CENTRAL NEURONAL ANGIOTENSIN RECEPTORS IN REGULATION OF CARDIOVASCULAR FUNCTION

中枢神经元血管紧张素受体调节心血管功能

• 批准号: 6564794
• 负责人: Curt Daniel Sigmund
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564794
• 关键词: angiotensin II; angiotensin receptor; baroreceptors; blood pressure; cardiovascular function; gene targeting; genetically modified animals; hormone regulation /control mechanism; hypertension; laboratory mouse; neuroregulation; receptor expression; renin angiotensin system; vascular smooth muscle

In addition to its classical role as an endocrine system, the renin- angiotensin system (RAS) exists in a number of individual tissues, resulting in the local synthesis, release, and action of angiotensin II (ANG-II). The RAS in the brain through the activation of AT1 receptors has been hypothesized to contribute to the regulation of cardiovascular (CV) function through its effects on central sympathetic nerve outflow and on secretion of vasoactive pituitary hormones including vasopressin, and may play a role in the pathogenesis of both experimental and genetic hypertension. Although the importance of the brain RAS in regulating normal and pathophysiological CV responses have been implicated in studies utilizing targeted application of lesions and pharmacological agents, the relative effect on blood pressure (BP) of stimulating central neural and peripheral vascular AT1 receptor remains unclear. Therefore, the purpose of this proposal is to test the hypotheses that 1) the RAS in the brain, through the action of ANG-II at neuronal AT1 receptors localized in several CV control centers, in an important determinant in the regulation of BP, heart rate (HR), sympathetic outflow, and baroreceptor reflex function under normal conditions and in hypertension, 2) CNS responses to ANG-II are differentially mediated by AT1 subtype-A and subtype-B receptors which exhibit differential localization in the brain, and 3) over expression of AT1 receptors in the brain may be involved in the pathogenesis of hypertension. We will test these hypothesis by performing integrative cardiovascular physiology, pharmacology and molecular biology in transgenic and gene-targeted ("knockout") mice. We will take advantage of AT1A and AT1B deficient mice as genetic tools to examine the CV consequences of the loss of one AT1 receptor subtype versus the other. Moreover, we will combine the use of strong highly-specific promoters to target AT1 receptor expression to neurons in the CNS and to smooth muscle cells (SMC) in the vasculature with the AT1 receptor deficient mice in order to selectively complement (genetically replace) AT1 receptors in a cell-specific fashion. These studies will provide important information on the differential contribution of neuronal and vascular AT1A and AT1B receptors in mediating central CV responses to ANG-II.

除了其作为内分泌系统的经典作用外，肾素 - 血管紧张素系统（RAS）存在于许多单个组织中， 导致血管紧张素II的局部合成，释放和作用 （ang-ii）。通过AT1受体的激活，大脑中的Ras具有 假设有助于对心血管的调节（CV） 通过对中央交感神经流出以及效果的作用 血管活性垂体激素在内的分泌，包括加压素，5月 在实验和遗传的发病机理中起作用 高血压。虽然大脑RAS在调节中的重要性 正常和病理生理简历反应与研究有关 利用针对性的病变和药理学剂的靶向应用， 刺激中心神经和血压的相对影响（BP） 周围血管AT1受体尚不清楚。因此，目的 该建议的是测试假设1）大脑中的Ras， 通过ANG-II在神经元AT1受体上的作用 在调节中的重要决定因素中，几个简历控制中心 BP，心率（HR），交感神经流出和压力感受器反射 在正常条件下和高血压下的功能，2）CNS对 ANG-II通过AT1亚型A和亚型B差异介导 在大脑中表现出差异定位的受体，3） 大脑中AT1受体的表达可能参与 高血压的发病机理。我们将通过执行这些假设来检验这些假设 综合心血管生理学，药理学和分子生物学 在转基因和靶向基因的小鼠中。我们将利用 AT1A和AT1B缺乏小鼠作为检查CV的遗传工具 一个AT1受体亚型与另一个AT1受体亚型丧失的后果。 此外，我们将结合使用强大的高度特异性启动子的使用 将AT1受体表达靶向中枢神经系统的神经元和平滑肌 脉管系统中的细胞（SMC），AT1受体缺乏小鼠 为了选择性补体（遗传替代）AT1受体 特定于细胞的时尚。这些研究将提供有关的重要信息 神经元和血管AT1A和AT1B的差异贡献 介导中央简历反应的受体对ANG-II。