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感受/整合中心与其他外周和中枢呼吸相关传入输入之间的呼吸性刺激的相互依赖的存在及其生理意义。最近的一种基于对呼吸控制系统的新的神经解剖学知识的呼吸控制模型预测了这种相互依赖。我们的方法将是量化中枢化学感受器与关键传入输入之间的相互作用(高加性、低加性或加性-即没有相互作用)，这些关键传入输入被预测为调节假定的中枢化学传感器/整合子。具体地说，我们将测试以下因素对中枢化学感受器获得的影响：a)清醒和睡眠时颈动脉小体(CB)化学感受器的急性刺激和抑制；b)清醒(习服)期间颈动脉小体(CB)化学感受器的慢性低氧刺激；c)正常生理运动中颈动脉小体(CB)化学感受器保持常压和常氧。为了实现这一点，我们将使用我们独特的未麻醉动物制剂，它允许通过可逆地分离和灌流CB化学感受器来分离中枢和外周化学感受器的环境。使用这种制剂，我们可以刺激、抑制或维持正常的颈动脉小体化学感受器，而不依赖于中枢化学感受器。我们预测，我们将观察到中枢化学感受器与所有关键的传入输入之间的高加性相互作用，从而证实了它们之间的相互依赖。如果得到证实，这一概念将对我们目前对健康和疾病中呼吸控制的理解产生重大影响。我们的发现在理解以下方面可能特别重要：a)在常氧环境中正常驱动静息状态下自发的Eupnea是否严重依赖于CB化学感受器的紧张性感觉输入对中枢化学受体/整合分子的增益设定效应；b)睡眠呼吸暂停的发生；c)心力衰竭的周期性呼吸；d)存在慢性缺氧的任何病理或环境情况；e)中枢化学敏感性增强是否显著导致健康的运动性高呼吸，尤其是在存在心力衰竭或慢性低氧的情况下，即已知CB化学感受器敏感性上调的情况下。

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.