Central Angiotensin receptors and teh neural control of homeostasis

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Hypertension affects approximately 50 million Americans and progression of this disease significantly increases risk for cardiovascular disease. Recent clinical studies demonstrate that hypertension also is associated with mental health disorders. Specifically, hypertension increases the risk of anxiety disorders, and inversely, anxiety disorders predict the risk and severity of hypertension and cardiovascuiar disease. While the onset of hypertension is attributed to over activity ofthe renin-angiotensin-system (RAS), the development of anxiety is associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The effector peptide ofthe RAS, angiotensin II (ANGII), exerts the majority of its biological effects via activation of angiotensin type 1 receptors (AT1R). Interestingly, AT1R are expressed throughout the HPA axis and emerging evidence has implicated ANGII as an important mediator of the stress response. Chronic exposure to stress up-regulates the HPA axis and RAS, thereby negatively affecting cardiovascular and mental health. Given that chronic stress similarly up-regulates the HPA axis and the RAS, it is likely that an Interaction between these systems underlies the effects that chronic stress has on mental health and cardiovascular function. Because repeated stress increases AT1R expression in the brain, it is likely that chronic stress potentiates the influence of ANGII on the HPA axis, thereby inducing cardiovascular and affective disorders. Collectively, these studies suggest that therapies targeting the RAS may influence the onset of brain-basied disorders like anxiety, and therefore, it is important to understand the central angiotensinergic pathways that influence responses to stress. Accordingly, the proposed experiments will to inhibit ATI R in the brains of laboratory rats and mice to detemriine the contribution of these receptors to the cardiovascular, HPA and behavioral responses to chronic exposure to stress. These studies are designed to test the overall hypothesis that inhibition of AT1R in the brain will limit stress responding and alleviate the deleterious consequences of stress related illnesses.