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Methylxanthines like caffeine and theophylline have long been used to treat apnea of prematurity. Despite their success in stimulating neonatal breathing, their mechanism of action remains poorly understood. Methylxanthines can act as both non-specific adenosine receptor antagonists and inhibitors of cAMP-dependent phosphodiesterases, sarcoplasmic/endoplasmic reticulum calcium ATPases or receptor-coupled anion channels, depending on the dose used. Though there is evidence for methylxanthine action at the level of the carotid body, the consensus is that methylxanthines stimulate the respiratory centers of the brainstem. Here we used the in situ neonatal rat working heart-brainstem preparation and the ex vivo neonatal rat carotid body preparation to test the hypothesis that methylxanthines act at the level of the carotid body. We conclude that although the neonatal carotid body has active adenosine receptors, the effects of methylxanthine therapy are likely mediated centrally, predominantly via inhibition of cAMP-dependent phosphodiesterase-4., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Pituitary adenylate cyclase-activating peptide (PACAP) is an important mediator of the stress response and is crucial in maintaining breathing in neonates. Here we investigate the role of exogenously applied PACAP in neonatal breathing using the neonatal rat in situ working heart-brainstem preparation. A 1-min bolus of 250 nM PACAP-38 caused an increased in respiratory frequency that was rapid and transient, but had no effect on neural tidal volume or neural minute ventilation. Denervation of the carotid body abolished this effect. PACAP had a persistent effect on breathing stability in both carotid body-intact and -denervated preparations, as shown by decreases in respiratory variability 5 min following application. These data suggest that PACAP released during stress acts via carotid body dependent and independent mechanisms to stimulate and stabilize breathing. These mechanisms may account for PACAP's critical role in defending neonatal breathing against environmental stress., (Copyright © 2013 Elsevier B.V. All rights reserved.)