Reflex responses to intermittent hypoxia in humans: Mechanisms and consequences

项目摘要/摘要 睡眠呼吸暂停是睡眠呼吸紊乱的最常见形式，睡眠呼吸暂停患者表现为 持续激活交感神经系统--已知的负面后果，包括 慢性高血压的发展。间歇性低氧(IH)已被认为是主要的 用于唤起交感神经活动的刺激会增加交感神经活性，并导致反复出现呼吸暂停的高血压。 来自动物的证据表明，高血压患者交感神经系统活动持续增加 通过化学反射和压力反射功能的改变；然而，关于 这些反射对人类交感神经放电模式的贡献。沿着这些思路，在 动物支持内皮素-1在高血压自主神经改变中的作用，然而这些发现尚未 被翻译成人类。因此，此K99/R00应用程序的总体目标是更好地理解 高压氧对人交感神经元放电模式的影响及其机制 用IH介导持续性交感兴奋。我们将使用交感神经系统的测量方法 测试反射介导交感想法的活动和一种新的动作电位分析方法 高血压性脑脊髓炎的放电模式和致病机制。在目标1中，我们将描述交感神经元 健康人对急性高血压反应的放电模式。在目标2中，我们将使用急性高氧来 明确颈动脉化学反射在IH交感神经系统激活中的作用。在《目标3》中， 我们将使用静脉注射苯肾上腺素来确定压力感受器反射对交感神经的贡献。 用IH激活系统。在目标4中，我们将确定内皮素-1对交感神经放电的作用。 中枢性中耳炎的类型及其在化学反射和压力反射介导的交感神经系统改变中的作用 活动。拟议的新人体研究旨在为理解人类健康问题向前迈进一大步。 高血压和持续性交感神经兴奋之间的联系--进而，高血压和相关 睡眠呼吸暂停患者患心血管疾病的风险。据我们所知，这是第一次努力了解 人类对IH反应的交感放电模式既有描述性的(目标1)也有机械性的 (目标2-4)立场。重要的是，我们将在严格控制的条件下收集基本生理数据 以系统地检查IH的影响并确定主要的致病机制 交感神经控制对我们在对睡眠呼吸暂停患者进行有针对性的工作之前的理解至关重要。 通过更好地了解急性高血压对交感神经活动的影响，治疗方法可以 旨在系统地正常化交感神经对心血管系统的控制 预防高血压和其他与高血压相关的并发症 同情的过度活动。此外，这些项目将作为一种工具，在申请者的 神经血管控制方面的培训和她最近完成的F32资助的工作，为 她需要获得更多的知识并学习新的实验技术和方法。重要的是，这将 还为申请者的智力和技术技能创造了一个调查利基，这将使她 独立的事业。

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.