Peripheral and Central Interactions in Ventilatory Control

描述（由申请人提供）：本提案的总体目标是确定中枢化学接受/整合中心与其他外周和中枢通气相关传入输入之间通气刺激相互依赖的存在及其生理意义。这种相互依赖是由最近的通气控制模型预测的，该模型基于更新的通气控制系统的神经解剖学知识。我们的方法将是量化中枢化学感受器与关键传入输入的相互作用（超加性、低加性或加性-即无相互作用），预测这些输入可以调节假定的中枢化学感受器/积分器。具体来说，我们将测试对中枢化学感受器增益的影响：a)清醒和睡眠期间颈动脉体（CB）化学感受器的急性刺激和抑制；b)清醒时颈动脉体（CB）化学感受器的慢性缺氧刺激（适应）；c)正常生理运动，使CB化学感受器保持常值和常值。为了实现这一目标，我们将使用我们独特的非麻醉动物制剂，通过可逆分离和灌注CB化学感受器来分离中枢和周围化学感受器的环境。使用该制剂，我们可以刺激、抑制或维持颈动脉体化学感受器独立于中枢化学感受器的正常。我们预测，我们将观察到中枢化学感受器与所有关键传入输入的超加性相互作用，从而确认它们之间的相互依存关系。如果得到证实，这一概念将对我们目前对健康和疾病呼吸控制的理解产生重大影响。我们的研究结果对于理解以下问题具有特别重要的意义：a)在常压环境中，正常的自发呼吸是否取决于中枢化学感受器/整合器的增益设定效应，该效应是由来自CB化学感受器的紧张性感觉输入水平决定的；B)睡眠呼吸暂停的起源；C)周期性呼吸性心力衰竭；D)存在慢性缺氧的任何病理或环境情况；e)中枢性化学敏感性的增加是否对健康，特别是在心力衰竭或慢性缺氧的情况下（即在已知CB化学受体敏感性上调的情况下）的运动性呼吸急促有显著贡献。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to determine the existence and physiological significance of interdependence of ventilatory stimuli between central chemoreceptive/integrative centers and other peripheral and central ventilatory-related afferent inputs. Such interdependence is predicted by a recent model of ventilatory control based on newer neuroanatomical knowledge of the ventilatory control system. Our approach will be to quantify the interaction (hyperadditive, hypoadditive, or additive - i.e. no interaction) of the central chemoreceptors with key afferent inputs predicted to modulate the putative central chemosensors/integrator. Specifically, we will test the effect on the gain of the central chemoreceptors of: a) acute stimulation and inhibition of carotid body (CB) chemoreceptors during wakefulness and sleep; b) chronic hypoxic stimulation of carotid body (CB) chemoreceptors during wakefulness (acclimatization); c) normal physiological exercise with CB chemoreceptors held normocapnic and normoxic. To achieve this we will use our unique unanesthetized animal preparation, which allows separation of the environments of the central and peripheral chemoreceptors by means of reversible isolation and perfusion of the CB chemoreceptors. Using this preparation we can stimulate, inhibit, or maintain normal the carotid body chemoreceptors independently from the central chemoreceptors. We predict that we will observe hyperadditive interaction of the central chemoreceptors with all key afferent inputs thus confirming an interdependence between them. If confirmed, this concept will have a significant impact on our current understanding of the control of breathing in both health and disease. Our findings could be of particular importance in understanding: a) if the normal drive to spontaneous eupnea at rest in a normoxic environment depends critically on a gain-setting effect on the central chemoreceptor/integrator by the level of tonic sensory input from the CB chemoreceptors; b) the genesis of sleep apnea; c) the periodic breathing of heart failure; d) any pathological or environmental situation where chronic hypoxia is present; e) whether increased central chemosensitivity contributes significantly to exercise hyperpnea in health and especially in the presence of heart failure or chronic hypoxia, i.e., under conditions where CB chemoreceptor sensitivity is known to be upregulated.