The research objectives of this proposal are to investigate the chemical control of respiration, and to develop new knowledge of control of respiration that can be applied to the therapy of patients with chronic obstructive pulmonary disease. Basic animal studies will be undertaken to directly measure the influence of hypoxia and hypercapnia on cerebral blood flow and tissue oxygen and carbon dioxide tensions in the medullary ventrolateral chemosensitive areas for correlation with ventilation. Reversal of local tissue oxygen deficit by superfusion with flourocarbons over the chemosensitive area will be used to determine whether hypoxia of the central chemoreceptors contributes to ventilatory depression. A second specific area to be investigated in this proposal is alteration of medullary amino acids in animals under conditions of combined hypoxia- hypercapnia characteristic of carbon dioxide narcosis. 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 apparently comparable degree of airway obstruction, hypoxemia and hypercapnia, needs to be defined. Of every 100 patients with chronic obstructive pulmonary disease admitted to the hospital with an exacerbation of their disease requiring supplemental oxygen therapy, 25 develop progressive carbon dioxide retention and CO2 narcosis. Approximately 5% die. Prime candidates among the possible causes for this respiratory failure are alteration of amino acid neurotransmitters in the area of the respiratory center neurons or central medullary chemoreceptor tissue. Measurements in the proposed animal model will be made of the excitatory transmitter amino acids, glutamate and aspartate; the depressant transmitter amino acid, glycine and gamma-aminobutyrate (GABA); and the depressant neuromodulator amino acid, taurine. The relationship between the level of amino acids in the medulla, lumbar cerebrospinal fluid, and plasma will be measured to provide information for use in human studies where brain levels of these amino acids must be estimated indirectly from levels of other amino acids in cerebrospinal fluid or plasma. Specific agonist and antagonist agents will be applied to the ventrolateral medullary chemoreceptive area of the brain to determine the influence of amino acid transmitter receptors on ventilation in animals.
| Dutton, C B; Pigeon, M J; Renzi, P M et al. (1993) Lung function in workers refining phosphorus rock to obtain elementary phosphorus. J Occup Med 35:1028-33 |
| Donnelly, D F; Nolan, W F; Smith, E J et al. (1987) Effect of dopamine antagonism on carotid chemoreceptor interspike intervals. Brain Res 407:195-8 |
| Dutton, R E; Renzi, P M; Lopez-Majano, V et al. (1986) Total and regional lung function in sarcoidosis. Smokers versus nonsmokers. Ann N Y Acad Sci 465:502-14 |
| Donnelly, D F; Nolan, W F; Smith, E J et al. (1985) Interspike interval dependency from arterial chemoreceptors. J Appl Physiol 59:1566-70 |
| Nolan, W F; Donnelly, D F; Smith, E J et al. (1985) Haloperidol-induced suppression of carotid chemoreception in vitro. J Appl Physiol 59:814-20 |
