ANGIOTENSIN RECEPTOR SUBTYPES IN THE RAT BRAIN

该提案的目标是确定血管紧张素受体的特征。 大鼠大脑中的亚型，并定义亚型特异性 血管紧张素II(AII)在这个器官中的升压和降压作用。 最近，使用新的AII受体亚型选择性化合物的研究已经 外周器官有明确的受体亚型，但有多种AII受体 中枢神经系统中的人群尚未确定其特征。 最初目的是利用两个非多肽亚型选择性 化合物DUP 753和PD123177，以记录受体的定位 竞争受体放射自显影在大鼠脑内的亚型。这个 分析将包括大约30个受体种群 不同的原子核。各原子核的竞争曲线分析 将测试单部位和双部位模型以估计是否有受体 种群只有一个亚型或两个亚型的混合。初步 对受体亚型的研究表明，重新评估受体亚型 多肽类似物的研究是有根据的。具体地说，可能的子类型 自然产生的同系物血管紧张素III(AIII)的特异性 将会被检查。AIII受体亚型选择性的建立 将会助长支持特定生理行为的争论 多肽。对外周组织中AII受体的研究表明 其结合被巯基还原剂(SH-RA)增强的亚型 而中枢神经系统中的几个受体群体 基本不受SH-RAS影响。来检验这两种情况的假设 相同的，实验将重新检查SH-RAS对大脑的影响 通过DUP753消除可能的污染亚型后的站点。它 据预测，该方法将在剩余时间揭示增强的绑定 SH-RA的受体，与在外周观察到的效果一致 纸巾。 提案的第二部分涉及AII的职能方面 受体亚型分类。具体地说，子类型选择性 拮抗剂DuP753和PD123177将用于测试哪种受体 亚型介导中枢诱导的所有升压和致糖尿病作用。 将AII的生理功能与AII联系起来的科学重要性 特定受体亚型与治疗性 后果。新开发的拮抗剂化合物显示出治疗作用 在心血管疾病方面的潜力，以及目前的研究 将有助于预测可能的行动和副作用。

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.