Life‐long impairment of hypoxic phrenic responses in rats following 1 month of developmental hyperoxia

Abstract

Hypoxic ventilatory and phrenic responses are reduced in adult rats (3-5 months old) exposed to hyperoxia for the first month of life (hyperoxia treated). We previously reported that hypoxic phrenic responses were normal in a small sample of 14-to 15-month-old hyperoxia-treated rats, suggesting slow, spontaneous recovery. Subsequent attempts to identify the mechanism(s) underlying this spontaneous recovery of hypoxic phrenic responses led us to re-evaluate our earlier conclusion. Experiments were conducted in two groups of aged Sprague-Dawley rats (14-15 months old) which were anaesthetized, vagotomized, neuromuscularly blocked and ventilated: (1) a hyperoxia-treated group raised in 60 % O 2 for the first 28 postnatal days; and (2) an age-matched control group raised in normoxia. Increases in minute phrenic activity and integrated phrenic nerve amplitude (ıPhr) during isocapnic hypoxia (arterial partial pressures of O 2 , 60, 50 and 40 ± 1 mmHg) were greater in aged control (n = 15) than hyperoxia-treated rats (n = 11; P ≤ 0.01). Phrenic burst frequency during hypoxia was not different between groups. To examine the central integration of carotid chemoafferent inputs, steady-state relationships between carotid sinus nerve (electrical) stimulation frequency and phrenic nerve activity were compared in aged control (n = 7) and hyperoxia-treated rats (n = 7). Minute phrenic activity, ıPhr and burst frequency were not different between groups at any stimulation frequency between 0.5 and 20 Hz. Carotid body chemoreceptor function was examined by recording whole carotid sinus nerve responses to cessation of ventilation or injection of cyanide in aged control and hyperoxia-treated rats. Electrical activity of the carotid sinus nerve did not change in five out of five hyperoxia-treated rats in response to stimuli that evoked robust increases in carotid sinus nerve activity in five out of five control rats. Estimates of carotid body volume were lower in aged hyperoxia-treated rats (4.4 (± 0.2) w 10 6 mm 3 ) compared to controls (17.4 (± 1.6) w 10 6 mm 3 ; P <0.01). We conclude that exposure to hyperoxia for the first month of life causes life-long impairment of carotid chemoreceptor function and, consequently, blunted phrenic responses to hypoxia.

Invited Review: Neuroplasticity in respiratory motor control

“…Hyperoxia during the neonatal period also affects adult ventilatory control, suppressing the normal development of arterial chemoreceptors (132,133). For example, rats raised in enriched oxygen mixtures for the first postnatal month have impaired hypoxic ventilatory responses for the duration of life (62). The functional impairment is not due to alterations in pulmonary mechanics or gas exchange (135) or changes in the central integration of carotid chemoafferent inputs (62,134).…”

“…For example, rats raised in enriched oxygen mixtures for the first postnatal month have impaired hypoxic ventilatory responses for the duration of life (62). The functional impairment is not due to alterations in pulmonary mechanics or gas exchange (135) or changes in the central integration of carotid chemoafferent inputs (62,134). Rather, carotid chemoreceptor development is impaired because the carotid bodies are hypoplastic (47,66), the number of chemoafferent neurons in the carotid sinus nerve is reduced (47), and carotid sinus nerve afferent responses to cyanide, asphyxia, and hypoxia are reduced (20,62,133).…”

Long-term effects of the perinatal environment on respiratory control

“…Phrenic nerve responses to electrical stimulation of the carotid sinus nerve are virtually identical between hyperoxia-treated and control rats (33,57), suggesting that central integration of chemoafferent inputs is not impaired. On the other hand, normal phrenic responses to carotid sinus nerve stimulation are somewhat surprising because the number of chemoafferent neurons stimulated is reduced in hyperoxia-treated rats (29).…”

“…Similarly, Prieto-Lloret et al (81) report that ϳ75% of the CSN fibers and carotid body preparations that respond to increasing extracellular K ϩ fail to respond to hypoxia in adult rats exposed to developmental hyperoxia, suggesting a longlasting loss of O 2 sensitivity in these cells. As a result, adults previously exposed to perinatal hyperoxia exhibit severely attenuated CSN responses to hypoxia (14,33,57,81).…”

“…Sheep receiving hyperoxic ventilation (Ͼ24 h) exhibited increased carotid body sensitivity to hypoxia relative to sheep receiving normoxic ventilation. In contrast, prolonged exposure to hyperoxia during the early postnatal period causes life-long impairment of hypoxic responses (4,33,57). In kittens raised in 30% O 2 for the first 12-13 days of life, the acute HVR is abolished immediately following the hyperoxic exposure (43).…”