Sympathetic activation by intermittent hypoxia

间歇性缺氧激活交感神经

• 批准号: 6564829
• 负责人: THOMAS E DICK
• 金额: $ 26.7万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564829
• 关键词: GABA receptor; brain stem; enzyme inhibitors; hypoventilation; hypoxia; laboratory rat; neural information processing; neural plasticity; neuroregulation; nitric oxide synthase; phrenic nerve; pons; pulmonary respiration; respiration regulatory center; respiratory hypoxia; sympathetic nervous system

DESCRIPTION (provided by applicant): The ventrolateral pons plays a key role in the short-term depression (STD) in respiratory frequency following hypoxia; and serotonin, as well as nitric oxide, play a part in the development of long-term facilitation (LTF) following repetitive bouts of hypoxia. GABAa-receptor sub-units in the pontomedullary circuits controlling sympathetic nerve activation (SNA) and phrenic nerve activity (PNA) show differential expression of mRNA following conditioning with hypoxia. Our data indicate that respiratory modulation of SNA not only occurs in a reduced preparation but also quantitatively (increases) and quantitatively changes its activation pattern within a breathing cycle during and following brief periods of hypoxia. Thus, we hypothesize that the up-regulation of SNA results from plasticity in the respiratory neural systems associated with repetitive hypoxic events, a study design called conditioning. To test this hypothesis, we propose a series of neurophysiologic and molecular biologic experiments addressing the following specific aims: 1) to differentiate central versus peripheral mechanisms underlying the increases in SNA following conditioning, 2) to correlate the short-term potentiation and depression (STD) as well as long-term facilitation (LTF) evident in phrenic nerve activity (PNA) with changes in SNA, and 3) to characterize the temporal expression of subunits of GABAa receptors in the brainstem nuclei controlling SNA and PNA in this study design, and 4) to compare the effects of CIH conditioning in two rodent strains with different responses to hypoxia and to nitric oxide synthetase inhibitors. This approach provides an opportunity to determine whether these animals develop increased SNA in proportion to the hypoxic response, and the interrelationship of sympathetic and respiratory control plasticity. These proposed studies examine neurophysiologic and molecular mechanisms relevant to the up-regulation of SNA activity which seems to occur in clinical conditions associated with repetitive hypoxia; e.g., sleep apnea and congestive heart failure.

描述（由申请人提供）： 腹外侧脑桥在短期抑郁（STD）中起着关键作用 缺氧后呼吸频率；和血清素以及硝酸 氧化物，在长期促进（LTF）的发展中发挥作用 反复缺氧后。 GABAa 受体亚基 脑桥延髓回路控制交感神经激活（SNA）和 膈神经活动 (PNA) 显示以下 mRNA 的差异表达 进行缺氧调理。我们的数据表明，呼吸调节 SNA 不仅以减少的制备方式发生，而且还以定量方式发生 （增加）并在一定范围内定量地改变其激活模式 短暂缺氧期间和之后的呼吸周期。因此，我们 假设 SNA 的上调是由于 呼吸神经系统与重复性缺氧事件相关，一项研究 设计称为调节。为了检验这个假设，我们提出了一系列 神经生理学和分子生物学实验解决以下问题 具体目标：1）区分中枢机制和外周机制 调节后 SNA 增加的基础，2) 将 短期增强和抑制（STD）以及长期促进 (LTF) 膈神经活动 (PNA) 明显，且 SNA 发生变化，并且 3) 表征 GABAa 受体亚基的时间表达 在本研究设计中，脑干核控制 SNA 和 PNA，4) 比较 CIH 调节对两种不同啮齿动物品系的影响 对缺氧和一氧化氮合成酶抑制剂的反应。这种做法 提供了一个机会来确定这些动物是否发育增强 SNA 与缺氧反应的比例，以及相互关系 交感神经和呼吸控制可塑性。这些拟议的研究 检查与上调相关的神经生理学和分子机制 临床条件下似乎发生的 SNA 活性 与反复缺氧有关；例如，睡眠呼吸暂停和充血性心脏 失败。