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.

项目概要/摘要 睡眠呼吸暂停是睡眠呼吸障碍最常见的形式，患有睡眠呼吸暂停的患者表现出 交感神经系统的持续激活——已知的负面后果包括 慢性高血压的发生被认为是主要的原因。 引起交感神经活动增加和由此导致的高血压并伴有反复呼吸暂停的刺激。 来自动物的证据表明 IH 导致交感神经系统活动持续升高 然而，我们对化学反射和压力反射功能的变化知之甚少。 沿着这些思路，研究人员研究了这些反射对人类交感神经放电模式的贡献。 动物支持内皮素 1 对 IH 自主神经变化的贡献，但这些发现尚未证实 因此，这个 K99/R00 应用程序的总体目标是更好地理解 IH 对人类交感神经放电模式的影响以及机制 通过 IH 介导持续的交感兴奋 我们将使用交感神经系统的措施。 活动和新颖的动作电位分析方法来测试反射介导的交感神经的想法 IH 中的放电模式和贡献机制 在目标 1 中，我们将描述交感神经元的特征。 在目标 2 中，我们将使用急性高氧来应对健康人的急性 IH 的放电模式。 通过 IH 确定颈动脉化学反射对交感神经系统激活的贡献。 我们将使用静脉注射去氧肾上腺素来确定压力反射对交感神经的贡献 在目标 4 中，我们将确定内皮素 1 对交感神经放电的贡献。 IH 模式及其在化学反射和压力反射介导的交感神经系统变化中的作用 拟议的新型人类研究旨在为理解这一问题迈出重要一步。 IH 与持续交感神经兴奋之间的联系，以及高血压和相关的 据我们所知，这是首次了解睡眠呼吸暂停患者的心血管疾病风险。 从描述性（目标 1）和机械性角度研究人类对 IH 的交感神经放电模式 （目标 2-4） 重要的是，我们将在严格控制的条件下收集基本的生理数据。 在健康人类中系统地研究 IH 的影响并确定关键的影响机制 交感神经控制对于我们在针对睡眠呼吸暂停患者开展针对性工作之前的理解至关重要。 通过更好地了解急性 IH 对交感神经活动的影响，可以采取治疗方法 旨在系统地使心血管系统的交感神经控制正常化 IH（例如睡眠呼吸暂停）以预防高血压和其他相关并发症的发生 此外，这些项目将成为在申请人的基础上发展的工具。 神经血管控制方面的培训以及她最近完成的 F32 资助的工作，为 她将获得更多知识并学习新的实验技术和方法。 还为申请人的智力和技术技能创造了一个调查利基，这将启动她 独立的职业生涯。