CNS mechanisms of ventilatory acclimatization to hypoxia

本项目的目的是确定在中枢神经系统的分子和神经生理学机制，导致慢性低氧血症的缺氧性反应（HVR）的时间依赖性变化。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Po 2增加的特异性反应和对神经活动变化的继发性反应。慢性缺氧，颈动脉体去神经支配和慢性给药的受体激动剂和拮抗剂在中枢神经系统中的特定部位将被用来确定独立的影响Po 2与神经活动。受体激动剂和拮抗剂的显微注射或反向微透析将用于定量谷氨酸、GABA和一氧化氮在CNS核沿着HVR反射途径中的作用。神经递质水平、氨基酸受体蛋白及其mRNA将采用微透析/HPLC、放射自显影和定量RT-PCR进行测量。我们将使用类似的方法来检验假设，即在间歇性和慢性缺氧期间的不同时间，不同的机制参与了解释性习服，即使测量的HVR变化可能是相同的。预测在低氧暴露期间的任何时间操作的机制的特定套件取决于先前已经引起的特定机制的顺序和性质和性质。将在人类中研究多巴胺在解释具有间歇性和连续性低氧的HVR的差异中的神经调节作用。最后，我们将研究在慢性缺氧大鼠的O2需求（即休息Vo 2）的神经控制的变化。我们推测，同样的变化，氨基酸神经传递研究上述将发生在CO2敏感的神经元在延髓也，这些解释的变化，在神经控制的VO 2在慢性缺氧。这些结果将产生关于慢性低氧血症时呼吸控制的新假设，并为慢性肺病提出新的治疗方法。

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.