Reflex responses to intermittent hypoxia in humans: Mechanisms and consequences

人类对间歇性缺氧的反射反应：机制和后果

• 批准号: 9513791
• 负责人: Jacqueline K Limberg
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9513791
• 关键词: Action Potentials; Acute; Address; Adult; Air; Animal Model; Animals; Apnea; Award; Axon; Baroreflex; Breathing; Cardiovascular Diseases; Cardiovascular system; Chemoreceptors; Chronic; Clinical; Data; Depressed mood; Development; Disease Progression; Endothelin A Receptor; Endothelin-1; Exhibits; Exposure to; Functional disorder; Funding; Goals; Human; Human Volunteers; Hyperoxia; Hypertension; Hypoxia; Intravenous; Knowledge; Learning; Link; Measures; Mediating; Mentors; Muscle; Nerve; Neurons; Patients; Pattern; Pharmacology; Phase; Phenylephrine; Physiological; Placebos; Pressoreceptors; Recruitment Activity; Recurrence; Reflex action; Research; Risk; Role; Sleep Apnea Syndromes; Stimulus; Sympathetic Nervous System; Technical Expertise; Techniques; Testing; Therapeutic; Training; Translating; Work; blood pressure regulation; bosentan; cardiovascular disorder risk; career; clinically relevant; desensitization; design; experience; experimental study; innovation; neurovascular; novel; prevent; response; targeted treatment

PROJECT SUMMARY/ABSTRACT Sleep apnea is the most common form of sleep disordered breathing and patients with sleep apnea exhibit persistent activation of the sympathetic nervous system – which has known negative consequences, including the development of chronic hypertension. Intermittent hypoxia (IH) has been implicated as the primary stimulus for evoking increases in sympathetic activity and resultant hypertension with recurrent apneas. Evidence from animals suggests the persistent rise in sympathetic nervous system activity with IH occurs through changes in both chemoreflex and baroreflex function; however, little is known regarding the contribution of these reflexes to sympathetic discharge patterns in humans. Along these lines, research in animals supports a contribution of endothelin-1 to autonomic changes with IH, however these findings have yet to be translated to humans. Thus, the overall goal of this K99/R00 application is to better understand the effect of IH on sympathetic neuronal discharge patterns in humans, as well as mechanisms that mediate persistent sympathoexcitation with IH. We will use measures of sympathetic nervous system activity and a novel action potential analysis approach to test ideas about reflex-mediated sympathetic discharge patterns and contributing mechanisms in IH. In Aim 1, we will characterize sympathetic neuronal discharge patterns in response to acute IH in healthy humans. In Aim 2, we will use acute hyperoxia to identify the contribution of the carotid chemoreflex to sympathetic nervous system activation with IH. In Aim 3, we will use intravenous phenylephrine to identify the contribution of the baroreflex to sympathetic nervous system activation with IH. In Aim 4, we will identify the contribution of endothelin-1 to sympathetic discharge patterns with IH and its role in chemoreflex- and baroreflex-mediated changes in sympathetic nervous system activity. The proposed novel human studies are designed to provide a major step forward in understanding the link between IH and persistent sympathoexcitation – and by extension, hypertension and associated cardiovascular disease risk in humans with sleep apnea. To our knowledge, this is the first effort to understand sympathetic discharge patterns in response to IH in humans from both a descriptive (Aim 1) and mechanistic (Aims 2-4) standpoint. Importantly, we will collect basic physiological data under tightly-controlled conditions in healthy humans to systematically examine the effect of IH and identify key contributing mechanisms on sympathetic control that will be critical to our understanding prior to targeted work in patients with sleep apnea. By better understanding the effect of acute IH on sympathetic activity, therapeutic approaches can be designed to systematically normalize sympathetic control of the cardiovascular system in conditions of IH (e.g. sleep apnea) to prevent the development of hypertension and other complications related to sympathetic over-activity. Furthermore, these projects will serve as a vehicle to build upon the Applicant's training in neurovascular control and her recently completed F32-funded work by providing opportunities for her to gain additional knowledge and learn new experimental techniques and approaches. Importantly, this will also generate an investigative niche for the Applicant's intellectual and technical skill sets that will launch her independent career.

项目摘要/摘要 睡眠呼吸暂停是睡眠失调呼吸的最常见形式，睡眠呼吸暂停患者 交感神经系统的持续激活 - 已知负面后果，包括 慢性高血压的发展。间歇性缺氧（IH）被认为是主要的 诱发交感神经活动的刺激和复发性呼吸暂停的高血压增加。 来自动物的证据表明，IH发生交感神经系统活动的持续增长 通过变化化学反射和压力反射功能；但是，关于 这些反射对人类的交感神经放电模式的贡献。沿着这些思路进行研究 动物支持内皮素-1对IH的自主变化的贡献，但是这些发现尚未 被翻译成人类。这是此K99/R00应用程序的总体目标是更好地了解 IH对人类交感神经元排出模式的影响以及机制 与IH一起介导持续的同情兴趣。我们将使用交感神经系统的度量 活动和一种新型的动作潜在分析方法，用于测试有关反射介导的交感神经的想法 排放模式和IH的贡献机制。在AIM 1中，我们将表征同情神经元 响应健康人的急性IH的排放模式。在AIM 2中，我们将使用急性高氧 确定颈动脉化学反射对IH交感神经系统激活的贡献。在AIM 3中， 我们将使用静脉注射肾上腺素来识别降压反射对交感神经的贡献 IH的系统激活。在AIM 4中，我们将确定内皮素-1对交感神经排放的贡献 IH的模式及其在交感神经系统中的化学反射和压力反射介导的变化中的作用 活动。拟议的新型人类研究旨在为理解 IH与持续的交感神经激发 - 以及相关的高血压和相关的链接 睡眠呼吸暂停的人类心血管疾病的风险。据我们所知，这是了解 从描述性的人（AIM 1）和机械的人类中的IH响应IH的同情放电模式 （目标2-4）立场。重要的是，我们将在严格控制条件下收集基本物理数据 在健康的人类中，可以系统地检查IH的效果，并确定关键的促成机制对 在睡眠呼吸暂停患者的目标工作之前，对我们的理解至关重要，这对我们的理解至关重要。 通过更好地了解急性IH对交感活动的影响，可以是治疗方法 旨在系统地使心血管系统的交感神经控制 IH的（例如睡眠呼吸暂停），以防止高血压的发展和其他并发症 同情的过度活动。此外，这些项目将成为建立申请人的工具 神经血管控制的培训以及她最近完成的F32资助的工作，提供了机会 她获得额外的知识并学习新的实验技术和方法。重要的是，这将是 还为申请人的智力和技术技能生成一个调查台，以启动她 独立职业。