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）。大脑中的 RAS 通过 AT1 受体的激活 被假设有助于心血管（CV）的调节 通过影响中枢交感神经流出和 分泌血管活性垂体激素，包括加压素，并且可能 在实验和遗传的发病机制中发挥作用 高血压。尽管大脑 RAS 在调节中的重要性 研究表明正常和病理生理的 CV 反应有关 利用针对病变部位和药物的针对性应用， 刺激中枢神经和血压对血压（BP）的相对影响 外周血管AT1受体尚不清楚。因此，目的 该提案的目的是测试以下假设：1) 大脑中的 RAS， 通过 ANG-II 对位于神经元 AT1 受体的作用 多个 CV 控制中心，是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 正常情况下和高血压情况下的功能，2）中枢神经系统对 ANG-II 由 AT1 A 亚型和 B 亚型差异介导 在大脑中表现出差异定位的受体，以及 3) 大脑中 AT1 受体的过度表达可能与 高血压的发病机制。我们将通过执行来测试这些假设 综合心血管生理学、药理学和分子生物学 在转基因和基因靶向（“敲除”）小鼠中。我们将利用 AT1A 和 AT1B 缺陷小鼠作为检查 CV 的遗传工具 一种 AT1 受体亚型相对于另一种受体亚型缺失的后果。 此外，我们将结合使用强大的高度特异性启动子 AT1 受体表达靶向中枢神经系统神经元和平滑肌 AT1受体缺陷小鼠血管系统中的细胞（SMC） 为了选择性地补充（基因替换）AT1受体 细胞特异性时尚。这些研究将提供重要信息 神经元和血管 AT1A 和 AT1B 的不同贡献 介导 ANG-II 中枢 CV 反应的受体。