Regulation of neuro-cardiovascular function during stress

应激期间神经心血管功能的调节

• 批准号: 10376718
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376718
• 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; Hyperactivity; Individual; Kidney; Laboratories; Link; Measurement; Mediating; Mental Depression; 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 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 disorder risk; cardiovascular risk factor; combat; depression model; design; experience; gamma-Aminobutyric Acid; hemodynamics; high risk; hypothalamic-pituitary-adrenal axis; improved outcome; instrument; knock-down; magnocellular; male; military veteran; mortality; mortality risk; 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，与其他因素无关 慢性疾病或社会经济状况等因素。抑郁症现在被认为是一种非传统疾病 心血管疾病的危险因素。近三分之一的退伍军人在某些时候患有抑郁症， 无论他们是否被部署在战斗中。激活血管加压素 (AVP) 受体 中枢神经系统，特别是室旁核（PVN）与抑郁症有关。 最近的研究表明，AVP 由 PVN 内的树突释放，并且中央 AVP 介导 交感兴奋观察心力衰竭。交感神经兴奋也与更大的 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兴奋。新的 有证据表明，由于可塑性，GABA 可能对 AVP 信号传导产生矛盾的刺激作用 这发生在神经元内的氯离子浓度中。细胞内氯离子浓度为 通过氯化钠协同转运蛋白 1 (NKCC1) 进行氯离子转运控制，该转运蛋白转运氯离子 进入细胞或氯化钾协同转运蛋白 2 (KCC2)，排出氯离子。因此，我们 假设 AVP 激活 PVN 内的 V1a 受体 (V1aR) 和/或 V1b 受体 (V1bR) 以增加 动脉压、心率和交感神经活动，从而有助于增强这些 抑郁症动物模型对急性应激的反应。将解决三个具体目标。具体来说 目标 1，我们将使用药物抑制和基因敲除以及 siRNA 方法来评估是否 外源性 AVP 单独或联合激活 V1aR 或 V1bR 会导致动脉压、心脏 率和 RSNA 以及对急性应激的夸大反应。在具体目标 2 中，我们将测试是否发生变化 PVN 中的 NKCC1 或 KCC2 转运减弱甚至逆转 GABA 能对血流动力学和 RSNA 在基础状态或急性应激期间对 V1aR 和/或 V1bR 激活的反应。在具体目标 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 慢性不可预测应激 (CMS) 大鼠模型中动脉压和 RSNA 增加，这是一个经过验证的模型 抑郁症的发生，以及通过 NKCC1 的转运增加或通过 KCC2 的转运减少是否可以预防 GABA 能抑制这些反应。我们将在有意识、不受约束的斯普拉格身上检验这个假设 道利大鼠长期使用遥测发射器测量血流动力学和神经活动 测量。通过遥测技术不仅可以监测清醒大鼠的动脉压，还可以监测 RSNA 只有包括我们自己在内的少数实验室掌握，并提供了强大的评估工具 基础和应激条件，研究者干扰最小。我们将确定的贡献 血管加压素受体参与对外源性 AVP 以及急性应激源的反应：空气喷射、 鼻咽反射、50°C 水中的尾巴和约束应力。然后我们将确定 GABA 抑制是否 NKCC1 或 KCC2 的阻断会改变 AVP 信号传导。然后，我们将对大鼠进行 CMS 并评估 阻断 V1aR 和/或 V1bR 是否会降低基线动脉压、心率和 RSNA。我们将 评估 CMS 是否倾向于增强对急性应激源的反应，以及该反应是否是由于 血管加压素信号可能受到 GABA 能系统可塑性的影响。伴随着激动人心的 新的脑渗透性、高选择性 V1aR 拮抗剂的出现已经在其他疾病的 I 期试验中， 研究应激障碍中 V1aR 和 V1bR 拮抗作用的需要是及时且明显可转化为 治疗患有慢性压力（例如抑郁症）的人。拟议的研究将提供关键的 设计临床试验的基本原理和强有力的机制证据。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，建议的临床前 研究将为新的辅助治疗奠定重要基础，以改善抑郁退伍军人的治疗结果。