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通气相关传入输入之间的刺激相互依赖性的存在和生理意义。这种相互依赖性是预测的最新模型的基础上更新的神经解剖学知识的控制系统的控制。我们的方法将是量化的相互作用（hyperadditive，hypoadditive，或添加剂-即没有相互作用）的中央化学感受器与关键传入输入预测调制推定的中央化学传感器/积分。具体地，我们将测试以下对中枢化学感受器的增益的影响：a）在觉醒和睡眠期间对颈动脉体（CB）化学感受器的急性刺激和抑制; B）在觉醒（适应）期间对颈动脉体（CB）化学感受器的慢性低氧刺激; c）在CB化学感受器保持正常碳酸和常氧的情况下进行正常生理运动。为了实现这一点，我们将使用我们独特的未麻醉的动物制剂，其允许通过CB化学感受器的可逆分离和灌注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体化学感受器独立于中央化学感受器。我们预测，我们将观察到超加性的相互作用的中央化学感受器与所有关键的传入输入，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中呼吸控制的理解产生重大影响。我们的发现对于理解以下内容具有特别重要的意义：a）在含氧量正常的环境中，静息时自发性正常呼吸的正常驱动力是否严重依赖于CB化学感受器的紧张性感觉输入水平对中枢化学感受器/整合器的增益设定效应; B）睡眠呼吸暂停的发生; c）心力衰竭的周期性呼吸; e）中枢化学敏感性的增加是否显著地有助于健康中的运动呼吸过度，特别是在心力衰竭或慢性缺氧的存在下，即，在已知CB化学感受器敏感性上调的条件下。 公共卫生相关性：这项研究与公共卫生有关，因为它将试图解释健康和疾病中呼吸控制的一些基本机制。希望更好地理解这些机制将导致更好的解决方案，用于预防和/或治疗呼吸障碍，特别是睡眠呼吸暂停，以及心血管疾病如充血性心力衰竭中的运动不耐受。

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. PUBLIC HEALTH RELEVANCE: This study is relevant to public health because it will attempt to explain some of the fundamental mechanisms underlying the control of breathing in health and disease. It is hoped that better understanding of these mechanisms will lead to better solutions for prevention and/or treatment of breathing disorders, particularly that of sleep apnea, as well as exercise intolerance in cardiovascular diseases such as congestive heart failure.