The effect of AT1R antisense on centrally-mediated responses to angiotension II

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DESCRIPTION (provided by applicant): Hypertension affects approximately 50 million Americans and progression of this disease significantly increases risks for heart and renal failure. The development of hypertension is believed to be due, in part, to overactivity of the Renin-Angiotensin-System (RAS), an endocrine system critical for the regulation of cardiovascular function and hydromineral balance. The effector peptide of the RAS, angiotensin II (ANGII), mediates compensatory responses to blood loss, sodium depletion, and hypotension. In the periphery, ANGII elicits vasoconstriction and promotes Na+ reabsorption by binding to angiotensin type 1 receptors (AT1R) on blood vessels. In the brain, ANGII binds to AT1R in circumventricular organs (CVOs) to initiate changes in hormone release, sympathetic outflow, and increased water and sodium consumption. While much is known about the effects of ANGII on vasculature reactivity and renal Na+ handling, the central pathways governing responses to ANGII remain unclear. Previous studies have used AT1R antagonists or brain lesions to examine central responses to ANGII, but these approaches have limitations. Lesion studies allow for the evaluation of the function of brain regions, but lack the resolution to provide information about specific neuronal phenotypes. Conversely, pharmacological manipulations allow evaluation of neuronal phenotypes, but limiting the administration of the drug to discrete brain regions is problematic. An alternative method is to use antisense methodology to inhibit the expression of target genes in discrete brain regions. Administration of antisense alters specific neuronal phenotypes within individual brain regions, thereby allowing evaluation of the function of neurons within this discrete population. For the proposed experiments, antisense will be used to inhibit the expression of the AT1R in specific brain nuclei, thereby allowing evaluation of the role of these receptors in mediating responses to circulating ANGII. Specifically, antisense targeted against the AT1R will be injected into specific CVOs of rats. Subsequently, I will examine behavioral, endocrine, and neural responses to treatments that differentially increase circulating ANGII. The results will provide valuable insight to the function of AT1R within specific brain regions and the role they play in mediating responses to circulating ANGII, while also serving as a foundation for future studies employing central genetic manipulations.