RESUMO
Estrogens are known to contribute to endothelial function and sympathetic activity, both of which are strongly associated with the pathogenesis of ischemic heart disease. In addition, estrogens improve impaired lipid profile, a risk factor of endothelial dysfunction. In this study, we investigated the effects of OS-0544, a structurally new selective estrogen receptor modulator (SERM), on endothelial function, sympathetic activity, and plasma cholesterol level in ovariectomized (OVX) rats. Female Sprague-Dawley rats were ovariectomized and orally treated with OS-0544 (or OS-0689, the (R)-enantiomer of OS-0544), or 17beta-estradiol (E2) for 4 weeks, starting the next days after ovariectomy or for 1 week, starting 6 weeks after ovariectomy. Ovariectomy significantly increased vasopressin-induced mean blood pressure (AVP-MBP) (57+/-3.3 mm Hg vs. 46+/-3.5 mm Hg, P<0.05) and decreased acetylcholine (Ach)-induced maximum vasorelaxation response (69+/-5.6% vs. 81+/-4.0%, P<0.05). OS-0544 significantly inhibited AVP-MBP elevation (46+/-3.5 mm Hg vs. 57+/-3.3 mm Hg, P<0.05) and decreased Ach-induced maximum vasorelaxation response (90+/-3.3% vs. 69+/-5.6%, P<0.05) in OVX rats. In addition, OS-0689 as well as E2 significantly reduced (up to 67%) the increase in sympathetic activity in OVX rats. Moreover, like E2, OS-0544 significantly decreased plasma cholesterol level in OVX rats. These results demonstrate that OS-0544 has vascular protective effect on vascular function after ovariectomy. It is therefore believed that OS-0544 has vascular protective effect in postmenopausal woman.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Indanos/farmacologia , Ovariectomia , Piperidinas/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Compostos de Espiro/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Colesterol/sangue , Feminino , Ratos , Ratos Sprague-Dawley , Sistema Nervoso Simpático/fisiologia , Vasodilatação/efeitos dos fármacos , Vasopressinas/farmacologiaRESUMO
In the structure-activity relationships of spiro[indene-1,1'-indane] series, the 4-(4-alkylpiperazin-1-yl)phenyl group was found to be functionally equipotent to the 4-(1-piperidinoethoxy)phenyl group, the most widely used basic side chain in selective estrogen receptor modulators.
Assuntos
Alcanos/síntese química , Alcanos/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Receptores de Estrogênio/antagonistas & inibidores , Alcanos/química , Animais , Colesterol/sangue , Feminino , Humanos , Cinética , Modelos Moleculares , Conformação Molecular , Piperazinas/química , Ratos , Relação Estrutura-Atividade , Útero/efeitos dos fármacos , Útero/fisiologiaRESUMO
In our studies of the development of a novel class of selective estrogen receptor modulators, (+)-3-[4-(1-piperidinoethoxy)phenyl]spiro[indene-1,1'-indane]-5,5'-diol hydrochloride (1) was found to be an estrogen receptor ligand with beneficial effects in rat models for human hot flush. Moreover, 1 was found to have beneficial effects on lipid and bone metabolism while maintaining marginal effects on the uterus and breasts. These findings suggest that 1 would provide a new treatment for hot flush.
