Chronic hyperoxia alters the early and late phases of the hypoxic ventilatory response in neonatal rats

Abstract

Chronic hyperoxia during the first 1-4 postnatal weeks attenuates the hypoxic ventilatory response (HVR) subsequently measured in adult rats. Rather than focusing on this long-lasting plasticity, the present study considered the influence of hyperoxia on respiratory control during the neonatal period. Sprague-Dawley rats were born and raised in 60% O2 until studied at postnatal ages (P) of 4, 6-7, or 13-14 days. Ventilation and metabolism were measured in normoxia (21% O2) and acute hypoxia (12% O2) using head-body plethysmography and respirometry, respectively. Compared with age-matched rats raised in room air, the major findings were 1) diminished pulmonary ventilation and metabolic O2 consumption in normoxia at P4 and P6-7; 2) decreased breathing stability during normoxia; 3) attenuation of the early phase of the HVR at P6-7 and P13-14; and 4) a sustained increase in ventilation during hypoxia (vs. the normal biphasic HVR) at all ages studied. Attenuation of the early HVR likely reflects progressive impairment of peripheral arterial chemoreceptors while expression of a sustained HVR in neonates before P7 suggests that hyperoxia also induces plasticity within the central nervous system. Together, these results suggest a complex interaction between inhibitory and excitatory effects of hyperoxia on the developing respiratory control system.

Fig. 1.

Minute ventilation, tidal volume, and respiratory frequency in normoxia for neonatal rats raised in 21% O₂ (control) or 60% O₂ (hyperoxia). Values are means ± SE. Sample sizes (P4, P6–7, and P13–14) are 17, 16, and 15 for control and 15, 15, and 17 for hyperoxia. Where treatment × age was significant, *P < 0.05 vs. control within the same age group. †P < 0.05 for treatment main effect. For clarity, only statistical comparisons between treatment groups are presented; please see the text for comparisons among age groups. P4, P6–7, and P13–14 refers to postnatal ages of 4 days, 6–7 days, and 13–14 days, respectively.

Fig. 2.

Breathing variability in normoxia for neonatal rats raised in 21% O₂ (control) or 60% O₂ (hyperoxia). In A, instantaneous ventilation is plotted for 75 consecutive breaths for representative P4 control and hyperoxia rats. Although both individuals display periodic peaks in ventilation, note the greater breath-to-breath variability in the hyperoxia rat. In B, the coefficient of variation (CV) for instantaneous ventilation is presented for control and hyperoxia rats at P4, P6–7, and P13–14. Values are means ± SE. Sample sizes (P4, P6–7, and P13–14, respectively) are 16, 15, and 15 for control and 13, 12, and 16 for hyperoxia. †P < 0.05 for treatment main effect. For clarity, only statistical comparisons between treatment groups are presented; please see the text for comparisons among age groups.

Fig. 3.

Changes in ventilation during an 8-min exposure to 12% O₂ for P4 (A), P6–7 (B), and P13–14 rats (C) raised in 21% O₂ (control) or 60% O₂ (hyperoxia). Responses are presented both in units of raw ventilation (left panels) and as a percentage increase from baseline (BL) (right panels). Values are means ± SE. Sample sizes (P4, P6–7, and P13–14, respectively) are 17, 16, and 15 for control and 15, 15, and 17 for hyperoxia. *P < 0.05 vs. control within the same minute of hypoxia. #P < 0.05 vs. minute 1 of hypoxia within the same treatment group.

Fig. 4.

Early (left panels) and late (right panels) phases of the hypoxic ventilatory response to 12% O₂ in neonatal rats raised in 21% O₂ (control) or 60% O₂ (hyperoxia). Values are means ± SE. Sample sizes (P4, P6–7, and P13–14, respectively) are 17, 16, and 15 for control and 15, 15, and 17 for hyperoxia. Where treatment × age was significant, *P < 0.05 vs. control within the same age group. †P < 0.05 for treatment main effect. For clarity, only statistical comparisons between treatment groups are presented; please see the text for comparisons among age groups.

Fig. 5.

Metabolic O₂ consumption for neonatal rats raised in 21% O₂ (control) or 60% O₂ (hyperoxia). O₂ consumption is presented in absolute units for rats in normoxia (21% O₂; A) and as a percentage decrease from baseline for the same rats in 12% O₂ (B). Values are means ± SE. Sample sizes (P4, P7, and P14) are 13, 9, and 9 for control and 11, 12, and 13 for hyperoxia. †P < 0.05 for treatment main effect. For clarity, only statistical comparisons between treatment groups are presented; please see the text for comparisons among age groups.