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ANGIOTENSIN RECEPTOR SUBTYPES IN THE RAT BRAIN

大鼠大脑中的血管紧张素受体亚型

基本信息

批准号：
2222993
负责人：
BRIAN PETER ROWE
金额：
$ 9.8万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-09-01 至 1995-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2222993
关键词：
angiotensin II autoradiography brain hormone receptor inhibitor /antagonist laboratory rat neuropharmacology receptor binding receptor sensitivity sulfhydryl reagents

项目摘要

The objectives of the proposal are to characterize angiotensin receptor subtypes in the rat brain and define subtype specificity for the dipsogenic and pressor action of angiotensin II (AII) in this organ. Recent studies, using new AII receptor subtype selective compounds have defined receptor subtypes in peripheral organs but multiple AII receptor populations in the central nervous system have yet to be characterized. The initial aim is to utilize two non-peptidic subtype selective compounds, DuP 753 and PD123177, to document the localization of receptor subtypes in the rat brain by competitive receptor autoradiography. The analysis will include receptor populations at approximately thirty different nuclei. The analysis of competition curves for each nucleus will test both one and two site models to estimate if receptor populations are exclusively one subtype or a mixture of two. Preliminary studies to characterize receptor subtypes indicate that a re-evaluation of peptidic analogues is warranted. In particular, possible subtype specificity of the naturally occurring congener, angiotensin III (AIII) will be examined. Establishment of a receptor subtype selective for AIII will fuel the argument supporting a specific physiological action of the peptide. Studies of AII receptors in peripheral tissues indicate a subtype whose binding is enhanced by sulfhydryl reducing agents (SH-RA) while several receptor populations in the central nervous system are largely unaffected by SH-RAS. To test the hypothesis that both are identical, experiments will re-examine the effect of SH-RAs at the brain sites after elimination of possible contaminating subtypes by DuP753. It is predicted that the approach will reveal enhanced binding at remaining receptors by a SH-RA, consistent with the effects observed in peripheral tissues. The second part of the proposal addresses functional aspects of AII receptor subtype classification. Specifically, the subtype selective antagonists, DuP753 and PD123177, will be used to test which receptor subtype mediates centrally induced AII pressor and dipsogenic actions. The scientific importance of linking physiological functions of AII with specific receptor subtypes is complemented with the therapeutic ramifications. The newly-developed antagonist compounds show therapeutic potential with respect to cardiovascular disease, and the current studies will assist in the prediction of possible actions and side-effects.

该提案的目的是表征血管紧张素受体在大鼠大脑中的亚型，并定义亚型特异性，血管紧张素II（AII）在该器官中的致渴和升压作用。最近的研究，使用新的AII受体亚型选择性化合物，外周器官中有明确的受体亚型，但有多种AII受体中枢神经系统中的人群尚未得到表征。最初的目标是利用两个非肽亚型选择性化合物，DuP 753和PD 123177，以记录受体的定位通过竞争性受体放射自显影术测定大鼠脑中的亚型。的分析将包括大约30个受体群体，不同的原子核各核竞争曲线的分析将测试一个和两个网站模型，以估计如果受体一个种群仅是一种亚型或两种亚型的混合物。初步表征受体亚型的研究表明，肽类似物的研究是必要的。特别是，可能的亚型天然同源物血管紧张素III（AIII）的特异性将被审查。 AIII特异性受体亚型的建立将助长支持一个特定的生理作用的论点，肽。外周组织中AII受体的研究表明，通过巯基还原剂增强结合的亚型（SH-RA）而中枢神经系统中的几种受体群体基本不受SH-RAS的影响。为了验证两者都是同样，实验将重新检查SH-RA在大脑中的作用，通过DuP 753消除可能的污染亚型后的位点。它预测该方法将揭示在剩余时间的增强结合。受体，与外周血中观察到的作用一致。组织中建议的第二部分涉及自动信息基础设施的功能方面受体亚型分类具体来说，拮抗剂DuP 753和PD 123177将用于测试哪种受体亚型介导中枢诱导的AII升压和致渴作用。将AII的生理功能与特异性受体亚型与治疗性后果新开发的拮抗剂化合物显示出治疗作用，潜在的心血管疾病，以及目前的研究将有助于预测可能的行动和副作用。