Mechanisms of Alcohol-Estrogen Hemodynamic Interaction

描述(申请人提供)：酒精在女性人群中引起独特的心血管反应，不仅不同于男性，而且还受到卵巢激素，特别是雌激素的显著影响。本研究的目的是阐明乙醇诱导雌性大鼠雌激素依赖性血流动力学反应的分子机制。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的表现非常相似，我们推测NOS-NO信号通路在这些反应中起着关键作用。为了验证这一假设，我们建议在三个目标下进行一系列整合的、信号转导和基因表达的研究。目的1验证血管和/或心脏一氧化氮合酶(NOS)激活介导雌性大鼠急性酒精所致的雌激素依赖性低血压和心肌抑制的假说。由于孤束核(NTS)中NO的产生增加会引起低血压，AIM 2研究将验证这样一种假设，即乙醇与雌激素的相加或协同作用导致NTS中一氧化氮合酶衍生的NO的过度产生与急性乙醇对雌性大鼠的降压和压力感受性反射抑制作用有关。目的3项研究将在外科绝经模型中确定乙醇的慢性雌激素依赖性降压和压力感受性反射抑制作用的细胞机制。该建议采用精心设计的实验方法，结合已建立的动物模型、适当的对照和药物干预，以：(I)建立外周细胞(肌细胞和血管平滑肌)和神经元(NTS)中NOS来源的NO上调与乙醇的雌激素依赖性心血管效应之间的因果关系，以及(Ii)确定乙醇、雌激素及其组合对NOS-NO信号转导的分子机制。这项拟议的研究主要集中在探索乙醇对雌激素依赖的血流动力学效应的分子机制，及时解决了一个重要的生物医学问题，并有望获得临床相关信息。

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.