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

OBJECTIVE: Menopause is associated with an increased incidence of cardiovas cular disease among women, and estrogen replacement therapy is thought to r educe the risk of coronary artery disease. The mechanism by which this occu rs 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 prepar ation (Premarin) is widely used in postmenopausal hormone replacement thera py, but little is known about its effects on cardiovascular hemodynamics. STUDY DESIGN: This study was designed to determine whether Premarin, like 1 7 beta-estradiol, has significant effects on cardiac output and coronary an d uterine blood flows at doses used clinically (0.625, 1.25, and 2.5 mg). N onpregnant oophorectomized sheep were implanted with instruments to measure cardiac output, left coronary (circumflex) artery blood flow, uterine bloo d flow, heart rate, and systemic arterial blood pressure. After recovery fr om 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 al so 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-est radiol increased uterine blood flow from a baseline of 15 +/- 3 mL/min to 1 69 +/- 19 mL/min. Premarin treatment was associated with a significant incr ease 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 a t the three doses tested (0.625, 1.25, and 2.5 mg, respectively). 17 beta-E stradiol also increased cardiac output by 12% +/- 3%. Premarin increased ca rdiac output 2% +/- 3%, 9% +/- 4%, and 11% +/- 3%, with only the highest do se producing a significant change. 17 beta-Estradiol also increased heart r ate by 12% +/- 1%, whereas Premarin at doses of 0.625, 1.25, and 2.5 mg inc reased it by 4% +/- 3%, 7% +/- 4%, and 10% +/- 2%, respectively (increase s ignificant only at the highest dose). Neither 17 beta-estradiol nor Premari n altered either stroke volume or systemic arterial pressure. CONCLUSION: Premarin, like 17 beta-estradiol, has significant systemic, cor onary, and uterine vascular effects, These vascular effects may help to exp lain in part why these compounds are cardioprotective.