Mechanisms of Alcohol-Estrogen Hemodynamic Interaction

酒精-雌激素血流动力学相互作用的机制

• 批准号: 7046143
• 负责人: ABDEL A ABDEL-RAHMAN
• 金额: $ 33.05万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046143
• 关键词: alcohols; baroreflex; biological signal transduction; blood pressure; calmodulin; caveolins; endotoxins; enzyme activity; estrogens; female; gender difference; gene expression; hemodynamics; hypotension; immunocytochemistry; intermolecular interaction; isozymes; laboratory rat; muscle cells; neurons; nitric oxide; nitric oxide synthase; solitary tract nucleus; telemetry

DESCRIPTION (provided by applicant): Alcohol elicits unique cardiovascular responses in the female population that are not only different from those seen in males but are also significantly influenced by the ovarian hormones, particularly estrogen. The objective of this proposal is to elucidate the molecular mechanisms implicated in the estrogen-dependent hemodynamic responses elicited by ethanol in female rats. Given the remarkable resemblance of the estrogen-dependent hemodynamic responses elicited by ethanol to the manifestations associated with mild endotoxicemia, we hypothesize that the NOS-NO signaling pathway plays a pivotal role in these responses. To test this hypothesis, we propose to conduct a series of integrative, signal transduction and gene expression studies under three aims. Aim 1 tests the hypothesis that activation of the vascular and/or cardiac nitric oxide synthases (NOS) mediates the estrogen-dependent hypotension and myocardial depression caused by acute alcohol in female rats. Since increased production of NO in the nucleus tractus solitarius (NTS) elicits hypotension, aim 2 studies will test the hypothesis that overproduction of NOS-derived NO in the NTS caused by additive or synergistic ethanol-estrogen interaction is implicated in the hypotensive and baroreflex depressant effects of acute ethanol in female rats. Aim 3 studies will identify the cellular mechanisms implicated in the chronic estrogen-dependent hypotensive and baroreflex depressant effects of ethanol in a model of surgical menopause. The proposal adopts a well-designed experimental approach that incorporates an established animal model, appropriate controls, and pharmacological interventions to: (i) establish a causal relationship between the up-regulation of NOS-derived NO in peripheral cells (myocyte and vascular smooth muscle) and neurons (NTS) and the estrogen-dependent cardiovascular effects of ethanol, and (ii) identify the molecular mechanisms implicated in the actions of ethanol, estrogen and their combination on NOS-NO signaling. The proposed research, whose primary focus is to probe the molecular mechanisms of estrogen-dependent hemodynamic effects of ethanol, addresses in a timely manner a significant biomedical problem and is expected to yield clinically relevant information.

描述（由申请人提供）：酒精会在女性群体中引发独特的心血管反应，这些反应不仅与男性不同，而且还受到卵巢激素（尤其是雌激素）的显着影响。该提案的目的是阐明雌性大鼠中乙醇引起的雌激素依赖性血流动力学反应所涉及的分子机制。鉴于乙醇引起的雌激素依赖性血流动力学反应与轻度内毒素血症相关的表现非常相似，我们推测 NOS-NO 信号通路在这些反应中发挥着关键作用。为了检验这一假设，我们建议在三个目标下进行一系列综合、信号转导和基因表达研究。目标 1 检验以下假设：血管和/或心脏一氧化氮合酶 (NOS) 的激活介导雌性大鼠急性酒精引起的雌激素依赖性低血压和心肌抑制。由于孤束核 (NTS) 中 NO 的产生增加会引起低血压，因此目标 2 研究将检验这样的假设：由加性或协同的乙醇-雌激素相互作用引起的 NTS 中 NOS 衍生的 NO 过量产生与急性乙醇对雌性大鼠的降血压和压力反射抑制作用有关。目标 3 研究将确定手术绝经模型中乙醇的慢性雌激素依赖性低血压和压力感受反射抑制作用所涉及的细胞机制。该提案采用精心设计的实验方法，结合了已建立的动物模型、适当的对照和药理学干预措施，以：(i) 建立外周细胞（心肌细胞和血管平滑肌）和神经元 (NTS) 中 NOS 衍生的 NO 上调与乙醇雌激素依赖性心血管效应之间的因果关系，以及 (ii) 确定分子机制 涉及乙醇、雌激素及其组合对 NOS-NO 信号传导的作用。该研究的主要重点是探讨乙醇雌激素依赖性血流动力学效应的分子机制，及时解决了一个重大的生物医学问题，并有望产生临床相关信息。