Characterization of adenosine-induced respiratory depression in the preterm rabbit

The respiratory performance was studied after intraperitoneal administration of the adenosine agonists N6-phenyl-isopropyl-adenosine (PIA) and adenosine-5-ethylcarboxamide to preterm (gestational age 29-30 days) newborn halothane-anesthetized rabbits. Both agonists induced marked hypoventilation and irregular breathing by decreases in the breathing frequency as well as the tidal volume. Expiratory time was markedly prolonged, resulting in a decrease in the respiratory duty cycle (inspiratory time/total cycle duration). Analysis using the occluded-breath technique revealed that the adenosine analogues altered the time setting of the expiratory (inspiratory) neuronal circuits and lowered the inspiratory off-switch level, while inspiratory drive and the bulbopontine setting of the inspiratory phase were unaltered. The ventilatory response to CO2 was blunted after both adenosine analogues studied. Theophylline almost completely reversed the hypoventilation and irregular breathing seen after PIA injection. It is concluded that activation of central nervous adenosine receptors induced a marked respiratory depression in the preterm rabbit. Furthermore, our data imply that an overactivity of central adenosine mechanisms may have a pathophysiological significance for the irregular breathing or apnea of prematurity sometimes seen in the human neonate.