The long term goals of the project are to more fully understand the neurochemical mechanisms which regulate central respiratory drive. Because of special vulnerability these mechanisms are of most interest in newborn and anesthetized animals. The ultimate aim is to develop a neuropharmacological approach to be applied in managing conditions of hypoxia-induced respiratory depression in patients with neonatal apnea or under general anesthesia. Specific attention will be focused on the roles of adenosine and endogenous opiates (Beta-endorphin, met-enkephalin) in determining these responses. The experiments will permit us to test our hypothesis that hypoxic ventilatory depression is brought about by the sequence: Hypoxia greater than release of adenosine greater than release of opiate peptides greater than respiratory depression. In order to approach these goals we will specifically: 1) Examine if the administration of stable adenosine analogs, and inhibitors of adenosine uptake and adenosine deaminase alter the duration or pattern of the response to hypoxia in neonatal rats (3-5 days old). Similar studies will be done with hypoxia-induced respiratory depression in carotid body denervated; halothane anesthetized rats. 2) Examine the time course of adenosine accumulation in specific brain stem areas during exposure to: a) graded hypercarbia with hyperoxia; b) graded hypoxia in intact rats (isocarbia produced by altering the concentration of inspired gas mixtures: c) graded hypoxia in carotid body denervated rats and after application of neonatal hypoxemia. 3) Examine the possibility that the respiratory depression models examined in 1) are related to accumulation or release of Beta endorphin or met-enkephalin. Both naloxone antagonism and measurements of brain stem peptide content will be used. 4) Search for xanthine antagonists of adenosine which are superior to aminophylline in stimulating respiration but which are less active than aminophylline as generalized CNS stimutants (i.e. potentiation of pentylenetetrazol-induced convulsions) or as stimulators of oxygen consumption. 5) Assess the ability of the most specific respiratory stimulant xanthine from 4) to alter the neonatal asphyxia-induced and/or hypoxia-induced respiratory depression in carotid body denervated adult rats examined in 1) above.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031424-03
Application #
3342534
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1984-01-01
Project End
1986-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Criswell, H; Mueller, R A; Breese, G R (1988) Assessment of purine-dopamine interactions in 6-hydroxydopamine-lesioned rats: evidence for pre- and postsynaptic influences by adenosine. J Pharmacol Exp Ther 244:493-500
Hedner, J; McCown, T J; Mueller, R A et al. (1987) Respiratory stimulant effects by TRH into the mesencephalic region in the rat. Acta Physiol Scand 130:69-75
Hedner, J; Hedner, T; Breese, G R et al. (1987) Changes in cerebrospinal fluid homovanillic acid in children with Ondine's curse. Pediatr Pulmonol 3:131-5
Breese, G R; Duncan, G E; Napier, T C et al. (1987) 6-hydroxydopamine treatments enhance behavioral responses to intracerebral microinjection of D1- and D2-dopamine agonists into nucleus accumbens and striatum without changing dopamine antagonist binding. J Pharmacol Exp Ther 240:167-76
Sivam, S P; Breese, G R; Krause, J E et al. (1987) Neonatal and adult 6-hydroxydopamine-induced lesions differentially alter tachykinin and enkephalin gene expression. J Neurochem 49:1623-33
Breese, G R; Mueller, R A; Napier, T C et al. (1986) Neurobiology of D1 dopamine receptors after neonatal-6-OHDA treatment: relevance to Lesch-Nyhan disease. Adv Exp Med Biol 204:197-215
Hedner, J; Lundell, K H; Breese, G R et al. (1986) Developmental variations in CSF monoamine metabolites during childhood. Biol Neonate 49:190-7
McCown, T J; Hedner, J A; Towle, A C et al. (1986) Brainstem localization of a thyrotropin-releasing hormone-induced change in respiratory function. Brain Res 373:189-96
Hedner, T; Hedner, J; Bergman, B et al. (1985) Characterization of adenosine-induced respiratory depression in the preterm rabbit. Biol Neonate 47:323-32
Hedner, J; Mueller, R A; Hedner, T et al. (1985) A centrally elicited respiratory stimulant effect by bombesin in the rat. Eur J Pharmacol 115:21-9

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