Bazedoxifene-induced vasodilation and inhibition of vasoconstriction is significantly greater than estradiol.
Bazedoxifene-induced vasodilation and inhibition of vasoconstriction is significantly greater than estradiol.
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DOI：
10.1097/gme.0000000000001195
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Lindsey SH
中科院分区：
文献类型：
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作者：
Zimmerman MA;Hutson DD;Mauvais-Jarvis F;Lindsey SH
绝经期激素治疗的一种新策略是用选择性雌激素受体调节剂苯多昔芬代替甲羟孕酮。虽然已在其他组织中检查了巴多昔芬的激动剂或拮抗剂活性，但本研究探讨了巴多昔芬对阻力动脉反应性的影响。我们推测，由于G蛋白偶联雌激素受体的激活增强，巴多昔芬可能比雌二醇诱导更大的血管保护作用。我们测量了成年雄性和雌性野生型和G蛋白偶联雌激素受体敲除小鼠（N=58）肠系膜阻力动脉的血管舒张反应，以增加巴多昔芬，甲羟孕酮和雌二醇的浓度，以及这些化合物对苯丙氨酸和硝普钠的反应的影响。巴多昔芬诱导的血管舒张作用大于雌二醇，并减弱了苯肾上腺素诱导的收缩，而雌二醇未观察到这种作用。雌二醇和巴多昔芬均未改变硝普钠的舒张作用。巴多昔芬+雌二醇的组合比甲羟孕酮+雌二醇促进更大的血管舒张，并对抗苯肾上腺素诱导的收缩，而甲羟孕酮+雌二醇未能减弱这种反应。巴多昔芬+雌二醇和甲羟孕酮+雌二醇均能增强女性硝普钠诱导的舒张作用。在野生型和G蛋白偶联雌激素受体敲除小鼠中，两种性别的血管反应相似。巴多昔芬和巴多昔芬+雌二醇松弛肠系膜动脉，并在更大程度上对抗血管收缩，而不是雌二醇或甲羟孕酮+雌二醇。这些影响是独立的性别和G蛋白偶联雌激素受体的表达。我们的结论是，bazedoxifene可能提供血管的好处比雌激素单独或雌激素加孕激素组合在绝经后妇女。
A new strategy for menopausal hormone therapy replaces medroxyprogesterone with the selective estrogen receptor modulator bazedoxifene. While the agonist or antagonist activity of bazedoxifene has been examined in other tissues, the current study explored the impact of bazedoxifene on resistance artery reactivity. We hypothesized that bazedoxifene may induce greater vasoprotective effects than estradiol due to enhanced activation of the G protein-coupled estrogen receptor. We measured the vasodilation of mesenteric resistance arteries from adult male and female wildtype and G protein-coupled estrogen receptor knockout mice (N=58) in response to increasing concentrations of bazedoxifene, medroxyprogesterone, and estradiol as well as the impact of these compounds on the responses to phenylephrine and sodium nitroprusside. Bazedoxifene-induced vasorelaxation was greater than estradiol and blunted phenylephrine-induced contraction, an effect not observed with estradiol. Neither estradiol nor bazedoxifene altered relaxation to sodium nitroprusside. The combination of bazedoxifene + estradiol promoted greater vasodilation than medroxyprogesterone + estradiol and opposed phenylephrine-induced contraction, while medroxyprogesterone + estradiol failed to attenuate this response. Both bazedoxifene + estradiol and medroxyprogesterone + estradiol enhanced sodium nitroprusside-induced relaxation in females. Vascular responses were similar in both sexes in wildtype and G protein-coupled estrogen receptor knockout mice. Bazedoxifene and bazedoxifene + estradiol relaxed mesenteric arteries and opposed vasoconstriction to a greater degree than estradiol or medroxyprogesterone + estradiol. These effects were independent of sex and G protein-coupled estrogen receptor expression. We conclude that bazedoxifene may provide vascular benefits over estrogen alone or estrogen plus progestogen combinations in postmenopausal women.