Premarin-induced increases in coronary and uterine blood flow in nonpregnant sheep

OBJECTIVE: Menopause is associated with an increased incidence of cardiovascular disease among women, and estrogen replacement therapy is thought to reduce the risk of coronary artery disease. The mechanism by which this occurs is unclear, but coronary arterial endothelial and vascular smooth muscle cells have been shown to contain estrogen receptors, and their stimulation appears to increase nitric oxide synthesis. One conjugated estrogen preparation (Premarin) is widely used in postmenopausal hormone replacement therapy, but little is known about its effects on cardiovascular hemodynamics. STUDY DESIGN: This study was designed to determine whether Premarin, like 17 beta-estradiol, has significant effects on cardiac output and coronary and uterine blood flows at doses used clinically (0.625, 1.25, and 2.5 mg). Nonpregnant oophorectomized sheep were implanted with instruments to measure cardiac output, left coronary (circumflex) artery blood flow, uterine blood flow, heart rate, and systemic arterial blood pressure. After recovery from surgery, the animals received intravenous bolus injections of either 17 beta-estradiol (1.0 mu g/kg), Premarin (0.625, 1.25, or 2.5 mg), or vehicle on different days. RESULTS: The 1.0-mu g/kg dose of 17 beta-estradiol significantly increased coronary blood flow by 15% +/- 2% from baseline (mean +/- SEM). Premarin also increased coronary blood flow significantly at the 1.25- and 2.5-mg dose levels by 12% +/- 3% and 14% +/- 4%, respectively. As expected 17 beta-estradiol increased uterine blood flow from a baseline of 15 +/- 3 mL/min to 169 +/- 19 mL/min. Premarin treatment was associated with a significant increase in uterine blood flow, which increased from an average baseline of 14 +/- 4 mL/min to 46 +/- 10 mL/min, 95 +/- 18 mL/min, and 135 +/- 20 mL/min at the three doses tested (0.625, 1.25, and 2.5 mg, respectively). 17 beta-Estradiol also increased cardiac output by 12% +/- 3%. Premarin increased cardiac output 2% +/- 3%, 9% +/- 4%, and 11% +/- 3%, with only the highest dose producing a significant change. 17 beta-Estradiol also increased heart rate by 12% +/- 1%, whereas Premarin at doses of 0.625, 1.25, and 2.5 mg increased it by 4% +/- 3%, 7% +/- 4%, and 10% +/- 2%, respectively (increase significant only at the highest dose). Neither 17 beta-estradiol nor Premarin altered either stroke volume or systemic arterial pressure. CONCLUSION: Premarin, like 17 beta-estradiol, has significant systemic, coronary, and uterine vascular effects, These vascular effects may help to explain in part why these compounds are cardioprotective.