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: 9253103
• 负责人: Steven W Mifflin
• 金额: $ 49.25万
• 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/9253103
• 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; Recruitment Activity; Resistance; Risk Factors; Rodent; Role; Sleep; Sleep Apnea Syndromes; Stress; Stroke; Synapses; System; Systems Analysis; Testing; Therapeutic; Tyrosine 3-Monooxygenase; Woman; Work; experimental study; high risk; hypothalamic-pituitary-adrenal axis; insight; men; mortality; pressure; relating to nervous system; 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