Neurohumoral Adaptations Induced by Intermittent Hypoxia Lead to Enhanced Chemoreflex Drive and Persistent Sympatho-Excitation

间歇性缺氧引起的神经体液适应导致化学反射驱动增强和持续交感神经兴奋

• 批准号: 9096156
• 负责人: Steven W Mifflin
• 金额: $ 51.25万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-05 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9096156
• 关键词: Acute; Animal Model; Animals; Apoptosis; Blood Pressure; CRH gene; Cardiovascular Diseases; Cardiovascular system; Chemoreceptors; Chronic; Communication; Corticosterone; Data; Event; Exposure to; Foundations; Functional disorder; Funding; Glutamates; Goals; Human; Hypercapnia; Hypertension; Hypoxemia; Hypoxia; Injury; Ischemia; Lead; Life; Mediating; Metabolic; Modeling; Morbidity - disease rate; Myocardial Infarction; Necrosis; Nerve; Neurons; Nucleus solitarius; Pathway interactions; Patients; Phenotype; Play; Rattus; Resistance; Risk Factors; Rodent; Role; Sleep; Sleep Apnea Syndromes; Stress; Stroke; Synapses; System; Systems Analysis; Testing; Therapeutic; Tyrosine 3-Monooxygenase; Woman; Work; abstracting; high risk; hypothalamic-pituitary-adrenal axis; insight; men; mortality; pressure; relating to nervous system; research study; response; transmission process

Project 1 Abstract According to a National Sleep Foundation study, 31% of men and 21% of women in the US are at high risk of suffering from sleep apnea (SA). There is a cause-and-effect relationship between SA and increased mean arterial pressure (MAP) and increased sympathetic nerve discharge (SND) which persist even during the daytime when apneic episodes are not occurring. Chronic exposure to intermittent hypoxia (CIH) is a widely used animal model of the arterial hypoxemia that occurs during SA. CIH in animals results in an increased MAP and SND as seen in human SA patients. CIH also enhances the hypothalamic-pituitary-adrenal axis response to stress. The overall hypothesis of this project is that repetitive activation of the arterial chemoreceptors during CIH increases the discharge of and the responsiveness of catecholaminergic and glutamatergic neurons in the nucleus of the solitary tract (NTS) and this provides a sympatho-excitatory drive that underlies the CIH-induced persistent increase in MAP and SND. Three specific aims are proposed to further test this hypothesis. Specific Aim 1 will test the hypothesis that during 7 and 28 days exposure to CIH and CIHHC, arterial chemoreceptor afferents stimulate NTS A2 neurons which activate the HPA axis and induce release of CORT. CORT then enhances glutamatergic transmission to NTS which contributes to the CIH-induced sustained increase in MAP and SND. Specific Aim 2 will test the hypothesis that following 7 & 28 days CIH and CIHHC, descending CRF inputs from PVN provide an excitatory drive to catecholaminergic and glutamatergic NTS neurons that contributes to the sustained increase in MAP and SND. Specific Aim 3 will test the hypothesis that the resistance of NTS neurons to ischemic injury is reduced following 7 & 28 days CIH and CIHHC due to changes in KATP currents. The results of these studies will provide a comprehensive analysis from the system to the cellular level of neuronal and humoral adaptations to CIH will provide new insights into the mechanisms whereby CIH leads to elevated MAP and SND.

项目1 根据国家睡眠基金会的一项研究，美国31%的男性和21%的女性处于高风险状态， 睡眠呼吸暂停综合征（sleep apnea，SA）SA和平均值增加之间存在因果关系 动脉压（MAP）和交感神经放电（SND）增加，即使在 白天，呼吸暂停发作不发生。慢性间歇性低氧暴露（CIH）是一种广泛的 使用SA期间发生的动脉低氧血症的动物模型。CIH在动物中导致 在人类SA患者中观察到的MAP和SND。CIH还增强下丘脑-垂体-肾上腺轴 对压力的反应。该项目的总体假设是动脉的重复激活 CIH期间的化学感受器增加了儿茶酚胺能神经元的放电和反应性， 孤束核（NTS）中的交感神经能神经元，这提供了交感兴奋驱动 这是CIH诱导的MAP和SND持续增加的基础。提出了三个具体目标， 进一步验证这一假设。具体目标1将检验以下假设：在CIH暴露7天和28天期间， 和CIHHC，动脉化学感受器传入刺激激活HPA轴的NTS A2神经元， 诱导CORT释放。CORT然后增强了向NTS的突触能传递，这有助于 CIH诱导MAP和SND持续增加。具体目标2将测试以下假设7和28 在CIH和CIHHC天，来自PVN的下行CRF输入提供了对儿茶酚胺能和 谷氨酸能NTS神经元有助于MAP和SND的持续增加。第3章测试 假设在CIH后7 & 28天，NTS神经元对缺血损伤的抵抗力降低， CIHHC由于KATP电流的变化。这些研究的结果将提供全面的分析 从系统到细胞水平的神经元和体液适应CIH将提供新的见解， CIH导致MAP和SND升高的机制。