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This Article Full Text Full Text (PDF) All Versions of this Article: 290/1/H295    most recent 00468.2005v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Mishra, R. G. Articles by Hermsmeyer, R. K. Search for Related Content PubMed PubMed Citation Articles by Mishra, R. G. Articles by Hermsmeyer, R. K.

Metabolite ligands of estrogen receptor- reduce primate coronary hyperreactivity

¹Dimera, Incorporated, and ³Oregon Health and Science University, Portland, Oregon; ²University of Southern California, Los Angeles, California; ⁴University of Alabama Birmingham, Birmingham, Alabama; and ⁵University of Illinois Urbana-Champaign, Urbana, Illinois

Submitted 9 May 2005 ; accepted in final form 24 August 2005

Previous reports showed that 17-estradiol implants attenuate in vivo coronary hyperreactivity (CH), characterized by long-duration vasoconstrictions (in coronary angiographic experiments), in menopausal rhesus monkeys. Prolonged Ca²⁺ contraction signals that correspond with CH in coronary vascular muscle cells (VMC) to the same dual-constrictor stimulus, serotonin + the thromboxane analog U-46619, in estrogen-deprived VMC were suppressed by >72 h in 17-estradiol. The purpose of this study was to test whether an endogenous estrogen metabolite with estrogen receptor- (ER-) binding activity, estriol (E₃), suppresses in vivo and in vitro CH. E₃ treatment in vivo for 4 wk significantly attenuated the angiographically evaluated vasoconstrictor response to intracoronary serotonin + U-46619 challenge. In vitro treatment of rhesus coronary VMC for >72 h with nanomolar E₃ attenuated late Ca²⁺ signals. This reduction of late Ca²⁺ signals also appeared after >72 h of treatment with subnanomolar 5-androstane-3,17-diol (3-Adiol), an endogenous dihydrotestosterone metabolite with ER- binding activity. R,R-tetrahydrochrysene, a selective ER- antagonist, significantly blocked the E₃- and 3-Adiol-mediated attenuation of late Ca²⁺ signal increases. ER- and thromboxane-prostanoid receptor (TPR) were coexpressed in coronary arteries and aorta. In vivo E₃ treatment attenuated aortic TPR expression. Furthermore, in vitro treatment with E₃ or 3-Adiol downregulated TPR expression in VMC, which was blocked for both agonists by pretreatment with R,R-tetrahydrochrysene. E₃- and 3-Adiol-mediated reduction in persistent Ca²⁺ signals is associated with ER--mediated attenuation of TPR expression and may partly explain estrogen benefits in coronary vascular muscle.

menopause; calcium; thromboxane-prostanoid receptor; angiography

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