BRAIN ANGIOTENSIN RECEPTOR FUNCTION CONTROL AND ANATOMY

脑血管紧张素受体功能控制和解剖学

基本信息

批准号：
2264137
负责人：
Robert Charles Speth
金额：
$ 8.97万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-07-01 至 1995-09-29
项目状态：
已结题

项目摘要

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。该项目将确定AII受体的最终目标亚型介导大脑中AII的各种功能。这这些研究的基本原理来自最近的观察结果还原剂抑制与脑AII受体之一的结合抑制了结合亚型。由于大多数大脑AII受体结合的研究已经完成在硫赖基还原剂的存在下，只有一个大脑已经详细研究了AII受体亚型。具体目的该项目是确定在大脑中充当选择性激动剂的代理 AII受体亚型，以药理表征AII受体亚型，确定是否发生了其他AII受体亚型大脑，以确定硫赖酰基反应剂对脑AII的影响受体，确定脑AII受体是否夫妇到G蛋白，然后检查对AII激动剂和拮抗剂的功能反应直接施用到大脑中。对于功能研究，选择性在激动剂之前将给出一种亚型的拮抗剂该亚型的响应调解。血管紧张素II在大脑主要是为了调节液体和电解质平衡，但是还被认为具有其他功能。发现AII的亚型大脑中的受体可能表明离散的非心血管将发现AII的功能。由于许多脑部疾病仍然有未知的病因，脑血管素能功能的障碍可能在这种疾病中发挥作用。该项目中要使用的方法是使用FMOC技术制备AII受体亚型的肽合成选择性类似物AII，放射性结合测定，包括体外受体放射自显影以确定AII受体亚型的谱图脑核心。结合测定将在配体的存在下进行，并且选择单个AII受体亚型的条件；和体内测试反应，例如倾向生成和血压变化，血管紧张素直接施用到大鼠脑中。放射性物体绑定数据将通过能够的非线性回归程序分析确定和评估多个受体的结合常数亚型。体内测试程序将比较AT1的疗效，并且在不存在和存在的情况下，AT2受体亚型选择性AII类似物学生T测试的所有受体选择性对手。