The research objectives of this proposal are to investigate the chemical control of respiration and to acquire new knowledge of control of respiration that can be applied to the investigation of patients with chronic obstructive pulmonary disease. Basic studies of ventilation and afferent neural output from the carotid bodies during transient and steady state hypoxia and hypercapnia at the carotid bodies will continue. These will consist of perfusion experiments in which forcing functions under open loop conditions are utilized in a control systems approach to the functional dissection of the respiratory control system. The effect of beta adrenergic stimulants and blockade on the transduction of chemical information to neural impulses in the carotid sinus nerve will be measured, with an emphasis on detection of possible coding of the afferent output. The mechanism of depression of the respiratory control system during supplemental oxygen administration in some patients with chronic obstructive pulmonary disease and carbon dioxide retention, but not in other patients with an apparantly comparable degree of airway obstruction, hypoxemia, and hypercapnia, needs to be defined. Animal studies will be conducted to establish the relationship between the level of putative amino acid neurotransmitters (gamma-aminobutyrate, glycine, glutamate and aspartate) in the pons and medulla, ventilation and degree of hypercapnia. Specific antagonists to GABA and glycine will establish the importance of endogenous levels of these amino acids as ventilatory depressants during hypercapnia. The relationship between level of amino acids in the pons and medulla and lumbar cerebrospinal fluid will be measured. This will provide information for use in human studies, where brain levels of glycine and glutamate must be estimated indirectly from levels of other amino acids in cerebrospinal fluid.
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