CAROTID BODY CHEMORECEPTION--MECHANISMS & DEVELOPMENT

颈动脉体化学感受器是引起 通气量随着PaO 2或pHa的降低而增加。 这 出生时反应较弱，在最初几周内反应增强 生命 虽然传入窦神经活动与 和PaO 2或pHa的特点，转导机制和 成熟是不理解的。 血管球细胞，与 传入神经末梢是最可能的转导部位， 在血管球细胞破坏后化学敏感性被消除。 然而，在这方面， 血管球细胞对缺氧反应的电生理研究结果 实验室和制剂之间存在不一致。 为 例如，存在相反的证据，即血管球细胞是电性的， 兴奋和不兴奋，膜离子电流增加， 随着缺氧而减少。 为了解决这些问题并了解 化学敏感性及其发展变化，我们建议采用贴片 血管球细胞的钳记录和光学测量， 急性分离自兔子。 我们的初步结果表明 我们从血管球中采集、膜片钳和光学记录的能力 成人和新生儿的细胞。 我们已经证明了缺氧性缺氧 和组织毒性缺氧引起特定的，但相反的， 血管球细胞表达的电压依赖性外向电流， 新生血管球细胞对两种药物的反应均不存在或降低。 提出了以下一般假设： 缺氧是由Ca++结合蛋白的O2依赖性变化介导的。 以下问题将得到解决：1）发生了什么变化 成人血管球钠、钾、钙离子膜电流 细胞对缺氧的反应，增加H+和减少能量 生产？2)血管球细胞内Ca ~（++）和pH是如何调节的 细胞和水平是否会随着缺氧而变化？3)哪些变化导致了 颈动脉体缺氧敏感性的成熟增加？ 的 这项工作的预期结果将使我们能够更好地了解 成熟过程中的化学感受器转导机制。 这可能 导致可以改变化学敏感性的治疗策略， 从而改善新生儿呼吸暂停和换气不足的治疗， 老话题

Carotid body chemoreceptors are the primary sensory organs that cause ventilation to increase in response to a decrease in PaO2 or pHa. This responsiveness is weak at birth and increases during the first few weeks of life. Although the relationship between afferent sinus nerve activity and PaO2 or pHa is well characterized, the mechanisms of transduction and maturation are not understood. The glomus cell, in apposition to the afferent nerve ending, is the most likely site of transduction since chemosensitivity is ablated following glomus cell destruction. However, results of electrophysiologic studies on glomus cell response to hypoxia have been inconsistent between laboratories and preparations. For instance, opposing evidence exists that glomus cells are electrically excitable and unexcitable and that membrane ionic currents increase and decrease with hypoxia. In order to resolve these issues and understand the basis for chemosensitivity and its developmental change, we propose to employ patch clamp recording and optical measurements of glomus cells which are acutely isolated from rabbits. Our preliminary results have established our ability to harvest, patch-clamp and optically record from glomus cells of adults and newborns. We have demonstrated that hypoxic hypoxia and histotoxic hypoxia cause specific, but opposite, changes in a voltage-dependent outward current expressed in glomus cells, and the response to both agents is absent or reduced in the newborn glomus cell. The following general hypothesis is formulated: Chemotransduction of hypoxia is mediated by an O2 dependent change in a Ca++ binding protein. The following questions will be addressed: 1) What changes occur in sodium, potassium and calcium ionic membrane currents of adult glomus cells in response to hypoxia, increased H+ and decreased energy production? 2) How are intracellular Ca++ and pH regulated in glomus cells and do levels change with hypoxia? 3) What changes account for the maturational increase in carotid body hypoxia sensitivity? The anticipated results from this work will allow us to better understand the mechanisms of chemoreceptor transduction during maturation. This may lead to therapeutic strategies that can alter chemosensitivity and thereby improve treatment of apnea and hypoventilation in the neonate and older subject.