Angiotensin Receptors in Central Osmonsensitivity

描述(申请人提供)：血管紧张素(Ang)AT1受体 在控制血压和水/电解质平衡方面至关重要。AT1 受体以两种形式存在，AT1a和AT1b，它们在基因和 蛋白质结构，使其无法从药理上加以区分。 基因工程技术已经产生了允许 基因/功能相互作用的研究。AT1a受体的移除出现 激活中枢血管紧张素受体，特别是在渗透敏感的大脑区域。 最终结果是血压和中枢神经系统的增强 神经内分泌对改变液体/电解质平衡的刺激的反应。我们 提出检验特定脑区血管紧张素受体的假设 在渗透平衡的调节中起关键作用。使用AT1 AKO模型，我们将 确定中枢神经系统变化的性质，重点放在 血管紧张素转换酶/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。对于活体研究，我们将 使用一种慢性心血管监测和采血的方法 清醒的老鼠。目的是确定血管紧张素转换酶受体在 渗透敏感性，研究血压、心率、多肽的调节 分泌和神经激活。中枢神经系统激活的标志物包括c-Fos、Ang 受体、血管紧张素受体基因和血管紧张素Ⅱ受体基因。细胞研究的目的是阐明 血管紧张素转换酶调节VP神经元渗透敏感性的机制。离体 研究将使用灌流的脑片来确定 渗透敏感性潜在的电生理特性。具体目标 1.血管紧张素转换酶1是否改变了渗透性多肽和心血管反应 亚子？这将解决急性或慢性渗透性的问题 刺激改变中枢和外周VP系统，即中枢MG 受体系统，以及心血管和体液平衡。实验将进一步 血管紧张素受体阻断和酶抑制对文献的影响 镁输入的范围和特异性。2.细胞机制是什么？ AT1aKO的潜在渗透敏感性？基本问题与自然有关 细胞的变化以及这些变化是否由内在机制介导。 3.中枢ANG系统与这些变化之间有什么关系 在渗透敏感性方面？这将解决以下问题： 对血管紧张素转换酶II或其他镁多肽的反应，以及这些反应是否在 渗透性反应。

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.