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Induced recovery of hypoxic phrenic responses in adult rats exposed to hyperoxia for the first month of life

D. D. Fuller, Z.-Y. Wang, L. Ling †, E. B. Olson *, G. E. Bisgard and G. S. Mitchell

1. Adult rats exposed to hyperoxia for the first month of life have permanently attenuated ventilatory and phrenic nerve responses to hypoxia. We tested the hypothesis that the blunted hypoxic phrenic response in hyperoxia-treated rats (inspired O₂ fraction, F_I,O2 = 0.6 for 28 post-natal days) could be actively restored to normal by intermittent (alternating 12 % O₂/air at 5 min intervals; 12 h per night for 1 week) or sustained (12 % O₂ for 1 week) hypoxia.
2. Phrenic responses to isocapnic hypoxia (P_a,O2 = 60, 50 and 40 ± 2 mmHg) were assessed in the following groups of anaesthetized, vagotomized adult Sprague-Dawley rats (age 4 months), treated with a neuromuscular blocking agent and ventilated: control, hyperoxia-treated and hyperoxia-treated exposed to either intermittent or sustained hypoxia as adults. Experiments on intermittent and sustained hypoxia-treated rats were performed on the morning following hypoxic exposures.
3. Both intermittent and sustained hypoxia enhanced hypoxic phrenic responses in hyperoxia-treated rats when expressed as minute phrenic activity (P < 0.05). Increases in phrenic burst amplitude during hypoxia were greater in hyperoxia-treated rats after intermittent hypoxia (P < 0.05), and a similar but non-significant trend was observed after sustained hypoxia. Hypoxia-induced changes in phrenic burst frequency were not significantly different among groups.
4. The estimated carotid body volume in control rats (11.5 (± 0.7) 10⁶ µm³) was greater than in the other treatment groups (P < 0.05). However, carotid body volume was significantly greater in hyperoxia-treated rats exposed to sustained hypoxia (6.3 (± 0.3) 10⁶ µm³; P < 0.05) compared to hyperoxia-treated rats (3.3 (± 0.2) 10⁶ µm³) or hyperoxia-treated rats exposed to intermittent hypoxia (3.8 (± 0.3) 10⁶ µm³).
5. Hypoxic phrenic responses in hyperoxia-treated rats 1 week after intermittent hypoxia were similar to responses measured immediately after intermittent hypoxia, indicating persistant functional recovery.
6. The results indicate that diminished hypoxic phrenic responses in adult rats due to hyperoxia exposure for the first 28 post-natal days can be reversed by intermittent or sustained activation of the hypoxic ventilatory control system. Although the detailed mechanisms of functional recovery are unknown, we suggest that sustained hypoxia restores carotid chemoreceptor sensitivity, whereas intermittent hypoxia primarily augments central integration of synaptic inputs from chemoafferent neurons.

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