CELLULAR MECHANISMS FOR ANGIOTENSIN RESPONSES IN BRAIN

中枢肾素-血管紧张素系统参与血管紧张素转换酶的调节 动脉压和体液平衡。因为神经元、神经胶质细胞和血管 中枢神经系统(CNS)内的元素都表现出高度的亲和力 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 星形胶质细胞可能负责肾素的许多中枢作用- 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，我们最近已经 证明血管紧张素Ⅱ可以在一个区域调节Aogen的分泌- 具体的方式。此外，我们还检测到存在多个 星形胶质细胞上的血管紧张素受体亚型 它们诱导的细胞信号，它们对血管紧张素转换酶的选择性，以及它们的 亚型选择性受体拮抗剂的抑制作用。例如，Ang II Ang-(2-8)通过激活细胞内钙离子 磷脂酶C、血管紧张素Ⅱ和血管紧张素Ⅱ-(1-7) 通过不依赖钙离子的途径释放前列腺素。自.以来 前列腺素表现出许多与Ang II相同的心血管作用 最近被认为是血管紧张素转换酶II导致 加压素的释放，我们假设许多已知的作用 中枢神经系统中的血管紧张素肽受星形胶质细胞的影响 功能。因为转化的星形胶质细胞是用来产生上述 信息，我们现在必须清楚地证明，没有转化 星形胶质细胞表达血管紧张素受体亚型，并产生不同的 手机信号。因此，我们将确定Ang肽结合位点， 它们对特定信号转导机制的激活及其作用 大鼠星形胶质细胞原代培养中Aogen mRNA的表达 大脑。此外，为了确定血管紧张素受体是否在 星形胶质细胞参与血压的中枢控制和 心血管功能，我们将从脑区分离出星形胶质细胞 都是已知的参与血压调节和研究的 血管紧张素转换酶受体的表达及其细胞反应 从这些特定区域培养的星形胶质细胞。然后我们将能够 将我们的发现与血液相关脑区的已知位置联系起来 压力调节和设计生理研究以阐明 星形胶质细胞上血管紧张素受体的可能参与 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.