Chronic intermittent hypoxia reduces ventilatory long-term facilitation and enhances apnea frequency in newborn rats

Abstract

Ventilatory long-term facilitation (LTF; defined as gradual increase of minute ventilation following repeated hypoxic exposures) is well described in adult mammals and is hypothesized to be a protective mechanism against apnea. In newborns, LTF is absent during the first postnatal days, but its precise developmental pattern is unknown. Accordingly, this study describes this pattern of postnatal development. Additionally, we tested the hypothesis that chronic intermittent hypoxia (CIH) from birth alters this development. LTF was estimated in vivo using whole body plethysmography by exposing rat pups at postnatal days 1, 4, and 10 (P1, P4, and P10) to 10 brief hypoxic cycles (nadir 5% O2) and respiratory recordings during the following 2 h (recovery, 21% O2). Under these conditions, ventilatory LTF (gradual increase of minute ventilation during recovery) was clearly expressed in P10 rats but not in P1 and P4. In a second series of experiments, rat pups were exposed to CIH during the first 10 postnatal days (6 brief cyclic exposures at 5% O2 every 6 min followed by 1 h under normoxia, 24 h a day). Compared with P10 control rats, CIH enhanced hypoxic ventilatory response (estimated during the hypoxic cycles) specifically in male rat pups. Ventilatory LTF was drastically reduced in P10 rats exposed to CIH, which was associated with higher apnea frequency during recovery. We conclude that CIH from birth enhances hypoxic chemoreflex and disrupts LTF development, thus likely contributing to increase apnea frequency.

Carotid sinus nerve stimulation, but not intermittent hypoxia, induces respiratory LTF in adult rats exposed to neonatal intermittent hypoxia

“…Although we have previously shown that this pattern of n-IH exposure enhances the ventilatory response to repeated hypoxic cycles (i.e., involving peripheral chemoreceptors) in 10-day-old rats (25), our actual results show that this altered response is not persistent in adults. Contrastingly, responses involving central integration of the cardiorespiratory control system (posthypoxic frequency decline and phrenic LTF) are altered in adult rats exposed to n-IH.…”

“…We have recently reported in rat pups that n-IH during 10 days from birth increases ventilatory response to brief (50 s) hypoxic exposure (25), strongly suggesting higher sensitivity of peripheral chemoreceptors as reported by in vitro recordings (47), while the ventilatory LTF was suppressed (25), as reported by Reeves et al (50) in 2-mo-old rats raised under n-IH for 30 days from birth. Accordingly, this model might be useful to determine whether n-IH-related alterations in respiratory regulation persist into adulthood and alter the central integration of peripheral chemoreceptor inputs.…”

“…Accordingly, our results strongly suggest that hypoxic sensitivity in peripheral chemoreceptors was not altered in n-IH rats. Contrastingly, in rat pups, hypoxic ventilatory response (25) and carotid body response to hypoxia (47) were increased following chronic intermittent hypoxic exposure. On the other hand, a similar model of n-IH induced a persistent enhancement in the hypoxic response of the superfused in vitro carotid body/CSN preparation from 60-day-old rats (47) while we studied in vivo rats at 90 days of age.…”

“…However, in 10-day-old rats, we have reported a marked ventilatory LTF using whole body plethysmography (25). In adult humans, LTF is modulated by sleep/wake states, being apparent during non-rapid eye movement sleep (1, 5) but not during wakefulness (24).…”

“…Sixty-four male Sprague-Dawley rats born in our animal care facility were exposed to either n-IH or ambient air (control) for 10 consecutive days starting at postnatal day 1 as previously described (25). We used adult male rats because they showed stronger hemodynamic and respiratory alterations than adult females after n-IH exposure (26).…”