The first major goal of this project is to examine ventilatory control mechanisms operating in prolonged exposure to hypoxia, i.e., ventilatory acclimatization to hypoxia (VAH) and deacclimatization upon return to normoxia. A second major goal is to better understand mechanism(s) of central-peripheral chemoreceptor interaction in the control of breathing . Two experimental approaches will be used: a) the awake goat carotid body (CB) perfusion model which allows separation and control of arterial blood gases reaching the CB from those reaching the brain, and b) the recording of single chemoreceptor fiber afferent activity from the CB of anesthetized goats and dogs and decerebrate dogs. The 1st specific aim is to determine if diminishing stimuli at the CB will produce VAH in the awake goat CB perfusion model and time-dependent increase in CB afferent activity as occurs with steady-state isocapnic-hypoxic stimulation. A 2nd aim is to determine what mechanisms contribute to the time-dependent, hypoxia-induced increasing CB activity observed in goats. We will measure afferent CB activity in goats and dogs before, during and after 4 hours of hypoxia to answer these questions: Is increasing CB activity during hypoxia a species specific phenomenon? Does CB dopamine depletion or increased responsiveness to CB stimuli other than hypoxia contribute to it? Does anesthesia or nerve degeneration confound these studies? We will also initiate studies of CB monoamine metabolism in VAH. A 3rd aim is to determine if central or peripheral chemoreceptor mechanisms or a combination of both, produce the maintained hyperventilation (decclimatization) occurring upon removal of CB (or whole animal) hypoxia? This question will be answered in part by studies described above under aim 2. We will also use the awake goat CB perfusion model to examine the role of central and peripheral chemoreceptors in deacclimatization by measuring separately the systemic hyperoxic-hypercapnic ventilatory response (central chemoreceptors) and the ventilatory response to CB hypercapnia before and after VAH induced by 4 hours of CB hypoxia. A 4th aim is to utilize the unique awake goat CB perfusion model to examine the interaction between central and peripheral chemoreceptors. The model avoids two major problems, anesthesia and brain hypoxia. The ventilatory response to systemic arterial hyperoxic-hypercapnia (central chemoreceptor stimulation) will be applied at three levels of CB stimulation. The proposed experiments will improve our understanding of ventilatory control in hypoxic states.
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