CELLULAR MECHANISMS FOR ANGIOTENSIN RESPONSES IN BRAIN

中枢肾素-血管紧张素系统参与调节 动脉压和液体平衡。 由于神经元、神经胶质和血管 中枢神经系统（CNS）内的元件都表达高亲和力 血管紧张素（Ang）受体，目前尚不清楚这些成分如何相互作用 来实现这一规定。 然而，我们有证据表明， 星形胶质细胞可能是负责许多中心作用的肾素， 血管紧张素系统 我们已经证明，培养的人类星形胶质细胞产生 并分泌血管紧张素原（Aogen）。 此外，我们最近 证明Aogen分泌可以由Ang II在一个区域调节- 具体方式。 此外，我们还发现了多个 星形胶质细胞上的血管紧张素受体亚型可通过 它们引发的细胞信号，它们对Ang肽的选择性，以及它们的 通过亚型选择性受体拮抗剂抑制。 例如，Ang II 和Ang-（2-8）通过激活细胞内的Ca ~（2+）通道， 磷酸肌醇特异性磷脂酶C，而Ang II和Ang-（1-7） 通过Ca 2+非依赖性途径释放胡枝子素。 以来 洋地黄素显示出许多与血管紧张素II相同的心血管作用 最近被认为是血管紧张素II引起 加压素释放，我们假设许多已知的行动， CNS中的血管紧张素肽是由星形胶质细胞的作用介导的， 功能协调发展的 因为转化的星形胶质细胞被用来产生上述 信息，我们现在必须清楚地表明， 星形胶质细胞表达Ang肽受体亚型，并产生不同的 蜂窝信号 因此，我们将鉴定Ang肽结合位点， 它们激活特定的信号转导机制及其作用 原代培养大鼠星形胶质细胞Aogen mRNA表达 个脑袋 此外，为了确定血管紧张素肽受体是否在 星形胶质细胞参与血压的中枢控制， 心血管功能，我们将从大脑区域分离星形胶质细胞， 已知参与血压调节和研究 血管紧张素肽受体的表达及其细胞反应 从这些特定区域培养星形胶质细胞。 我们将能够 将我们的发现与已知的与血液有关的大脑区域的位置联系起来， 压力调节和设计生理研究，以阐明 星形胶质细胞上的血管紧张素肽受体可能参与 心血管功能

The central renin-angiotensin system participates in the regulation of arterial pressure and fluid balance. Since neuronal, glial and vascular elements within the central nervous system (CNS) all express high affinity angiotensin (Ang) receptors, it is not clear how these components interact to bring about this regulation. However, we have evidence suggesting that astrocytes may be responsible for many of the central effects of the renin- angiotensin system. We have shown that cultured human astrocytes produce and secrete angiotensinogen (Aogen). Furthermore, we have recently demonstrated that Aogen secretion can be regulated by Ang II in a region- specific manner. In addition, we have detected the presence of multiple Ang receptor subtypes on astrocytes that are distinguishable by the cellular signals they elicit, their selectivity for Ang peptides, and their inhibition by subtype selective receptor antagonists. For example, Ang II and Ang-(2-8) mobilize intracellular Ca2+ by activation of a phosphoinositide-specific phospholipase C while Ang II and Ang-(1-7) release prostaglandins via a Ca2+-independent pathway. Since prostaglandins display many of the same cardiovascular effects as Ang II and have recently been suggested as the mechanism by which Ang II causes vasopressin release, we hypothesize that many of the known actions of angiotensin peptides in the CNS are mediated by effects of astrocyte functions. Because transformed astrocytes were used to generate the above information, we must now clearly demonstrate that non-transformed astrocytes express Ang peptide receptor subtypes and produce distinct cellular signals. We will therefore identify Ang peptide binding sites, their activation of specific signal transduction mechanisms and their role in expression of Aogen mRNA in primary cultures of astrocytes from rat brain. Furthermore, to determine whether Ang peptide receptors on astrocytes are involved in the central control of blood pressure and cardiovascular function, we will isolate astrocytes from brain areas which are known to participate in the regulation of blood pressure and study expression of Ang peptide receptors and their cellular responses in cultured astrocytes from these specific regions. We will then be able to relate our findings to the known location of brain areas involved in blood pressure regulation and design physiological studies to elucidate the potential involvement of Ang peptide receptors on astrocytes in cardiovascular function.