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This Article Full Text Full Text (PDF) All Versions of this Article: 291/3/H1216    most recent 00666.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zoma, W. D. Articles by Clark, K. E. Search for Related Content PubMed PubMed Citation Articles by Zoma, W. D. Articles by Clark, K. E.

Hemodynamic effects of acute and repeated exposure to raloxifene in ovariectomized sheep

Divisions of ²Maternal-Fetal Medicine and ¹Reproductive Endocrinology, Department of Obstetrics and Gynecology, College of Medicine, University of Cincinnati, Cincinnati, Ohio

Submitted 20 June 2005 ; accepted in final form 27 February 2006

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-17 (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-17 (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 ER and ER 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-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 ER and ER mRNA are present in both ovine coronary and uterine vessels. Hence, the hemodynamic effects of raloxifene are dose dependent, sustainable, and estrogen receptor mediated.

raloxifene; uterine; coronary; blood flow; estrogen receptor