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.
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