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: 6415221
• 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: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6415221
• 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.

除了作为内分泌系统的经典作用外， 血管紧张素系统（RAS）存在于许多个体组织中， 导致血管紧张素II的局部合成、释放和作用 （ANG-II）。通过激活AT 1受体， 假设有助于调节心血管（CV） 通过其对中枢交感神经流出的影响和对 包括加压素在内的血管活性垂体激素的分泌， 在实验性和遗传性的发病机制中发挥作用 高血压虽然大脑RAS在调节 研究中涉及正常和病理生理CV反应 利用病变和药理学试剂的靶向应用， 刺激中枢神经系统对血压的相对影响， 外周血管AT 1受体尚不清楚。因此，目的 这项提议的目的是检验以下假设：1）大脑中的RAS， 通过ANG-II作用于神经元AT 1受体， 几个CV控制中心，在调节的重要决定因素 血压、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中的功能，2）CNS对 ANG-II由AT 1亚型A和亚型B差异介导 在脑中表现出差异定位的受体，和3） 脑内AT 1受体的过度表达可能参与了 高血压的发病机制我们将测试这些假设， 心血管生理学、药理学和分子生物学综合 在转基因和基因靶向（“敲除”）小鼠中。我们将利用 AT 1A和AT 1B缺陷小鼠作为遗传工具检查CV 一种AT 1受体亚型相对于另一种亚型的损失的后果。 此外，我们将联合收割机结合使用强高度特异性启动子， 将AT 1受体表达靶向CNS中的神经元和平滑肌 血管系统中的平滑肌细胞（SMC）与AT 1受体缺陷小鼠， 为了选择性地补充（遗传取代）AT 1受体， 细胞特异性方式。这些研究将提供重要信息， 神经元和血管AT 1A和AT 1B的不同贡献 受体介导中枢CV对ANG-II的反应。