The objective of this project is to determine the physiological mechanisms of time-dependent changes in the hypoxic ventilatory response (HVR) that occur with chronic hypoxemia.. Although acute ventilatory responses have been studied intensely, many new time-dependent adaptations of the HVR have been described only recently and their mechanisms are unknown. They likely represent a major unresolved problem for patients with lung disease and normal subjects adapting to altitude. We hypothesize that ventilatory adaptations to chronic hypoxia involve neural adaptations at two levels; enhanced carotid body O2 sensitivity in the peripheral nervous system, and enhanced processing of arterial chemoreceptor afferent input in the CNS. We have developed a model that provides continuous measurement of unrestrained ventilation and arterial blood gases ot study this problem. The model permits studying the HVR in isocapnia and at different controlled levels of central ventilatory drive before and after acclimatization to different O2 and CO2 levels. The model will be used to test the hypotheses that; (A) chronic hypoxia increases carotid body O2-sensitivity by decreasing dopaminergic (DA) inhibition, (B) chronic hypoxia increases CNS respiratory center sensitivity to arterial chemoreceptor afferent input, and (C) such CNS adaptations involve excitatory DA and serotonergic (5-HT) mechanisms specific to chemoreflex neural pathways. In addition to the ventilatory response to arterial chemoreceptor stimulation with doxapram, cyanide and nicotine will be measured before and after chronic hypoxia. Chemoreceptor activity will be recorded from the carotid sinus nerve in anesthetized animals to quantify carotid body adaptations to chronic hypoxia. The roles of hypoxia and hypocapnia will be compared by making measurements in acclimatized isocapnic hypoxia. Adaptations not involving arterial chemoreceptors will be studied with carotid body denervation. The roles of DA and 5-HT adaptations will be studied with antagonists applied independently to arterial chemoreceptors and the CNS. Anesthetized animals will be used to measure changes in the effects of DA or 5-HT antagonists on the phrenic nerve response to carotid sinus nerve stimulation before and after chronic hypoxia. The specificity of the CNS neurotransmitter adaptations to the chemoreflex pathway will be tested by brain stem stimulation and microinjection experiments in anesthetized animals. These experiments should generate hypotheses about the role of ventilatory chemoreflex adaptations to chronic hypoxia in humans with health and diseased lungs.
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