BRAIN ANGIOTENSIN RECEPTOR FUNCTION CONTROL AND ANATOMY

脑血管紧张素受体功能控制和解剖学

• 批准号: 3402287
• 负责人: Robert Charles Speth
• 金额: $ 8.93万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-07-01 至 1994-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3402287
• 关键词: G protein; aminoacid analog; angiotensin II; animal tissue; autoradiography; blood pressure; brain; hormone receptor; hypothalamus; inhibitor /antagonist; laboratory mouse; laboratory rat; mathematical model; mesencephalon; neuropharmacology; nucleoside analog; peptide chemical synthesis; protein structure function; radiotracer; receptor binding; stereochemistry; stimulant /agonist; sulfhydryl reagents; synthetic peptide; thalamus

This project will characterize brain angiotensin H (AII) receptor subtypes. The ultimate goals this project will be to determine the AII receptor subtypes mediating the various functions of AII in the brain. The rationale for these studies derives from recent observations that sulfhydryl reducing agents inhibit binding to one of the brain AII receptor subtypes. Since most studies of brain AII receptor binding have been done in the presence of sulfhydryl reducing agents, only one the of the brain AII receptor subtypes has been studied in detail. The specific aims of this project are to identify agents that act as selective agonists at brain AII receptor subtypes, to pharmacologically characterize the AII receptor subtypes, to determine if additional AII receptor subtypes occur in the brain, to determine the effects of sulfhydryl reactive agents on brain AII receptors, to determine if brain AII receptors couple to G proteins, and to examine functional responses to agonists and antagonists of AII administered directly into the brain. For functional studies, selective antagonists for one subtype will be given prior to the agonist to preclude mediation of the response by that subtype. Angiotensin II acts in the brain primarily to regulate fluid and electrolyte balance, however, it is also thought to have additional functions. The discovery of subtypes of AII receptors in the brain, may indicate that discrete, noncardiovascular functions for AII will be discovered. Since many brain diseases still have unknown etiologies, disturbances in brain angiotensinergic function could play a role in such disorders. The methods to be used in this project are peptide synthesis using FMOC techniques to prepare AII receptor subtype selective of analogs AII, radioligand binding assays, including in vitro receptor autoradiography to determine the AII receptor subtype profile of brain-nuclei. Binding assays will be done in the presence of ligands and conditions selective for individual AII receptor subtypes; and in vivo testing of responses, e.g., dipsogenesis and blood pressure changes, to angiotensins directly administered into the rat brain. The radioligand binding data will be analyzed by nonlinear regression procedures capable of determining and evaluating binding constants for multiple receptor subtypes. In vivo testing procedures will compare the efficacy of AT1, and AT2 receptor subtypes selective AII analogs in the absence and presence of All receptor selective antagonists by Students's t tests.

该项目将表征脑血管紧张素H(AII)受体亚型。 这个项目的最终目标将是确定AII受体 亚型调节脑内AII的各种功能。这个 这些研究的理论基础来自于最近的观察 巯基还原剂抑制与脑内一种AII受体的结合 子类型。由于大多数关于脑内AII受体结合的研究已经完成 在巯基还原剂存在的情况下，只有一个大脑 所有的II受体亚型都进行了详细的研究。的具体目标 这个项目是为了确定在大脑中充当选择性激动剂的药物。 AII受体亚型，用于药理学研究AII受体 亚型，以确定额外的AII受体亚型是否出现在 脑，以确定巯基反应物对脑AII的影响 受体，以确定大脑AII受体是否与G蛋白偶联，并 检测AII激动剂和拮抗剂的功能反应 直接注射到大脑中。对于功能研究，选择性 一个亚型的拮抗剂将先于激动剂给予，以排除 该子类型对响应的调解。血管紧张素II作用于 然而，大脑主要是为了调节液体和电解质平衡。 也被认为具有额外的功能。AII亚型的发现 大脑中的受体，可能表明离散的，非心血管的 AII的功能将被发现。由于许多脑部疾病至今仍有 不明原因，脑血管紧张素能功能障碍可能 在这类疾病中起着一定的作用。此项目中将使用的方法包括 用Fmoc技术合成肽制备AII受体亚型 选择性类似物所有放射性配基结合分析，包括体外分析 受体放射自显影技术测定AII受体亚型 脑核。结合分析将在配体和 对单个AII受体亚型的选择性条件；以及在体内 测试对以下疾病的反应，例如，糖尿病的发生和血压的变化 血管紧张素直接注射到大鼠的大脑中。放射性配基 绑定数据将通过能够 多受体结合常数的测定与评价 子类型。体内测试程序将比较AT1和AT1的疗效 AT2受体亚型选择性AII类似物的存在和缺失 所有受体选择性拮抗剂均经学生t检验。