17β-Estradiol Attenuates Acetylcholine-Induced Coronary Arterial Constriction in Women but Not Men With Coronary Heart Disease
Authors: Collins Peter , Rosano Giuseppe M. C. , Sarrel Philip M. , Ulrich Lian , Adamopoulos Stamatis , Beale Carolyn M. , McNeill John G. , Poole-Wilson Philip A. 
Published: June 2012

Background
Women are protected from coronary artery disease until the menopause. Ovarian hormones are vasoactive substances that influence both hemodynamic parameters and atheroma formation. Intravenous ethinyl estradiol has been shown to reverse acetylcholine-induced vasoconstriction in cynomolgus monkeys and humans, and 17β-estradiol improves exercise-induced myocardial ischemia in female patients. We investigated the effect of the naturally occurring estrogen 17β-estradiol on the coronary circulation in postmenopausal women and men with coronary artery disease.

Methods and Results
We studied nine postmenopausal women 59±3 years old, mean±SEM, and seven men 52±4 years old with proven coronary artery disease. They underwent measurement of coronary artery diameter and coronary blood flow after intracoronary infusion of acetylcholine 1.6 and 16 μg/min before and 20 minutes after intracoronary administration of 2.5 μg of 17β-estradiol into atherosclerotic, nonstenotic coronary arteries. Changes in coronary artery diameter were measured by quantitative angiography, and changes in coronary blood flow were measured with an intracoronary Doppler catheter. In female patients, acetylcholine 1.6 and 16 μg/min caused constriction before the administration of 17β-estradiol (−6±2% and −8±5%, respectively, compared with baseline). This constrictor response was converted to dilatation after intracoronary administration of 17β-estradiol (+8±2% and +9±3%, respectively;
P
<.01 before versus after estrogen). Acetylcholine 1.6 and 16 μg/min increased coronary blood flow before and after the infusion of 17β-estradiol. However, the mean acetylcholine-induced increases in coronary flow were significantly greater (
P
<.009) after (126±37% and 248±89%, respectively) than before (94±31% and 143±49% mL/min, respectively) the administration of 17β-estradiol. 17β-Estradiol alone had no significant effect on coronary diameter or coronary blood flow (
P
>.05). Isosorbide dinitrate (1 mg) caused dilatation of the coronary arteries by 11±2% (
P
<.005). In men, acetylcholine 1.6 and 16 μg/min caused constriction both before and after the administration of 17β-estradiol and caused similar increases in coronary blood flow both before and after the intracoronary administration of 17β-estradiol. Infusion of intracoronary placebo in six female control patients 55±3 years old and six male control patients 56±3 years old did not change coronary diameter responses or coronary blood flow responses to acetylcholine.

Conclusions
17β-Estradiol modulates acetylcholine-induced coronary artery responses of female but not male atherosclerotic coronary arteries in vivo. These human data confirm reports from studies in cynomolgus monkeys that estrogen modulates the responses of atherosclerotic coronary arteries. An enhancement of endothelium-dependent relaxation by natural estrogen (as used in most hormone replacement therapy) may be important in postmenopausal women with established coronary heart disease and may contribute to the acute effect of 17β-estradiol on blood flow and its long-term protective effect on the development of coronary artery disease.