Angiotensin Receptors in Central Osmonsensitivity

描述（由申请人提供）：血管紧张素（Ang）AT1受体是 对控制血压和体液/电解质平衡至关重要。AT1 受体以两种形式存在，AT 1a和AT 1b，它们在基因上是同源的， 蛋白质结构，使其无法区分蛋白质。 基因工程技术已经产生了模型， 研究基因/功能相互作用。AT1a受体的去除似乎 激活中央血管紧张素受体，特别是在对血管紧张素敏感的大脑区域。 最终结果是血压和中枢神经系统功能的增强。 神经内分泌对刺激的反应，改变液体/电解质平衡。我们 我建议测试这一假设，即特定脑区的血管紧张素受体是 对调节渗透平衡至关重要。使用AT1 aKO模型，我们将 确定中枢神经系统变化的性质，重点是 血管紧张素/血管加压素（VP）相互作用。这个问题将在一级得到解决 整个动物和。单个神经元。对于体内研究，我们将 使用慢性心血管监测和血液采样的方法， 有意识的老鼠目的是确定血管紧张素受体在 高敏感性，研究血压、心率、肽的调节 分泌和神经激活。CNS活化的标志物包括c-Fos、Ang 受体、血管紧张素受体mRNA和VP mRNA。细胞研究旨在阐明 血管紧张素调节VP神经元对ATP敏感性的机制。体外 研究将使用灌注的脑切片来确定 电生理学特性潜在的电刺激敏感性。具体目标 是：1. AT1是否改变了促肾上腺皮质激素诱导的肽和心血管反应 aKO？这将解决急性或慢性渗透性 刺激改变了中枢和外周VP系统，中枢Mg 受体系统，心血管和体液平衡。实验将进一步 测试Ang受体阻断和酶抑制的效果，以记录 Mg输入的程度和特异性。2.细胞机制是什么 AT 1aKO的潜在渗透敏感性？基本问题涉及到 以及这些变化是否由内在机制介导。 3.中央昂制与这些变更有什么关系 在灵敏度？这将解决以下问题： 血管紧张素II或其他镁肽的反应，以及这些是否在 渗透反应性

DESCRIPTION (provided by applicant): Angiotensin (Ang) AT1 receptors are critical in the control of blood pressure and fluid/electrolyte balance. AT1 receptors exist in two forms, AT1a and AT1b, which are homologous in gene and protein structure, making it impossible to distinguish pharmacologically. Genetic engineering techniques have produced models which allow for the investigation of gene/function interactions. Removal of AT1 a receptors appears to activate central Ang receptors, particularly in osmosensitive brain regions. The net result is an enhancement of the blood pressure and central neuroendocrine responses to stimuli which alter fluid/electrolyte balance. We propose to test the hypothesis that Ang receptors in specific brain regions are critical in the regulation of osmotic balance. Using the AT1 aKO model, we will determine the nature of the central nervous system changes with a focus on Ang/vasopressin (VP) interactions. The problem will be addressed at the level of the whole animal and. the individual neuron. For in vivo studies, we will use a method for chronic cardiovascular monitoring and blood sampling in the conscious mouse. The goal is to determine the role of Ang receptors in osmosensitivity, studying the regulation of blood pressure, heart rate, peptide secretion and neural activation. Markers for CNS activation include c-Fos, Ang receptors, Ang receptor mRNA and VP mRNA. Cellular studies aim at elucidating the mechanisms by which Ang modulates osmosensitivity in VP neurons. In vitro studies will use perfused brain slices for determination of electrophysiological properties underlying osmosensitivity. The specific aims are: 1. Are osmotic-induced peptide and cardiovascular responses altered in AT1 aKO? This will address the issue of whether acute or chronic osmotic stimulation alters the central and peripheral VP system, the central Mg receptor system, and cardiovascular and fluid balance. Experiments will further test the effect of Ang receptor blockade and enzymatic inhibition to document the extent and specificity of Mg input. 2. What are the cellular mechanisms underlying osmosensitivity in AT1aKO? The basic question relates to the nature of the cellular changes and whether these are mediated by intrinsic mechanisms. 3. What is the relationship between the central Ang system and the alterations in osmosensitivity? This will address the issue of whether there are changes in responses to Ang II or other Mg peptides and whether these are important in osmotic responsiveness.