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

项目1摘要 根据美国国家睡眠基金会的一项研究，在美国，31%的男性和21%的女性患有高血压的风险很高 患有睡眠呼吸暂停(SA)。SA和增加的平均值之间存在因果关系 动脉压(MAP)和交感神经放电(SND)增加，即使在 不发生呼吸暂停发作的白天。慢性暴露于间歇性低氧(Cih)是一种广泛的 所用动物模型为SA期间发生的动脉低氧血症。动物的CIH结果是增加了 在人类SA患者中可见MAP和SND。脑出血还能增强下丘脑-垂体-肾上腺轴 对压力的反应。这个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儿茶酚胺能和 孤束核(NTS)内的谷氨酸能神经元，这提供了交感-兴奋驱动 这是CIH引起的MAP和SND持续升高的基础。提出了三个具体目标来 进一步检验这一假设。特定目标1将检验假设，在暴露于CIH的7天和28天内 动脉化学感受器传入刺激NTS A2神经元，激活HPA轴，并 诱导皮质醇释放。皮质醇然后增强谷氨酸能向NTS的传递，这有助于 CIH诱导的MAP和SND持续升高。具体目标2将检验以下假设：7和28 在CIH和CIHHC，来自PVN的CRF递减输入为儿茶酚胺能和 参与MAP和SND持续升高的谷氨酸能NTS神经元。《特定目标3》将进行测试 脑出血后7天和28天NTS神经元对缺血性损伤的抵抗力降低的假说 这是由于KATP电流的变化造成的。这些研究的结果将提供一个全面的分析 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。

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.