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Objective This study was undertaken to determine whether Viagra (Pfizer, New York, NY), a type 5 phosphodiesterase (PDE-5) inhibitor, increases baseline coronary and uterine blood flow or potentiates estrogen-induced increases in blood flow. Study design Seven nonpregnant ovariectomized ewes were chronically instrumented to measure blood pressure, heart rate, cardiac output, and coronary and uterine blood flow. Estradiol-17β (E2, 0.3 μg/kg) (Sigma Chemical Co, St Louis, Mo) and Viagra (50 mg) were intravenously administered separately or together and hemodynamic responses monitored. Results Viagra alone rapidly decreased mean arterial pressure and cardiac output while increasing heart rate and uterine blood flow. Viagra tended to decrease coronary blood flow but not significantly. E2 by itself increased coronary and uterine blood flow over a 2-hour time course, whereas mean arterial pressure, cardiac output, and heart rate remained unchanged. Administration of E2 to animals pretreated with Viagra reversed Viagra-related decrease in cardiac output and coronary blood flow, resulting in a time-related increase in both parameters over baseline values. Viagra significantly augmented estradiol-related increases in uterine blood flow. Conclusion In our surgically menopausal ovine model, Viagra alone has a tendency to decrease baseline coronary blood flow, but the reduction does not reach statistical significance. The presence of estradiol reverses this Viagra-related negative trend and results in a net increase in coronary blood flow and cardiac output. Furthermore, Viagra significantly augments baseline and estrogen-induced increases in uterine blood flow suggesting the presence of PDE-5 in the ovine uterine vasculature.

Objective: Hormone replacement therapy has been implicated in the increased incidence of breast cancer, although selective estrogen receptor modulators have been shown to be effective in the prevention of breast cancer. Breast cancers are associated with increased mammary blood flow compared to benign breast lesions. However, few studies have examined the hemodynamic effects of hormonal agents on the mammary circulation that promote or reduce the risk of breast cancers. Although estradiol-17β has been shown to increase mammary blood flow, the effect of selective estrogen receptor modulators remains undetermined. We therefore compared the vascular effects of selective estrogen receptor modulators and estrogens on mammary blood flow. Study Design: Fourteen nonpregnant ovariectomized ewes were instrumented to measure mean arterial pressure, heart rate, and uterine and mammary blood flows. Compounds were administered intravenously on separate days, and responses were monitored up to 4 hours. Compounds that were studied included estradiol-17β (1 μg/kg), conjugated equine estrogens (0.625 and 1.25 mg), tibolone (2.5 and 5 mg), raloxifene (10 μg/kg), and tamoxifen (300 μg/kg). Results: None of these compounds significantly affected mean arterial pressure or heart rate, but all of the compounds significantly increased uterine blood flow. Estradiol-17β increased mammary blood flow by 98% ± 25%; conjugated equine estrogen increased mammary blood flow by 46% ± 6% and 68% ± 13% at the 0.625 and 1.25 mg doses, respectively. Tibolone increased mammary blood flow by 37% ± 13% at the 2.5-mg dose and by only 14% ± 4% at the 5-mg dose. Neither raloxifene nor tamoxifen significantly altered mammary blood flow. Conclusion: Although estrogens and selective estrogen receptor modulators induced similar increases in uterine blood flow, they had differential effects on mammary blood flow. (Am J Obstet Gynecol 2002;187:1555-60.)

Objective: We sought to determine the hemodynamic effects of tibolone in reproductive and nonreproductive tissues in the nonpregnant ovariectomized sheep. Study Design: Six ewes were chronically instrumented for measurement of mean arterial pressure, heart rate, cardiac output, and coronary and uterine blood flow. A dose response curve was generated for intravenous tibolone (1.25, 2.5, and 5 mg) and compared with intravenous 17β-estradiol (1 μg/kg body weight). To determine whether tibolone-related cardiovascular responses were estrogen receptor mediated and produced by nitric oxide, animals were treated on separate days with either estrogen receptor antagonist ICI 182,780 or the nitric oxide synthase inhibitor, L -nitroarginine methyl ester. Results: Tibolone significantly increased coronary blood flow in a dose-related fashion by 5% ± 3%, 9% ± 2%, and 11% ± 2% for the 1.25, 2.5, and 5 mg doses, respectively. Uterine blood flow was also increased significantly in a dose-dependent manner by 98 ± 15, 216 ± 59, and 303 ± 56 mL/min, for the 1.25, 2.5, and 5 mg doses, respectively. L -Nitroarginine methyl ester attenuated tibolone-induced increases in uterine blood flow by 84% ± 4% and abolished the increase in coronary blood flow. ICI 182,780 inhibited all tibolone-induced cardiovascular responses. Conclusion: Tibolone significantly increases coronary and uterine blood flow in ovariectomized ewes. The coronary and uterine vascular responses are mediated via an estrogen receptor–dependent mechanism and are produced mainly by nitric oxide. (Am J Obstet Gynecol 2001;184:544-51.)

Objective: We sought to determine whether raloxifene increases coronary and uterine blood flow in ovariectomized ewes. Study Design: Twelve ewes were chronically instrumented for measurement of mean arterial pressure, heart rate, cardiac output, coronary blood flow, and uterine blood flow. Sheep received 17β-estradiol, Estrace, raloxifene, or KY Jelly vehicle on separate days. Results: 17β-Estradiol increased uterine blood flow from 21 ± 3 to 254 ± 36 mL/min and coronary blood flow by 21% ± 2% within 2 hours. Estrace increased uterine blood flow from 30 ± 7 to 260 ± 62 mL/min and coronary blood flow by 8% ± 4% within 3 hours. Raloxifene increased uterine blood flow from 20 ± 3 mL/min to 220 ± 53 mL/min by 6 hours and coronary blood flow by 22% ± 5% within 24 hours. To determine whether hemodynamic responses were mediated by nitric oxide, L -nitroarginine methyl ester was administered and produced an approximate 50% decrease in uterine blood flow for all 3 compounds. L -Nitroarginine methyl ester attenuated increases in coronary blood flow induced by 17β-estradiol, Estrace, and raloxifene. Conclusion: Raloxifene has significant coronary and uterine vascular effects in the ovariectomized ewe. The coronary and uterine responses are partially mediated by nitric oxide. (Am J Obstet Gynecol 2000;182:521-8.)

We hypothesize that administration of acute and daily doses of raloxifene will have significant effects on ovine coronary and uterine hemodynamics and that these changes are estrogen receptor dependent. Eleven ovariectomized sheep were instrumented to measure mean arterial pressure, heart rate (HR), cardiac output (CO), and coronary (CBF) and uterine artery blood flows (UBF). A dose-response curve was generated for raloxifene (1, 3, and 10 μg/kg) and compared with a standard dose of estradiol-17β (1 μg/kg) given intravenously. In a second group of animals, raloxifene (10 μg·kg−1·day−1) was administered intravenously for 14 consecutive days, and cardiovascular responses were compared with a group of animals administered estradiol-17β (10 μg/kg) daily for the same period. To determine whether raloxifene-related vascular responses were estrogen receptor (ER) mediated, the animals were pretreated with estrogen antagonist ICI-182,780 given intravenously. Finally, RT-PCR was preformed to determine the presence of ERα and ERβ mRNA in ovine coronary and uterine vessels. Raloxifene increased CBF and UBF dose dependently with a parallel decrease in the associated vascular resistances. Acute cardiovascular responses to daily doses of raloxifene and estradiol-17β were sustainable. In contrast to estradiol-17β, which significantly increases CO by increasing HR but not stroke volume, raloxifene significantly increased stroke volume without a significant parallel increase in HR. ICI-182,780 abolished raloxifene-induced hemodynamic responses, and ERα and ERβ mRNA are present in both ovine coronary and uterine vessels. Hence, the hemodynamic effects of raloxifene are dose dependent, sustainable, and estrogen receptor mediated.