CNS mechanisms of ventilatory acclimatization to hypoxia

本项目的目的是确定慢性低氧血症患者低氧通气反应（HVR）发生时间依赖性变化的中枢神经系统的分子和神经生理机制。我们建议在中枢神经系统中使用氨基酸神经传递。此外，我们假设导致这些变化的分子事件代表了对Po2增加的特定反应和对神经活动变化的次要反应。慢性缺氧、颈动脉体去神经支配和慢性给药受体激动剂和拮抗剂到中枢神经系统的特定部位将被用来确定Po2对神经活动的独立影响。受体激动剂和拮抗剂的微注射或反向微透析将用于量化谷氨酸、GABA和一氧化氮在沿HVR反射通路的中枢神经系统核中的作用。神经递质水平、氨基酸受体蛋白及其mRNA将通过微透析/HPLC、放射自显影和定量RT-PCR检测。我们将使用类似的方法来检验假设，即间歇性和慢性缺氧期间不同时间的通气适应涉及不同的机制，即使测量的HVR变化可能相同。在缺氧暴露的任何时候，特定的一套机制的运作被预测取决于先前所引发的特定机制的顺序和性质，多巴胺在解释间歇性和持续缺氧HVR差异中的神经调节作用将在人类中进行研究。最后，我们将研究大鼠慢性缺氧时神经对氧气需求（即静息Vo2）的控制变化。我们假设上述研究中氨基酸神经传递的变化也会发生在髓质中对二氧化碳敏感的神经元中，这也解释了慢性缺氧时神经对Vo2控制的变化。这些结果将对慢性低氧血症期间的通气控制产生新的假设，并为慢性肺部疾病提供新的治疗方法。

The objective of this project is to determine the molecular and neurophysiological mechanisms in the CNS that cause time-dependent changes in the hypoxic ventilatory response (HVR) with chronic hypoxemia. We propose using amino acid neurotransmission in the CNS. Further, we hypothesize that the molecular events leading to these changes represent specific responses to increased Po2 and secondary responses to changes in neural activity. Chronic hypoxia, carotid body denervation and chronic administration of receptor agonists and antagonists to specific sites in the CNS will be used to determine the independent effects of Po2 versus neural activity. Microinjection or reverse microdialysis of receptor agonists and antagonists will be used to quantify the role of glutamate, GABA and nitric oxide in CNS nuclei along the HVR reflex pathway. Neurotransmitter levels, amino acid receptor proteins and their mRNA will be measured with microdialysis/HPLC, autoradiography and quantitative RT-PCR. We will use similar methods to test the hypotheses that different mechanisms are involved in ventilatory acclimatization at different times during intermittent and chronic hypoxia, even through the measured change in HVR may be identical. The specific suite of mechanisms operative at any time during hypoxic exposure is predicted to depend on the order and nature and nature of the specific mechanisms that have been elicited previously, The role of neuromodulation by dopamine in explaining differences in the HVR with intermittent and continuous hypoxia will be studied in humans. Finally, we will study changes in the neural control of O2 demand (i.e. resting Vo2) during chronic hypoxia in rats. We hypothesize that the same changes in amino acid neurotransmission studied above will occur in CO2-sensitive neurons in medulla also, and these explain changes in neural control of Vo2 during chronic hypoxia. The results should generate new hypotheses about ventilatory control during chronic hypoxemia, and suggest new treatments for chronic lung disease.