HRT, SERMs and LEG BLOOD FLOW IN POSTMENOPAUSAL WOMEN

绝经后女性的 HRT、SERM 和腿部血流

• 批准号: 6881353
• 负责人: DOUGLAS R SEALS
• 金额: $ 37.22万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6881353
• 关键词: aging; cardiac output; cardiovascular disorder risk; clinical research; electrocardiography; estradiol; estrogen receptors; female; gas chromatography mass spectrometry; gene expression; homozygote; hormone therapy; human middle age (35-64); human subject; human therapy evaluation; leg; musculoskeletal circulation; photon absorptiometry; postmenopause; raloxifene; selective estrogen receptor modulators; sympathetic nervous system; transdermal drug delivery; vascular endothelium; vasodilation; women' s health

DESCRIPTION (provided by applicant): The purpose of this amended RO1 proposal is to re-establish funding for the research supported by our recently completed 2-year exploratory research grant (R21 AG19365) that was responsive to PA-00-056 "Skeletal Muscle Perfusion, Aging, and Cardiovascular Disease". Our R21 award work demonstrated that: 1) basal whole-leg blood flow (LBF) and vascular conductance (LVC) are 25-30% lower in men and women 65 years of age compared with young adult controls; and 2) the decreases in LBF and LVC are associated with increased tonic sympathetic nervous system (SNS) alpha-adrenergic vasoconstriction and reduced nitric oxide (NO) vasodilatory tone. Among postmenopausal women, however, those taking hormone replacement therapy (HRT) had greater LBF and LVC than their estrogen deficient peers. The primary working hypothesis of the present proposal is that HRT (transdermal estradiol) and/or a selective estrogen receptor modulator (SERM; raloxifene) will increase LBF in healthy previously estrogen deficient postmenopausal women by increasing LVC, with or without increasing systemic BF (cardiac output). Secondary hypotheses are: 1) the increases in LVC with HRT and SERM administration will be associated with an increased local vasodilatory state (increased NO bioavailability/reduced oxidative stress; decreased endothelin-1 lET-1] concentrations), and either unchanged or reduced SNS activity; and 2) the increases in LBF and LVC in response to HRT and a SERM will be greatest in women homozygous for the C allele of the estrogen receptor (ER)-a gene IVSI 401 polymorphism and least in women who are homozygous for the T allele. LBF, arterial blood pressure, LVC, cardiac output, muscle sympathetic nerve activity, plasma catecholamine concentrations, leg peak reactive hyperemia and VC, measures of local vasodilatory/vasoconstrictor influences (including flow-mediated dilation and vascular oxidative stress), and ER-alpha gene IVS1401 polymorphisms will be determined in healthy postmenopausal females before and during 2, 6, and 12 weeks of either HRT, SERM administration, or placebo control (randomized, double blind). Insight into the molecular mechanisms involved will be provided by a novel translational research approach in which eNOS, ET-1, and other protein expressions of interest will be determined from vascular endothelial cell "biopsies". All experimental protocols will be conducted in the UC-Boulder General Clinical Research Center. The results should provide new insight into the effects of HRT and a SERM for augmenting LBF and LVC in estrogen deficient postmenopausal women and the underlying physiological mechanisms.

描述（由申请人提供）：本修订后的 RO1 提案的目的是为我们最近完成的 2 年探索性研究补助金 (R21 AG19365) 支持的研究重新建立资金支持，该补助金响应 PA-00-056“骨骼肌灌注、衰老和心血管疾病”。我们的 R21 奖励工作表明：1) 与年轻成人对照组相比，65 岁男性和女性的基础全腿血流量 (LBF) 和血管电导率 (LVC) 降低 25-30%； 2) LBF 和 LVC 的降低与强直性交感神经系统 (SNS) α-肾上腺素能血管收缩的增加和一氧化氮 (NO) 血管舒张张力的降低有关。然而，在绝经后女性中，接受激素替代疗法 (HRT) 的女性的 LBF 和 LVC 高于雌激素缺乏的同龄人。本提案的主要工作假设是，HRT（透皮雌二醇）和/或选择性雌激素受体调节剂（SERM；雷洛昔芬）将通过增加 LVC 来增加先前缺乏雌激素的绝经后健康女性的 LBF，同时增加或不增加全身 BF（心脏功能）。输出）。次要假设是：1) HRT 和 SERM 给药引起的 LVC 增加将与局部血管舒张状态增加（NO 生物利用度增加/氧化应激减少；内皮素 1 [ET-1] 浓度降低）以及 SNS 不变或减少相关活动; 2) 响应 HRT 和 SERM 的 LBF 和 LVC 增加在雌激素受体 (ER)（基因 IVSI 401 多态性）的 C 等位基因纯合的女性中最大，而在 T 等位基因纯合的女性中最小。 LBF、动脉血压、LVC、心输出量、肌肉交感神经活动、血浆儿茶酚胺浓度、腿部峰值反应性充血和 VC、局部血管舒张/血管收缩影响的测量（包括血流介导的扩张和血管氧化应激）和 ER-α基因 IVS1401 多态性将在健康绝经后女性中在 HRT 之前和 2、6 和 12 周期间进行测定， SERM 给药或安慰剂对照（随机、双盲）。一种新颖的转化研究方法将深入了解所涉及的分子机制，其中 eNOS、ET-1 和其他感兴趣的蛋白质表达将从血管内皮细胞“活检”中确定。所有实验方案将在加州大学博尔德分校综合临床研究中心进行。这些结果将为了解 HRT 和 SERM 对雌激素缺乏的绝经后妇女增加 LBF 和 LVC 的影响及其潜在的生理机制提供新的见解。