Angiotensin (Ang) AT1 receptors are critical in the control of blood pressure and fluid/electrolyte balance. AT1 receptors exist in two forms, AT1a and AT1b, which are homologous in gene and protein structure, making it impossible to distinguish pharmacologically. Genetic engineering techniques have produced models which allow for the investigation of gene/function interactions. Removal of AT1 a receptors appears to activate central Ang receptors, particularly in osmosensitive brain regions. The net result is an enhancement of the blood pressure and central neuroendocrine responses to stimuli which alter fluid/electrolyte balance. We propose to test the hypothesis that Ang receptors in specific brain regions are critical in the regulation of osmotic balance. Using the AT1 aKO model, we will determine the nature of the central nervous system changes with a focus on Ang/vasopressin (VP) interactions. The problem will be addressed at the level of the whole animal and. the individual neuron. For in vivo studies, we will use a method for chronic cardiovascular monitoring and blood sampling in the conscious mouse. The goal is to determine the role of Ang receptors in osmosensitivity, studying the regulation of blood pressure, heart rate, peptide secretion and neural activation. Markers for CNS activation include c-Fos, Ang receptors, Ang receptor mRNA and VP mRNA. Cellular studies aim at elucidating the mechanisms by which Ang modulates osmosensitivity in VP neurons. In vitro studies will use perfused brain slices for determination of electrophysiological properties underlying osmosensitivity.
The specific aims are: 1. Are osmotic-induced peptide and cardiovascular responses altered in AT1 aKO? This will address the issue of whether acute or chronic osmotic stimulation alters the central and peripheral VP system, the central Mg receptor system, and cardiovascular and fluid balance. Experiments will further test the effect of Ang receptor blockade and enzymatic inhibition to document the extent and specificity of Mg input. 2. What are the cellular mechanisms underlying osmosensitivity in AT1aKO? The basic question relates to the nature of the cellular changes and whether these are mediated by intrinsic mechanisms. 3. What is the relationship between the central Ang system and the alterations in osmosensitivity? This will address the issue of whether there are changes in responses to Ang II or other Mg peptides and whether these are important in osmotic responsiveness.
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