CATECHOLAMINE/ANGIOTENSIN II INTERACTIONS IN THE BRAIN

儿茶酚胺/血管紧张素 II 在大脑中的相互作用

• 批准号: 2263597
• 负责人: COLIN SUMNERS
• 金额: $ 21.28万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2263597
• 关键词: aldosterone; angiotensin II; brain cell; brain metabolism; brain stem; calcium flux; cyclic GMP; glucose transport; high performance liquid chromatography; hydrolysis; hypothalamus; inositol phosphates; laboratory rat; messenger RNA; neuropeptide receptor; neurotransmitter biosynthesis; neurotransmitter metabolism; norepinephrine; nucleic acid probes; phosphodiesterases; protein kinase C; radiotracer; receptor binding; receptor coupling; scintillation counter; tissue /cell culture

Angiotensin II (AII) acts at neuronal receptors in the hypothalamus and brainstem to stimulate numerous physiological effects including increased blood pressure, fluid intake and vasopressin secretion, and also possibly neurotrophic actions (either direct or by modulation of the effects of growth factors). The overall aim of this proposal is to investigate the characteristics, intracellular coupling, cellular functions and regulation of AII receptor subtypes in neurons cultured from rat hypothalamus and brainstem. These brain areas contain AT1- receptors (AT1-R) and AT2-receptors (AT2-R), and current knowledge of the cellular mechanisms mediated by these receptors in neurons, and also their regulation, is rudimentary. Our published studies, preliminary data and also the background literature are consistent with the following hypotheses: Neurons contain AT1-R which are coupled to a stimulation of inositol phospholipid (IP) hydrolysis, with subsequent Ca2+ mobilization and protein kinase C (PKC) activation. Further, these AT1-R mediate the effects of AII on a variety of cellular functions, including: (a) PKC-and Ca2+-dependent stimulation of norepinephrine (NE) synthesis, release and metabolism; (b) PKC-dependent increases in d- glucose transport into neurons, mediated via a cascade of events that includes stimulation of c-fos mRNA, c-fos, and glucose transporter 3 (Glut-3) mRNA. Neurons also contain AT2-R, which are coupled to increased Ca2+ entry, with subsequent activation of a phosphodiesterase (PDE) and a decrease in cGMP, but the cellular functions of these AT2-R are unknown. Lastly, modulators of neuronal AII receptors and responses (e.g., NE, aldosterone [ALDO] show selective regulatory effects for each neuronal AII receptor subtype. In the studies proposed here we plan to investigate each of the above hypotheses, and also determine the binding characteristics (levels/affinities) of each neuronal AII receptor subtype. The present studies are thus designed to investigate the cell physiology of AT1-R and AT2-R in neurons. The significance of the studies is that we will identify mechanisms (i.e., AII receptor subtype/intracellular event/cellular function/receptor regulation) which are involved in the physiological actions mediated by neuronal AII receptors. This fundamental information is for a full understanding of the CNS-mediated actions of AII on the cardiovascular system and fluid intake (both of which involve neuronal NE) and also neurotrophic effects of this peptide (which involve c-fos and d-glucose transport). In the long term this information will be valuable for determining the mechanism which underlie abnormalities in AII effects in the CNS, e.g., the increased expression and responsiveness of neuronal AII receptors which occur in certain forms of hypertension.

血管紧张素II（AII）作用于下丘脑中的神经元受体， 脑干刺激许多生理影响 升高血压，液体摄入和加压素分泌，以及 还可能采取神经营养作用（直接或通过调制 生长因素的影响）。 该提议的总体目的是 研究特征，细胞内耦合，细胞 培养的神经元中AII受体亚型的功能和调节 来自大鼠下丘脑和脑干。 这些大脑区域包含1- 受体（AT1-R）和AT2受体（AT2-R）以及当前的知识 这些受体在神经元中介导的细胞机制，也是 他们的监管是基本的。 我们发表的研究，初步 数据以及背景文献与 以下假设：神经元包含AT1-R，该神经元耦合到A 刺激肌醇磷脂（IP）水解，随后 Ca2+动员和蛋白激酶C（PKC）激活。 此外，这些 AT1-R介导AII对各种细胞功能的影响， 包括：（a）PKC-and Ca2+依赖性刺激去甲肾上腺素（NE） 合成，释放和代谢； （b）d-的PKC依赖性增加 葡萄糖转运到神经元中，通过一系列级联事件介导 包括刺激C-FOS mRNA，C-FOS和葡萄糖转运蛋白3 （Glut-3）mRNA。 神经元还包含AT2-R，它们耦合到 CA2+进入增加，随后激活磷酸二酯酶 （PDE）和CGMP的降低，但是这些AT2-R的细胞功能 是未知的。 最后，神经元AII受体和反应的调节剂 （例如，NE，醛固酮[Aldo]显示了每个的选择性调节作用 神经元AII受体亚型。 在这里提出的研究中，我们计划 研究上述每个假设，还确定结合 每个神经元AII受体的特征（水平/亲和力） 亚型。 因此，目前的研究旨在研究细胞生理 神经元中的AT1-R和AT2-R。 研究的意义是 我们将确定机制（即AII受体亚型/细胞内 事件/细胞功能/受体调节）与 神经元AII受体介导的生理作用。 这 基本信息是为了充分了解CNS介导的 AII对心血管系统和液体摄入的作用（这两个 涉及该肽的神经元NE）和神经营养作用 （涉及c-fos和D-葡萄糖运输）。 从长远来看 信息对于确定哪些机制很有价值 中枢神经系统中AII效应的基础，例如增加 发生的神经元AII受体的表达和反应性 某些形式的高血压。