Central Angiotensin receptors and teh neural control of homeostasis

高血压影响了大约5000万美国人，而且这种疾病的发展速度很快 增加患心血管疾病的风险。最近的临床研究表明，高血压也是 与精神健康障碍有关。具体地说，高血压会增加焦虑症的风险， 相反，焦虑症预测高血压和心血管疾病的风险和严重程度。 虽然高血压的发病归因于肾素-血管紧张素系统(RAS)的过度活动，但 焦虑症的发生与下丘脑-垂体-肾上腺(HPA)轴的失调有关。 血管紧张素II(AngII)是RAS的效应肽，它的大部分生物学效应是通过 血管紧张素1型受体(AT1R)的激活。有趣的是，AT1R在整个HPA中都有表达 Axis和新出现的证据表明，Angii是应激反应的重要调节因子。慢性 暴露在压力下会上调HPA轴和RAS，从而对心血管和 心理健康。鉴于慢性应激同样上调HPA轴和RAS，很可能 这些系统之间的相互作用强调了慢性应激对心理健康和 心血管功能。由于反复应激会增加大脑中AT1R的表达，因此很可能 慢性应激增强血管紧张素转换酶对HPA轴的影响，从而导致心血管和 情感障碍。总的来说，这些研究表明，针对RAS的治疗可能会影响 焦虑等脑源性疾病的发病，因此，重要的是了解中枢神经系统 影响应激反应的血管紧张素能通路。因此，拟议的实验将有助于 抑制实验大鼠和小鼠脑内ATI R，以确定这些受体对 心血管、HPA和行为对长期应激的反应。这些研究旨在 测试AT1R在大脑中的抑制将限制应激反应和缓解压力的总体假设 与压力相关的疾病的有害后果。

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.