Aminophylline modulation of the mouse respiratory network changes during postnatal maturation

Aminophylline is a respiratory stimulant commonly used for the treatment of central apnea. Experiences from clinical practice, however, revealed that aminophylline is not reliably effective in preterm infants, whereas it is n ormally effective in infants and mature patients. In an established animal model for postnatal development of respiratory control mechanisms, we there fore examined the hypothesis that the clinical observations reflect a devel opmental change in the sensitivity of the central respiratory network to me thylxanthines. The medullary respiratory network was isolated at different postnatal ages (postnatal days 1-13; P1-P13) in a transverse mouse brain st em slice preparation. This preparation contains the pre-Botzinger complex ( PBC), a region that is critical for generation of respiratory rhythm. Spont aneous rhythmic respiratory activity was recorded from the hypoglossal (XII ) rootlets and from neurons in the PBC by using the whole cell patch clamp technique. Bath-applied aminophylline [20 muM] increased the frequency (+41 %) in neonatal animals (P1-P6) without affecting the amplitude of respirato ry burst activity in XII rootlets. The same concentration of aminophylline did not have any significant effect on the frequency of respiratory XII bur sts but increased the amplitude (+31%) in juvenile animals (P7-P13). In the same age group, aminophylline also augmented the amplitude and the duratio n of respiratory synaptic drive currents in respiratory PBC neurons. The da ta demonstrate that augmentation of the respiratory output is due to direct enhancement of central respiratory network activity and increase of synapt ic drive of hypoglossal motoneurons in juvenile, but not neonatal, animals. This indicates a developmental change in the efficacy of aminophylline to reinforce central respiratory network activity. Therefore, we believe that the variable success in treating respiratory disturbances in premature infa nts reflects maturational changes in the expression of receptors and/or int racellular signal pathways in the central respiratory network.