Alterations in chemoafferent integration induced by chronic intermittent hypoxia

描述(申请人提供)：慢性暴露于间歇性低氧(CIH)是睡眠呼吸暂停期间发生的动脉低氧血症的一种广泛使用的动物模型。动物的脑出血已被证明会导致血压升高，就像人类睡眠呼吸暂停患者一样，这种高血压依赖于交感神经系统(SNS)和血管紧张素(Ang11)。目前对CIH诱发高血压的解释包括动脉化学感受器的激活，为交感神经放电的持续增加提供了驱动力。孤束核(NTS)是动脉化学感受器传入纤维终末的主要中枢神经系统部位。这个项目的总体假设是，CIH重复激活动脉化学感受器增加了NTS中调节交感和HPA轴功能的神经元的放电和反应性。肾上腺类固醇皮质酮(CORT)已被证明在急性缺氧暴露后增加。皮质醇已被证明能增强中枢应用Ang11和NTS内Ang11的升压效应，从而促进突触和化学反射反应。据推测，Ang11介导的反应增强(钙内流增加)导致对兴奋性递质AMPA的反应增强。因此，NTS神经元对动脉化学感受器输入的敏感性增强，这是CIH后血压、交感神经放电和交感反应性升高的原因之一。推测NTS尾侧的儿茶酚胺能(A2)和谷氨酸能神经元是这些改变发生的主要部位。具体目标1：第一个目标是描述NTS神经元在暴露于CIH期间的反应和适应，以及低氧在介导/调节对化学感受器传入输入的反应中所起的作用。具体目标2：第二个目标是确定糖皮质激素II型受体作为NTS神经元适应性变化的中介的作用。具体目标3：第三个目标是确定血管紧张素在CIH诱导的NTS神经元改变中的作用。这些研究结果将对CIH导致血压升高、交感神经放电和交感反应的机制提供新的见解。这些因素在很大程度上介导了与睡眠呼吸暂停相关的病理，包括高血压、不良心血管事件风险增加和胰岛素抵抗。

DESCRIPTION (provided by applicant): Chronic exposure to intermittent hypoxia (CIH) is a widely used animal model of the arterial hypoxemia that occurs during sleep apnea. CIH in animals has been shown to result in an increased blood pressure as seen in human sleep apnea patients and this hypertension is dependent upon the sympathetic nervous system (SNS) and angiotensin (Angll). Current explanations for CIH-induced hypertension include arterial chemoreceptor activation providing a driving force for a persistent increase in sympathetic nerve discharge. The nucleus of the solitary tract (NTS) is the primary CNS site of termination of arterial chemoreceptor afferent fibers. The overall hypothesis of this project is that repetitive activation of the arterial chemoreceptors by CIH increases the discharge of and the responsiveness of neurons in the NTS that regulate sympathetic and HPA axis function. The adrenal steroid corticosterone (CORT) has been shown to be increased following acute exposures to hypoxia. CORT has been shown to enhance the pressor effect of centrally administered Angll and Angll within the NTS facilitates synaptic and chemoreflex responses. It is hypothesized that enhanced Angll mediated responses (increased calcium influx) result in enhanced responses to the excitatory transmitter AMPA. As a result, the sensitivity of NTS neurons to arterial chemoreceptor inputs is enhanced which contributes to the elevations in blood pressure, sympathetic nerve discharge and sympathetic reactivity observed after CIH. It is hypothesized that catecholaminergic (A2) and glutamatergic neurons in the caudal NTS are the primary sites where these alterations occur. Specific Aim 1: The first goal is to characterize how NTS neurons respond and adapt during exposure to CIH and the role of hypoxia in mediating/modulating responses to chemoreceptor afferent inputs. Specific Aim 2: The second goal is to determine the role of the glucocorticoid Type II receptor as a mediator of these adaptive changes in NTS neurons. Specific Aim 3: The third goal is to determine the role of angiotensin in the alterations in NTS neurons induced by CIH. The results of these studies will provide new insights into the mechanisms whereby CIH leads to elevated blood pressure, sympathetic nerve discharge and sympathetic reactivity. These factors mediate much of the pathology associated with sleep apnea including hypertension, increased risk of adverse cardiovascular events and insulin resistance.