Coronary arteries of the tamoxifen-treated group constricted in response to high-dose acetylcholine (−5.4± 2.3%, P <.05 versus control), whereas those of the CEE group did not ( P >.05 versus control). Conversely, arteries from the CEE group dilated in response to nitroglycerin (9.1±2.1%, P <.05 versus control), whereas those from the tamoxifen group did not ( P >.05 versus control). Statistical adjustments for variations in plaque extent (determined subsequently after necropsy) and plasma lipoproteins did not alter the results. Conclusions Tamoxifen has primarily estrogen-antagonistic effects on epicardial coronary artery dilator responses in atherosclerotic monkeys. Results implicate the estrogen receptor as a modulator of coronary artery dilator responses in ovariectomized, atherosclerotic monkeys.