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ABSTRACT: Newborn infants and animals typically exhibit a paradoxical ventilatory response to hypoxia. The depressive phase of the response has not been adequately explained. It has been suggested that hypoxia may cause the release of inhibitory neuromodulators which depress ventilation. We have postulated that the nucleoside, adenosine, may be involved because 1) it is rapidly released during hypoxia, 2) it depresses ventilation, and 3) theophylline, a competitive inhibitor, has successfully been used to treat apnea of prematurity. Herein we describe the effects of aminophylline on ventilation during hypoxia in the spontaneously breathing newborn piglet administered both rapidly after ventilatory depression has occurred (bolus) and before the onset of hypoxia (pretreatment). Ten percent oxygen breathing produced a typical biphasic ventilatory response. The decrease in minute ventilation was caused by a decrease in both tidal volume and respiratory frequency. The bolus administration of aminophylline reversed the depression in minute ventilation (p < 0.001) by increasing tital volume (p < 0.002). Pretreatment with aminophylline decreased the amount of ventilatory depression (p < 0.05) by preventing a decrease in respiratory frequency. We conclude that aminophylline, an adenosine antagonist, reduces the decrease in ventilation which occurs during hypoxia in the newborn. We speculate that adenosine may play a role in hypoxic ventilatory depression and respiratory control in the newborn.