Caffeine prevents prostaglandin E1-induced disturbances in respiratory control in neonatal rats: implications for infants with critical congenital heart disease

Abstract

Continuous infusion of prostaglandin E1 (PGE1) is used to maintain ductus arteriosus patency in infants with critical congenital heart disease, but it can also cause central apnea suggesting an effect on respiratory neural control. In this study, we investigated whether 1) PGE1 inhibits the various phases of the acute hypoxic ventilatory response (HVR; an index of respiratory control dysfunction) and increases apnea incidence in neonatal rats; and 2) whether these changes would be reversible with caffeine pretreatment. Whole body plethysmography was used to assess the HVR and apnea incidence in neonatal rats 2 h following a single bolus intraperitoneal injection of PGE1 with and without prior caffeine treatment. Untreated rats exhibited a biphasic HVR characterized by an initial increase in minute ventilation followed by a ventilatory decline of the late phase (~5th minute) of the HVR. PGE1 had a dose-dependent effect on the HVR. Contrary to our hypothesis, the lowest dose (1 µg/kg) of PGE1 prevented the ventilatory decline of the late phase of the HVR. However, PGE1 tended to increase postsigh apnea incidence and the coefficient of variability (CV) of breathing frequency, suggesting increased respiratory instability. PGE1 also decreased brainstem microglia mRNA and increased neuronal nitric oxide synthase (nNOS) and platelet-derived growth factor-β (PDGF-β) gene expression. Caffeine pretreatment prevented these effects of PGE1, and the adenosine A2A receptor inhibitor MSX-3 had similar preventative effects. Prostaglandin appears to have deleterious effects on brainstem respiratory control regions, possibly involving a microglial-dependent mechanism. The compensatory effects of caffeine or MSX-3 treatment raises the question of whether prostaglandin may also operate on an adenosine-dependent pathway.