Regulation of neuro-cardiovascular function during stress

应激期间神经心血管功能的调节

• 批准号: 9239217
• 负责人: Noreen F Rossi
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9239217
• 关键词: Acute; Address; Air; Animal Model; Assessment tool; Attenuated; Autonomic nervous system; Blood; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Brain; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Cells; Cessation of life; Chloride Ion; Chlorides; Chronic; Chronic Disease; Chronic stress; Clinical Trials; Conscious; Corticotropin; Dehydration; Dendrites; Depressed mood; Development; Disease; Exposure to; Female; Foundations; General Population; Genetic; Goals; Heart Rate; Heart failure; Hormones; Hydrocortisone; Hyperactive behavior; Individual; Kidney; Laboratories; Link; Measurement; Mediating; Mental Depression; Military Personnel; Modeling; Monitor; Morbidity - disease rate; Myocardial Infarction; Nerve; Neuraxis; Neurons; Output; Peripheral; Pharmacology; Pituitary Gland; Potassium Chloride; Rattus; Receptor Activation; Reflex action; Regulation; Research Personnel; Risk; Risk Factors; Rodent Model; Role; Signal Transduction; Small Interfering RNA; Sodium; Sodium Chloride; Sprague-Dawley Rats; Stimulus; Stress; Stroke; Sympathetic Nervous System; System; Tail; Telemetry; Testing; Time; Vasopressin Receptor; Vasopressins; Veterans; Water; Water Stress; acute stress; behavioral response; biological adaptation to stress; cardiovascular risk factor; combat; depression model; design; disorder risk; experience; gamma-Aminobutyric Acid; hemodynamics; high risk; hypothalamic-pituitary-adrenal axis; improved outcome; instrument; knock-down; magnocellular; male; mortality; novel therapeutic intervention; novel therapeutics; paraventricular nucleus; phase I trial; preclinical study; pressure; prevent; receptor; response; restraint stress; stress disorder; stressor; supraoptic nucleus; symporter

Cardiovascular morbidity and mortality is higher among Veterans than the general population independent of factors such as chronic illnesses or socio-econamic status. Depression is now recognized as a non-traditional risk factor for cardiovascular disease. Nearly one-third of Veterans suffer from depression at some point, regardless of whether they have been deployed in combat. Activation of vasopressin (AVP) receptors within the central nervous system, specifically the paraventricular nucleus (PVN) has been implicated in depression. Recent studies have shown that AVP is released from dendrites within the PVN and that central AVP mediates the sympathoexcitation observed heart failure. Sympathoexcitation is also strongly associated with greater cardiovascular risk. Notably, gamma-aminobutyric acid (GABA) typically suppresses sympathoexcitation. New evidence indicates that GABA may exert a paradoxically stimulatory effect on AVP signaling due to plasticity that occurs in the chloride ion concentration within neurons. The intracellular chloride concentration is controlled by chloride transport via the sodium chloride co-transporter 1 (NKCC1) which transports chloride ion into the cell or the potassium chloride co-transporter 2 (KCC2) which extrudes chloride ion. Thus, we hypothesize that AVP activates V1a receptors (V1aR) and/or V1b receptors (V1bR) within the PVN to increase arterial pressure, heart rate and sympathetic activity thereby contributing to the augmentation of these responses to acute stress in an animal model of depression. Three specific aims will be addressed. In Specific Aim 1, we will use pharmacologic inhibition and genetic knockdown with siRNA approaches to assess whether exogenous AVP activation of V1aR or V1bR alone or in combination results in increased arterial pressure, heart rate and RSNA and exaggerated responses to acute stress. In Specific Aim 2, we will test whether changes in NKCC1 or KCC2 transport in PVN attenuate, or even reverse, GABAergic inhibition of hemodynamic and RSNA responses to V1aR and/or V1bR activation in the basal state or during acute stress. In Specific Aim 3, we will ascertain whether endogenous AVP within the PVN activates V1aR and/or V1bR thereby contributing to the increased arterial pressure and RSNA in a rat model of chronic unpredictable stress (CMS), a validated model of depression, and whether increased transport via NKCC1 or decreased transport via KCC2 prevents GABAergic suppression of these responses. We will test this hypothesis in conscious, unrestrained Sprague Dawley rats chronically-instrumented with telemetry transmitters for both hemodynamic and nerve activity measurements. The ability to monitor not only arterial pressure but also RSNA by telemetry in conscious rats has been mastered by only a few laboratories including our own and provides a powerful tool for assessment of basal and stress conditions with minimal investigator interference. We will identify the contribution of the vasopressinergic receptor(s) involved in the responses to exogenous AVP as well as to acute stressors: air jet, nasopharyngeal reflex, tail in 50°C water, and restraint stress. We will then ascertain whether GABA inhibition of AVP signaling is altered by blockade of NKCC1 or KCC2. Then, we will subject the rats to CMS and assess whether blockade of V1aR and/or V1bR decreases baseline arterial pressure, heart rate and RSNA. We will evaluate whether CMS predisposes to enhanced responses to acute stressors and if that response is due to vasopressinergic signaling that may be impacted by plasticity of the GABAergic system. With the exciting advent of new brain-permeant, highly selective V1aR antagonists already in phase I trials in other disorders, the need for studying V1aR and V1bR antagonism in stress disorders is timely and distinctly translatable for treatment of people with chronic stress such as depression. The proposed studies will provide the crucial rationale and robust mechanistic evidence upon which to design a clinical trial. Given that our Veterans experience both depression and a high risk for cardiovascular morbidity and mortality, the proposed pre-clinical studies will lay a vital foundation for new adjunctive treatments to improve outcomes for depressed Veterans.

退伍军人的心血管发病率和死亡率高于一般人群 诸如慢性病或社会经济状况之类的因素。抑郁现在被认为是非传统的 心血管疾病的危险因素。在某个时候，将近三分之一的退伍军人患有抑郁症， 不管它们是否已在战斗中部署。激活加压素（AVP）接收器 抑郁症中隐含了中枢神经系统，特别是室室核（PVN）。 最近的研究表明，AVP是从PVN内的树突中释放出来的，并且中央AVP介导 交感神经观察到心力衰竭。交感神经也与更大的 心血管风险。值得注意的是，γ-氨基丁酸（GABA）通常会抑制交感神经。新的 证据表明，GABA可能会因可塑性而对AVP信号产生矛盾的刺激作用 这发生在神经元内的氯离子浓度中。细胞内氯化物浓度是 通过氯化钠共转运蛋白1（NKCC1）控制氯离子的转运 进入细胞或氯化钾共转运蛋白2（KCC2），挤出了氯离子。那，我们 假设AVP激活V1A受体（V1AR）和/或V1B受体（V1BR），以增加 动脉压，心率和同情活动，从而有助于增加这些 抑郁症模型中对急性应激的反应。将解决三个具体目标。具体 AIM 1，我们将使用siRNA方法使用药物学抑制和遗传敲低 单独或组合V1AR或V1BR的外源AVP激活导致动脉压升高，心脏 速率和rsna以及对急性应力的反应。在特定目标2中，我们将测试是否更改 PVN中的NKCC1或KCC2转运，甚至反向，对血液动力学的GABA能抑制 RSNA对基本状态或急性应力期间对V1AR和/或V1BR激活的反应。在特定的目标3中，我们 将确定PVN内的内源性AVP是否激活V1AR和/或V1BR，从而有助于 在慢性不可预测应力（CMS）的大鼠模型中，动脉压和rsnA升高，这是一个经过验证的模型 抑郁症，以及通过NKCC1的运输增加还是通过KCC2进行改善的运输阻止 对这些反应的GABA能抑制。我们将在有意识的，不受限制的Sprague中检验这一假设 Dawley大鼠长期用遥测发射器造成了血液动力学和神经活动 测量。不仅可以监测动脉压的能力，还可以通过有意识大鼠的遥测来监测RSNA 仅由包括我们自己在内的少数实验室掌握，并提供了一个有力的评估工具 基本和应力条件的研究者干扰最少。我们将确定 加压素能受体参与了对外源AVP的反应以及对急性应激源的反应：空气射流， 鼻咽反射，在50°C水中尾巴和约束应力。然后，我们将确定GABA是否抑制 NKCC1或KCC2的封锁改变了AVP信号的传导。然后，我们将使大鼠接受CMS和评估 V1AR和/或V1BR的封锁是否会降低基线动脉压，心率和RSNA。我们将 评估CMS是否容易增强对急性应激源的反应，以及该反应是否是由于 加压素能信号传导可能会受到GABA能系统的可塑性的影响。充满兴奋 新的脑部，高度选择性的V1AR拮抗剂的出现已经在其他疾病中的I期试验中 在应力障碍中研究V1AR和V1BR拮抗作用的需求是及时且可明显地翻译的 治疗慢性压力的人，例如抑郁症。拟议的研究将提供至关重要的 理由和强大的机械证据设计临床试验。鉴于我们的退伍军人 经历抑郁症和心血管发病率和死亡率的高风险，拟议的临床前 研究将为新的辅助治疗方法奠定至关重要的基础，以改善退伍军人的抑郁症。