CELLULAR MECHANISMS FOR ANGIOTENSIN RESPONSES IN BRAIN

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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.