Central Angiotensin receptors and teh neural control of homeostasis

中枢血管紧张素受体和稳态的神经控制

• 批准号: 8328924
• 负责人: Eric Gerald Krause
• 金额: $ 24.63万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-09 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8328924
• 关键词: Address; Adrenal Glands; Affect; American; Angiotensin II; Angiotensin Receptor; Angiotensins; Anxiety; Anxiety Disorders; Base of the Brain; Behavior; Behavioral; Biological; Blood Pressure; Brain; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Chronic; Chronic stress; Clinical Research; Corticosterone; Corticotropin; Corticotropin-Releasing Hormone; Disease; Disease Progression; Exposure to; Heart Rate; Homeostasis; Hypertension; Hypothalamic structure; Instruction; Laboratory Rat; Laboratory mice; Link; Mediator of activation protein; Mental Health; Mental disorders; Mood Disorders; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Peptides; Phase; Pituitary Gland; Rattus; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Reporting; Research; Research Design; Risk; Severities; Stress; Subfamily lentivirinae; Subfornical Organ; System; Systems Development; Testing; Therapeutic; Thymus Gland; United States; Up-Regulation; Weight; biological adaptation to stress; biological systems; cardiovascular disorder risk; clinical application; feeding; heart rate variability; hypothalamic-pituitary-adrenal axis; improved; neuroregulation; novel; paraventricular nucleus; pressure; prevent; receptor; receptor expression; research study; response

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.

高血压影响大约5000万美国人，并且这种疾病的进展显著 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 与精神疾病有关具体来说，高血压会增加焦虑症的风险， 相反，焦虑症可预测高血压和心血管疾病的风险和严重程度。 高血压的发生与肾素-血管紧张素系统（RAS）过度活跃有关， 焦虑的发展与下丘脑-垂体-肾上腺（HPA）轴的失调有关。 RAS的效应肽血管紧张素II（ANGII）通过以下途径发挥其大部分生物学效应： 血管紧张素1型受体（AT 1 R）的激活。有趣的是，AT 1 R在整个HPA中表达， 轴和新兴的证据表明ANGII作为应激反应的重要介质。慢性 暴露于压力上调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， 这些系统之间的相互作用是慢性压力对心理健康和 心血管功能由于反复的压力增加了AT 1 R在大脑中的表达， 慢性应激增强ANGII对HPA轴的影响，从而诱导心血管和 情感障碍总的来说，这些研究表明，靶向RAS的治疗可能会影响 因此，重要的是要了解大脑的中枢神经系统， 影响应激反应的血管紧张素途径。因此，拟议的实验将 抑制实验室大鼠和小鼠脑中的ATI R，以确定这些受体对 心血管，HPA和行为反应慢性暴露于压力。这些研究旨在 测试总体假设，即大脑中AT 1 R的抑制将限制应激反应并减轻 与压力有关的疾病的有害后果。