Attenuation of endothelin-1 induced vasoconstriction by 17β estradiol is not sustained during long-term therapy in postmenopausal women with coronary heart disease

OBJECTIVES The goal of this study was to determine the long-term effects of estrogen replacement therapy on the response to endothelin-1 (ET-1) in postmenopausal women with coronary heart disease. BACKGROUND It is thought that the vasoconstrictor ET-1 is involved in the development and progression of atherosclerosis. Estrogen replacement may slow the development of atherosclerosis in postmenopausal women. METHODS Nineteen of 20 postmenopausal women randomized to either three months of 2 mg oral estradiol or placebo completed the double-blind placebo-controlled protocol. Change in forearm blood flow (FBF) in response to a 60 min brachial arterial infusion of ET-1 (5 pmol/min) was measured before randomization, after one month of randomized therapy and after three months of therapy using venous occlusion plethysmography. RESULTS Estrogen treatment had no effect on baseline FBF. Systolic and diastolic blood pressure and heart rate did not change in response to estrogen therapy or ET-1. Before randomization, in response to ET-1, FBF was reduced by −21.9% (mean response over 60 min) in the placebo group and −19.0% in the estradiol group (p = 0.67). After one month of therapy, the response was attenuated in the estrogen group, −10.0%, compared with the placebo group, −23.6 (difference in means 13.6%, 95% confidence interval [0.7%, 26.6%], P = 0.041). After three months of therapy, there was no difference in response between the placebo group, −27.0%, and estrogen group, −30.2% (p = 0.65). CONCLUSIONS In postmenopausal women with coronary heart disease, estrogen therapy inhibits the vasoconstrictor response to ET-1 after one month of therapy. This effect is lost after three months of therapy, suggesting that tachyphylaxis to one potentially beneficial action of estradiol develops during chronic treatment.