Intermittent hypoxia and carotid body activity

描述(由申请人提供)： 这个项目的总体目标是定义慢性萎缩性胃炎 间歇性低氧(CIH)影响颈动脉体氧感受能力。 这项建议是基于我们的初步数据，表明：A)CIH 增强颈动脉小体对低氧和诱导的感觉反应 基线感觉活动的长时间激活类似于 呼吸运动输出的长时程易化现象；b)5- 羟色胺受体阻滞剂阻止感觉放电中的LTF，但不能增强 低氧敏感性；以及c)可比较的持续低氧时间(SH) 既没有增强对低氧的反应，也没有在感觉上诱导LTF 出院。这些观察表明：1)低氧的间歇性模式 在影响颈动脉体部功能方面比持续低氧更有效；以及 2)CIH影响颈动脉低氧敏感性的机制 在基线活动中，身体似乎不同于那些诱发LTF的人。这个 目前的提议检验了两个主要假设：1)CIH诱导的 颈动脉小体的低氧敏感性涉及体内 血管球体细胞内钙浓度的动态平衡和/或下调 抑制性递质(S)和/或球体细胞数量增加；和2)5- 羟色胺机制是CIH诱导大鼠感觉放电LTF的关键机制。 颈动脉小体。目标1中的实验确定了导致CIH诱导的因素 对颈动脉LTF的诱导和敏感性的提高 尸体。在目标2中提出的实验，测试内部是否有变化 血管球体细胞内钙浓度的动态平衡和/或下调 抑制性神经递质，如一氧化氮(NO)，和/或 球体细胞(可能是氧气敏感细胞)的数量对 颈动脉小体对化学药物的敏感性升高。在目标3中，我们将测试 认为5-羟色胺依赖机制在LTF的诱导中起关键作用 在颈动脉小体。目标4中的实验确定了CIH诱导的 基础感觉活动中低氧敏感性和长期转铁蛋白的增加 颈动脉体常转化为通气性改变。这个项目是 主题链接到项目18、14、19、16和20。此外，它还 卡茨、昆泽、迪克和库马尔博士的协作互动。 由此得出的呼吸机数据 项目将被纳入使用Core 9007的数学模型 设施。

DESCRIPTION (provided by applicant): The overall goal of this project is to define the mechanisms by which chronic intermittent hypoxia (CIH) affects O2 sensing ability of the carotid body. This proposal is based on our preliminary data suggesting that: a) CIH enhances the sensory response of the carotid body to hypoxia and induces prolonged activation of the baseline sensory activity resembling the phenomenon of long-term facilitation (LTF) in respiratory motor output; b) 5- HT receptor blockers prevent LTF in the sensory discharge but not the enhanced hypoxic sensitivity; and c) comparable duration of sustained hypoxia (SH) neither enhances the response to hypoxia nor induces LTF in the sensory discharge. These observations indicate that: 1) episodic pattern of hypoxia is more potent than continuous hypoxia in affecting carotid body function; and 2) the mechanisms by which CIH affects the hypoxic sensitivity of the carotid body seem to differ from those that induce LTF in the baseline activity. The current proposal tests two primary hypotheses: 1) the CIH-induced increase in hypoxic sensitivity of the carotid body involves alterations in internal calcium concentration homeostasis in glomus cells and/or down regulation of inhibitory transmitter(s) and/or increase in number of glomus cells; and 2) 5- HT mechanisms are critical for CIH-induced LTF in the sensory discharge in the carotid body. Experiments in Aim 1 define the factors that contribute to CIH-induced heightened sensitivity and to the induction of LTF in the carotid body. Experiments proposed in Aim 2, test whether alterations in internal calcium concentration homeostasis in glomus cells, and/or down-regulation of inhibitory neurotransmitters such as nitric oxide (NO), and/or an increase in the number of glomus cells (putative O2 sensing cells) contribute to the heightened chemosensitivity of the carotid body. In Aim 3, we will test the idea that 5-HT dependent mechanisms play a critical role in induction of LTF in the carotid body. Experiments in Aim 4 determine whether CIH-induced increases in hypoxic sensitivity and LTF in baseline sensory activity of the carotid body are translated to changes in ventilation. This project is thematically linked to Projects 18, 14, 19, 16, and 20. In addition, it has collaborative interactions from Drs. Katz, Kunze, Dick, and Kumar. The ventilatory data derived from this project will be incorporated into mathematical model utilizing Core 9007 facilities.