Hypothesis: 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. Study Design: Eleven ovariectomized sheep were instrumented to measure mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), coronary (CBF) and uterine artery blood flows (UBF). A dose-response curve was generated for raloxifene (1, 3 and 10 µg/kg) and compared to a standard dose of estradiol-17 (1 µg/kg) given intravenously (I.V.). In a second group of animals, raloxifene (10 µg/kg/day) was administered I.V. for 14 consecutive days and cardiovascular responses compared to a group of animals administered estradiol-17 (10 µg/kg) daily for the same period. To determine whether raloxifene-related vascular responses were estrogen receptors (ER) mediated, the animals were pretreated with estrogen antagonist ICI-182,780 given I.V. Finally, RT-PCR was preformed to determine the presence of ER and ER mRNA in ovine coronary and uterine vessels. Results: Raloxifene increased CBF and UBF dose-dependently with parallel decrease in the associated vascular resistances. Acute cardiovascular responses to daily doses of raloxifene and estradiol-17 were sustainable. In contrast to estradiol-17 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 ERand ER mRNA are present in both ovine coronary and uterine vessels. Conclusion: The hemodynamic effects of raloxifene are dose-dependent, sustainable and estrogen receptor mediated.