The long-term objective of this proposal is to understand the role of brain hypoxia in ventilatory and cardiovascular control. This is a crucial and controversial question, as it impinges upon both our fundamental understanding of how hypoxia affects central ventilatory and cardiovascular control systems and upon the pathophysiology of these control systems, particularly as they relate to sleep disordered breathing, hypertension, respiratory failure, and environmental hypoxia. To address this question adequately, we must also investigate fundamental questions about the physiology of the carotid body. Much of our knowledge about the integrative aspects of carotid body physiology may be based on animal and human models that were not appropriate to the problem. Accordingly, this proposal has 3 specific aims: 1) How does specific CNS hypoxia affect the control of ventilation and blood pressure? 2) What are the relative contributions of carotid body and central chemoreceptors to the ventilatory response to hypercapnia? 3) Is tonic carotid body afferent input important to the total system response to other stimuli? To accomplish these goals we will use a unique unanesthetized canine model that allows separation of the circulation to the carotid bodies from that of the rest of the systemic circulation so that peripheral and CNS responses can be studied separately in a neurally intact, unanesthetized preparation that can be studied during normal wakefulness and sleep. To date, we have used our unanesthetized carotid body perfusion to obtain preliminary data suggesting that specific CNS hypoxia stimulates breathing, and carotid body hyperoxia can reduce or eliminate the hyperventilatory response to CNS hypoxia. We also have preliminary data suggesting that carotid body denervation causes time-dependent changes in the CNS response to hypercapnia and thus may not be an appropriate model for studies designed to assess relative contributions of central and peripheral chemoreceptors.
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