CENTRAL NEURONAL ANGIOTENSIN RECEPTORS IN REGULATION OF CARDIOVASCULAR FUNCTION

除了作为内分泌系统的经典作用外，肾素- 血管紧张素系统(RAS)存在于许多单独的组织中， 导致血管紧张素II的局部合成、释放和作用 (Ang-II)。通过激活AT1受体，大脑中的RAS 被认为对心血管(CV)的调节有贡献 通过对中枢交感神经流出的影响而发挥作用 分泌血管活性垂体激素，包括加压素，并可能 在实验性和遗传性疾病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 正常和病理生理学的CV反应在研究中有牵连 利用靶向应用病变和药理药剂， 刺激中枢神经对血压的相对影响 外周血管AT1受体尚不清楚。因此，目的是 这一提议的目的是检验这样的假设：1)大脑中的RAS， 通过Ang-II在神经元AT1受体上的作用 几个CV控制中心，在调节中起着重要的决定作用 血压、心率、交感神经流出和压力感受器反射 正常情况下和高血压时的功能，2)中枢神经系统对 血管紧张素转换酶II受AT1亚型A和B亚型的差异调节 在大脑中表现出不同定位的受体，以及3) 脑内AT1受体的过度表达可能参与了 高血压的发病机制。我们将通过执行以下操作来验证这些假设 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(“基因敲除”)小鼠中。我们会利用这个优势 AT1a和AT1B基因缺陷小鼠作为遗传工具检查CV AT1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的启动子来 靶AT1受体在中枢神经系统神经元和平滑肌中的表达 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 细胞特有的时尚。这些研究将提供重要的信息 神经和血管AT1a和AT1B的不同贡献 介导血管紧张素Ⅱ中枢性心血管反应的受体。

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.