Interaction of central and peripheral chemoreflexes in neonatal mice: evidence for hypo-addition.

The potential for interaction between the peripheral (PCR) and central (CCR) chemoreflexes has not been studied in the neonatal period, when breathing is inherently unstable. Based on recent work in adult rodents, this study addresses the hypothesis that in neonatal mice there is a hypoadditive interaction between the chemoreflexes. To test this, a mask-pneumotach system was used to expose postnatal day (P) 11-12 mouse pups to square-wave hyperoxia (100% O2; n=8) or hypoxia (10% O2; n=11), administered in normocapnic conditions (inspired CO2 (FICO2)=0.001-0.005), or following an episode of re-breathing to increase FICO2 by 0.015-0.02. The immediate (i.e. PCR-mediated) responses of frequency (fB), tidal volume (VT) and ventilation (V˙E) to square-wave hyperoxia and hypoxia were assessed. When given in a normocapnic background, hyperoxia induced an immediate (within the first 20 breaths, or ∼6s) but transient fall in fB (-46±9breaths/min) and V˙E (-149±41μlmin(-1)g(-1)) (P<0.001 for both), with no effect on VT. In contrast, hyperoxia had no influence on breathing when it was administered following re-breathing. Similarly, the hypoxia-induced increase in fB was greater when applied under normocapnic conditions (50±8breaths/min) then when applied following re-breathing (21±5breaths/min) (P=0.02). These data demonstrate a hypo-additive interaction between the PCR and CCR with respect to the immediate frequency response to inhibition or excitation of the PCR. Hypoaddition of the chemoreflexes could cause or mitigate neonatal apnea, depending on the prevailing PCO2.