Mechanisms of Sympathetic Overactivity in Post-traumatic Stress Disorder

创伤后应激障碍中交感神经过度活跃的机制

• 批准号: 10409640
• 负责人: Jeanie Park
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10409640
• 关键词: Acute; Address; Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Afghanistan; Anti-Cholinergics; Anti-Inflammatory Agents; Baroreflex; Biological Markers; Blood Flow Velocity; Blood Pressure; Blood Vessels; Brain Stem; Cardiovascular Diseases; Cervical; Chronic Disease; Data; Development; Devices; Disease; Doppler Ultrasound; Dose; Efferent Neurons; Electrocardiogram; Future; General Population; Goals; Gold; Health; Human; Hypertension; Impairment; Inflammation; Inflammatory; Intervention; Iraq; Kidney; Measures; Mediating; Mental disorders; Muscle; Nerve; Nerve Fibers; Nervous System Physiology; Nucleus solitarius; Organ; Output; Parasympathetic Nervous System; Pathogenesis; Patients; Peripheral Resistance; Pharmacology; Phenylephrine; Physiology; Plasma; Post-Traumatic Stress Disorders; Psyche structure; Regulation; Renal Blood Flow; Renin; Renin-Angiotensin System; Research; Rest; Risk; Risk Factors; Role; Sodium; Stress; Sympathetic Nervous System; Techniques; Testing; Therapeutic; Time; Vagus nerve structure; Vascular resistance; Veterans; Work; afferent nerve; alpha-1 adrenergic receptors; blood pressure elevation; blood pressure regulation; cardiovascular disorder risk; cardiovascular risk factor; disorder control; experimental study; hemodynamics; high risk population; improved; insight; kidney vascular structure; military veteran; neurovascular; novel; patient population; peripheral blood; post 9/11; prevent; programs; receptor sensitivity; response; therapeutic target; time use; vagus nerve stimulation; vascular abnormality; vasoconstriction; young man; young woman

Post-traumatic stress disorder (PTSD) is a highly prevalent and debilitating mental health disorder that is independently associated with an increased risk of cardiovascular (CV) disease and hypertension. Given the large numbers of post-9/11 Veterans afflicted with PTSD, addressing this under-recognized but highly significant consequence of PTSD is of paramount importance to protect the future health of these young Veterans. We have shown that post-9/11 Veterans with PTSD have overactivation of the sympathetic nervous system (SNS) during mental stress and impaired arterial baroreflex sensitivity (BRS) that could contribute to the pathogenesis of hypertension and CV disease in these patients. While we have now established that central sympathetic output is augmented in PTSD, the downstream effects of SNS output on blood pressure (BP) regulation in PTSD remain unknown and is a major goal of this proposal. We hypothesize that augmented sympathetic nerve activity in PTSD leads to augmented SNS-mediated vasoconstriction within the kidney, an organ with a critical role in BP regulation. Exaggerated increases in sympathetically mediated renal vasoconstriction could perpetuate sustained increases in BP over time via renal sodium reabsorption and activation of the renin-angiotensin system (RAS). To test this hypothesis, we will measure renal blood flow velocity using Doppler ultrasound, continuous hemodynamics, muscle sympathetic nerve activity (MSNA) using microneurography, plasma renin activity and inflammatory biomarkers at rest and during mental stress in post 9/11 Veterans and matched controls. We further hypothesize that SNS activation leads to an exaggerated vasoconstrictive response (i.e. heightened neurovascular transduction of SNS activity) mediated by abnormal vascular adrenergic receptor sensitivity in PTSD. To test this hypothesis, we will determine vascular alpha-1 adrenergic receptor (α1AR) sensitivity by measuring vasoconstriction in response to exponentially increasing doses of the selective α1AR agonist phenylephrine using a linear variable differential transformer in PTSD and controls. Finally, prior studies have shown that transcutaneous vagus nerve stimulation (tVNS) reduces SNS activity, improves BRS, and lowers inflammation in healthy humans and a number of chronic diseases; however, the potential benefits of tVNS on SNS function and regulation in PTSD have never previously been investigated. We hypothesize that tVNS acutely lowers SNS activity and improves sympathetic and cardiovagal BRS in PTSD. To test this hypothesis, we will measure MSNA, EKG, hemodynamics, inflammation, and BRS using pharmacologic manipulation of BP at rest and during tVNS (versus sham stimulation) in PTSD patients. tVNS could be a novel nonpharmacologic approach to reducing SNS activity and restoring BRS in these patients. Improving SNS overactivity and BRS may have long term benefits on reducing CV risk in PTSD patients.

创伤后应激障碍（PTSD）是一种高度普遍且令人衰弱的心理健康 与心血管（CV）疾病风险增加有关的疾病 和高血压。鉴于大量的9/11后退伍军人患有PTSD， 解决这一不认可但高度重大的后果是最重要的 对于保护这些年轻退伍军人的未来健康的重要性。我们已经表明 PTSD的9/11后退伍军人对交感神经系统（SNS）过度激活 在精神压力和动脉压力反射敏感性（BRS）期间，可能有助于 这些患者的高血压和CV疾病的发病机理。当我们现在有 确定中心同情输出在PTSD中增加了 PTSD中血压（BP）调节的SNS输出仍然未知，是 这个建议。我们假设PTSD中增强的交感神经活动导致 肾脏内的增强SNS介导的血管收缩，这是BP中至关重要的器官 规定。夸张的同情介导的肾血管收缩的增加可能 随着时间的流逝，BP的持续增长通过肾脏钠的重吸收和激活 肾素 - 血管紧张素系统（RAS）。为了检验这一假设，我们将测量肾血流 使用多普勒超声，连续血流动力学，肌肉交感神经的速度 使用微功能学，血浆肾素活性和炎症生物标志物的活性（MSNA） 在9/11后退伍军人和匹配的对照中休息和精神压力。我们进一步 假设SNS激活会导致夸张的血管收缩反应（即 社交媒体活动的神经血管传播增强）由异常血管介导 PTSD中的肾上腺素受体敏感性。为了检验这一假设，我们将确定血管 α-1肾上腺素受体（α1AR）敏感性通过测量血管收缩以响应 使用线性，指数增加剂量的选择性α1AR激动剂苯肾上腺素 PTSD和控件中的可变差分变压器。最后，先前的研究表明 经皮神经刺激（TVNS）减少了社交媒体活动，改善了BR和 降低健康人的炎症和许多慢性疾病；但是， TVNS对SNS功能和PTSD的监管的潜在好处从未有过 调查。我们假设TVN急性降低SNS活动并改善同情 和PTSD中的Cardiovagal BRS。为了检验该假设，我们将测量MSNA，EKG， 血液动力学，感染和BR，使用BP的药物操纵在休息和 在PTSD患者的TVN（与假刺激）期间。电视可能是一本小说 减少社交媒体活动和恢复这些患者的BRS的非药物方法。 改善SN的过度活动和BRS可能会在减少PTSD中的简历风险方面具有长期利益 患者。