ANGIOTENSIN II BINDING SITES AND FUNCTION IN THE MEDULLA

血管紧张素 II 髓质中的结合位点和功能

• 批准号: 3471234
• 负责人: Debra I Diz
• 金额: $ 2.38万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3471234
• 关键词: afferent nerve; angiotensin /renin /aldosterone hypertension; angiotensin II; autoradiography; chemical binding; dogs; electron microscopy; hormone receptor; hormone regulation /control mechanism; laboratory rat; neuroanatomy; neuronal transport; neurons; neurotransmitters; solitary tract nucleus; tyrosine 3 monooxygenase; vagus nerve

The discovery that angiotensin II (Ang II) is present in central nervous system (CNS) neurons and pathways which are believed to be involved in cardiovascular (CV), fluid, and electrolyte regulation suggests that the peptide may function as a neurotransmitter (NT) or neuromodulator, as well as a circulating hormone. However, in addition to localization within the CNS, for Ang II to be recognized as a NT the following criteria must be met: 1) Release in response to physiological stimuli; 2) Identification of receptors in suitable target neurons; and, 3) Demonstration of physiologically significant responses. The objective of this proposal is to address two of the above criteria by: 1) demonstrating the anatomical origin and pharmacological characteristics of saturable, high affinity Ang II binding sites found in the dorsomedial medulla oblongata (DMM) and the intra- and extracranial segments of the vagus nerves (No. 2 above); and, 2) relating these findings to the production of CV responses following injection of Ang II into nuclei of the DMM at physiologically relevant doses (No. 3 above). By the use of the sensitive, quantitative "in vitro" autoradiography technique, characteristics of Ang II binding in the DMM and vagus nerve of dogs will be determined in terms of density, saturability, affinity, and ligand selectivity before and following vagotomy, nodose ganglionectomy, and transection of the rostral solitary tract in the medulla. The anatomical relationship of Ang II binding to neurons and pathways in the DMM will be examined initially at the light microscopic level by correlating: 1) the distribution of Ang II binding sites with cytoarchitectural subdivisions of the canine nucleus tractus solitarii, area postrema, and dorsal motor nucleus of the vagus; and, 2) the pattern of Ang II binding sites to neurons and fibers containing substance P, or synthetic enzymes such as tyroxine hydroxylase. The relationship between changes in Ang II binding following sino-vagal deafferentation or de- efferentation of the DMM and alterations in hemodynamic responses produced by microinjection of femtomole doses either Ang II or Ang II antagonists into these areas will be evaluated in both anesthetized and unanesthetized animals. Changes in density and affinity of Ang II binding sites in the DMM and hypothalamic- hypophysial region will be examined following maneuvers known to result in chronic alterations in cerebrospinal fluid or plasma Ang II. These studies will provide essential information about the contribution of specific DMM neurons and pathways to Ang II binding sites in this region, the relationship of binding with NT- identified systems, and factors which regulate the binding sites. Finally, microinjection studies will provide insights into Ang II's role in modulation of CV function and interaction with reflex regulation of blood pressure.

血管紧张素II（Ang II）存在于中枢神经系统， 神经系统（CNS）神经元和被认为 涉及心血管（CV）、体液和电解质 调节表明，该肽可能作为一种 神经递质（NT）或神经调质，以及循环神经递质（NT）或神经调质。 激素. 然而，除了中枢神经系统内的定位外， 血管紧张素II被认为是NT，必须符合以下标准： 满足：1）响应于生理刺激的释放; 2） 鉴定合适的靶神经元中的受体;以及，3） 证明生理上显著的反应。 的 本提案的目的是满足上述两项标准 通过：1）证明解剖学起源和药理学 可饱和的高亲和力血管紧张素II结合位点的特征 发现在延髓背内侧（DMM）和内- 和迷走神经的颅外段（上文第2段）;以及， 2)将这些发现与CV反应的产生联系起来， 在DMM的细胞核中注射Ang II后， 生理相关剂量（上文第3项）。 通过使用 灵敏、定量的“体外”放射自显影技术， DMM和迷走神经中Ang II结合的特征 将根据密度、饱和度、亲和力 迷走神经切断术前后的配体选择性， 神经节切除术，并切断吻侧孤束， 骨髓 血管紧张素Ⅱ结合的解剖关系， DMM中的神经元和通路将首先在 在光镜水平上，通过以下相关性：1） 血管紧张素Ⅱ结合位点与血管紧张素Ⅱ受体的细胞结构亚群 犬孤束核、最后区和背侧运动核 迷走神经核; 2）Ang II结合位点的模式， 含有P物质或合成酶的神经元和纤维 如酪氨酸羟化酶。 变化关系 在窦迷走神经传入阻滞或去 DMM的输出和血流动力学的改变 微注射飞摩尔剂量产生的反应， 血管紧张素II或血管紧张素II拮抗剂进入这些领域将评估， 麻醉和未麻醉的动物。 密度变化 以及DMM和下丘脑中Ang II结合位点的亲和力， 垂体区将在已知的操作后进行检查 导致脑脊液或血浆的慢性改变 Ang II. 这些研究将提供有关 特定DMM神经元和通路对Ang II的贡献 结合位点，与NT- 确定的系统，和调节结合位点的因素。 最后，显微注射研究将提供深入了解血管紧张素II的 在CV功能调节中的作用以及与反射的相互作用 调节血压。