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: 3471239
• 负责人: Debra I Diz
• 金额: $ 5.12万
• 依托单位: WAKE FOREST UNIVERSITY
• 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 1993-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3471239
• 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; pregnane compound; 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)神经元和通路被认为是 参与心血管(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 荷尔蒙。然而，除了在CNS内进行本地化之外， 要使Ang II被承认为NT，必须符合以下标准 MET：1)对生理刺激的反应释放；2) 识别合适的靶神经元中的受体；以及，3) 具有重要生理意义的反应的演示。这个 这项建议的目标是处理上述标准中的两项 通过：1)论证其解剖起源和药理作用 可饱和、高亲和力Ang II结合位点的特性 发现于背内侧延髓(DMM)和内侧 和迷走神经的颅外段(上文第2号)；以及， 2)将这些发现与简历回复的产生联系起来 DMM核团注射血管紧张素Ⅱ后， 生理上相关的剂量(上文第3号)。通过使用 灵敏、定量的“体外”放射自显影技术， 大鼠双侧迷走神经和迷走神经AngⅡ结合的特点 狗的密度，饱和度，亲和力， 迷走神经切断术前后的配体选择性、结节 神经节切除，吻侧孤束横断术 延髓。血管紧张素Ⅱ与血管紧张素转换酶结合的解剖学关系 DMM中的神经元和通路最初将在 通过相关的光镜水平：1)分布 血管紧张素转换酶II结合部位与细胞结构的细分 犬孤束核、最后区和背侧运动 迷走神经核团；2)血管紧张素转换酶II结合部位的模式。 含有P物质或合成酶的神经元和纤维 比如酪氨酸羟基酶。变化之间的关系 迷走神经去传入或去迷走神经后血管紧张素Ⅱ的结合 DMM的传出与血流动力学改变 微量注射飞托莫尔所产生的反应 血管紧张素转换酶II或血管紧张素转换酶拮抗剂进入这些区域将在 麻醉的和未麻醉的动物。密度的变化 和DMM和下丘脑Ang II结合部位的亲和力。 脑垂体区将在已知的动作后进行检查 导致脑脊液或血浆的慢性改变 这些研究将提供有关 特异性DMM神经元及其通路对血管紧张素Ⅱ的作用 该区域的结合部位，与NT-的结合关系 确定的系统，以及调节结合位点的因素。 最后，显微注射研究将提供对Ang II的洞察 心血管功能的调节及其与反射的相互作用 调节血压。