Central actions of angiotensin II in the control of fluid balance

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DESCRIPTION (provided by applicant): The renin-angiotensin system (RAS) is a focus of intense research because it has been strongly implicated in the development of cardiovascular disease. The active component of the RAS, the peptide hormone angiotensin II (AngII), is an important regulator of cardiovascular and body fluid homeostasis. Therefore, the receptors that respond to AngII and the cellular, genomic, and physiological actions initiated by AngII binding are actively studied in an effort to understand the foundation for the development of cardiovascular diseases, such as hypertension, atherosclerosis, and cardiac failure. Body fluid homeostasis, which is intricately connected with cardiovascular function, depends on the coordinated regulation of complementary physiological and behavioral mechanisms. The principle behaviors that ensure stability of volume and composition of the fluid matrix are water and salt intake. AngII is importantly involved in the control of these motivated behaviors. Adrenal steroids also further regulate the brain's responsivity to AngII, thereby modulating thirst and salt appetite. Because the regulation of sodium balance in all animals is a key aspect of body fluid homeostasis, control of sodium intake is an important point of emphasis in the treatment of hypertension. While all hypertensive patients are counseled to restrict their sodium intake, many have great difficulty in complying. Thus, an understanding of this behavior has important ramifications with respect to pathophysiology of hypertension and cardiovascular disease. The Type 1 (AT1) AngII receptor subtype is primarily responsible for the physiological and behavioral responses to this peptide. For the AT1 receptor, there is considerable literature on cell signaling mediated by G-protein activation. However, AT1 receptors are now also recognized to be linked to activation nontraditional signaling pathways, including activation of mitogen activated protein kinases (MAPK). Recently, we have demonstrated that AngII-induced salt appetite is initiated by MAPK activation and not the more traditional G- protein mediated signaling associated with AT1 receptors. In the present application, we propose to investigate the cellular and neuroanatomical mechanisms that subserve salt appetite by using various drug conditions to isolate different branches of AT1 receptor signaling: (1) AngII, which activates all signaling pathways; (2) the peptide Sar1,Ile4,Ile8-AngII, which activates only MAPK; and (3) AngII combined with a MEK inhibitor, which activates only the traditional G-protein mediated signaling. Using these drug combinations, we will address: (1) the cellular intermediary proteins that connect the AT1 receptor to MAPK signaling, (2) the role of AT1-R mediated MAPK activation under physiological states that induce salt appetite, (3) the neurocircuitry that is employed in the development of salt appetite, and (4) the cellular mechanisms that permit adrenal steroids to modulate salt appetite. The hormone angiotensin II is a focus of intense research because it has been strongly implicated in the development of cardiovascular disease. Of the many actions of this hormone within the body, angiotensin II is an important regulator of fluid balance by coordinating physiological actions, such as kidney and cardiovascular function, with the behaviors of water drinking and the ingestion of salt (sodium). Because the regulation of sodium balance in all animals is a key aspect of body fluid regulation, control of sodium intake is an important point of emphasis in the treatment of hypertension. While all hypertensive patients are counseled to restrict their sodium intake, many have great difficulty in complying. Thus, an understanding of this behavior has important ramifications with respect to the development of hypertension and cardiovascular disease.