Recovery of ventilatory and metabolic responses to hypoxia in neonatal rats after chronic hypoxia.

Chronic hypoxia (CH) during postnatal development attenuates the hypoxic ventilatory response (HVR) in mammals, but there are conflicting reports on whether this plasticity is permanent or reversible. This study tested the hypothesis that CH-induced respiratory plasticity is reversible in neonatal rats and investigated whether the initial plasticity or recovery differs between sexes. Rat pups were exposed to 3 d of normobaric CH (12 % O2) beginning shortly after birth. Ventilation and metabolic CO2 production were then measured in normoxia and during an acute hypoxic challenge (12 % O2) immediately following CH and after 1, 4-5, and 7 d in room air. CH pups hyperventilated when returned to normoxia immediately following CH, but normoxic ventilation was similar to age-matched control rats within 7 d after return to room air. The early phase of the HVR (minute 1) was only blunted immediately following the CH exposure, while the late phase of the HVR (minute 15) remained blunted after 1 and 4-5 d in room air; recovery appeared complete by 7 d. However, when normalized to CO2 production, the late phase of the hypoxic response recovered within only 1 d. The initial blunting of the HVR and subsequent recovery were similar in female and male rats. Carotid body responses to hypoxia (in vitro) were also normal in CH pups after approximately one week in room air. Collectively, these data indicate that ventilatory and metabolic responses to hypoxia recover rapidly in both female and male neonatal rats once normoxia is restored following CH.

Influence of chronic hypoxia on the hypoxic ventilatory response of juvenile and adult rats.

Chronic hypoxia (CH) from birth attenuates the acute hypoxic ventilatory response (HVR) in rats and other mammals, but CH is often reported to augment the HVR in adult mammals. To test the hypothesis that this transition - from blunting to augmenting the HVR - occurs in the third or fourth postnatal week in rats, juvenile and adult rats were exposed to normobaric CH (12% O2) for 7 days and the HVR was assessed by whole-body plethysmography. No transition was observed, however, and the acute HVR was reduced by 61 - 85% across all ages studied. The failure to observe an augmented HVR in adult rats could not be explained by the substrain of Sprague Dawley rats used, the duration of the CH exposure, the order in which test gases were presented, the level of hypoxia used for CH and to assess the HVR, or the effects of CH on the metabolic response to hypoxia and the hypercapnic ventilatory response. A literature survey revealed several distinct patterns of ventilatory acclimatization to hypoxia (VAH) in adult rats, with most studies (77%) revealing a decrease or no change in the acute HVR after CH. In conclusion, the effects of CH on respiratory control are qualitatively similar across age groups, at least within the populations of Sprague Dawley rats used in the present study, and there does not appear to be one "typical" pattern for VAH in adult rats.

Recovery of the biphasic hypoxic ventilatory response in neonatal rats after chronic hyperoxia.

Newborn mammals exhibit biphasic hypoxic ventilatory responses (HVR) characterized by an initial increase in ventilation and a secondary ventilatory depression. The magnitude of the hypoxic ventilatory decline (HVD) in the late phase of the HVR normally decreases with age, but this occurs sooner in rats reared in 60% O2. We investigated whether a lower level of hyperoxia (30% O2) or a short period of recovery (1 or 3 d in 21% O2) would affect the expression of this plasticity. Similar to 60% O2, rat pups reared in 30% O2 until 3-4 days of age exhibited a less biphasic HVR to 12% O2. When pups reared in 60% O2 were returned to normoxia, the magnitude of HVD increased such that pups expressed a biphasic HVR appropriate for their chronological age. Blocking synaptic input from the carotid bodies revealed that CNS hypoxia depressed ventilation less in hyperoxia-reared rats immediately following hyperoxia and after 1 d in normoxia despite recovery of the biphasic HVR. This suggests that recovery of the biphasic HVR occurs in pathways regulating HVD that depend on carotid body activity. The early, carotid body-mediated phase of the HVR was also blunted immediately and 1 d after the hyperoxia exposure, but not after 3 d of recovery. These data confirm that short exposures to mild-to-moderate hyperoxia elicit developmental plasticity in the HVR. However, reemergence of the biphasic HVR after return to normoxia argues against a heterokairic process for the premature transition from biphasic HVR to sustained HVR in hyperoxia-reared rat pups.

Influence of chronic hyperoxia on the developmental time course of the hypoxic ventilatory response relative to other traits in rats.

Newborn mammals exhibit a biphasic hypoxic ventilatory response (HVR) in which an initial increase in ventilation is followed by a decline back toward baseline levels. The magnitude of the secondary decline diminishes with postnatal age, but this transition occurs earlier in rat pups reared in moderate hyperoxia. This pattern is consistent with heterokairy, a form of developmental plasticity in which environmental factors alter the timing of developmental events. The present study investigated whether this plasticity is specific to the HVR or if hyperoxia instead accelerates overall development. Rat pups reared in 60 % O2 (Hyperoxia) exhibited a less biphasic ventilatory response to 12 % O2 than pups reared in 21 % O2 (Control) at 4 days of age (P4) and transitioned to a sustained HVR by P10-11; Control rats exhibited a biphasic HVR at both ages. However, the average ages at which pups attained other key developmental milestones (i.e., fur development at P5, incisor eruption at P9, and eye opening at P15) were similar between treatment groups. Moreover, growth rates and maturation of the metabolic response to cooling were not accelerated, and may have been delayed slightly, relative to Control rats. For example, the capacity for pups to increase their metabolic rate at low ambient temperatures increased with age, but this thermogenic capacity tended to be reduced in Hyperoxia pups at both P4 and P10-11 (i.e., lower CO2 production rates below the lower critical temperature). Collectively, these data support the conclusion that hyperoxia specifically advances the age at which rat pups exhibit a sustained HVR, altering the relative timing of developmental events rather than compressing the entire period of development.

Effects of Perinatal Hyperoxia on Breathing.

Air-breathing animals do not experience hyperoxia (inspired O2 > 21%) in nature, but preterm and full-term infants often experience hyperoxia/hyperoxemia in clinical settings. This article focuses on the effects of normobaric hyperoxia during the perinatal period on breathing in humans and other mammals, with an emphasis on the neural control of breathing during hyperoxia, after return to normoxia, and in response to subsequent hypoxic and hypercapnic challenges. Acute hyperoxia typically evokes an immediate ventilatory depression that is often, but not always, followed by hyperpnea. The hypoxic ventilatory response (HVR) is enhanced by brief periods of hyperoxia in adult mammals, but the limited data available suggest that this may not be the case for newborns. Chronic exposure to mild-to-moderate levels of hyperoxia (e.g., 30-60% O2 for several days to a few weeks) elicits several changes in breathing in nonhuman animals, some of which are unique to perinatal exposures (i.e., developmental plasticity). Examples of this developmental plasticity include hypoventilation after return to normoxia and long-lasting attenuation of the HVR. Although both peripheral and CNS mechanisms are implicated in hyperoxia-induced plasticity, it is particularly clear that perinatal hyperoxia affects carotid body development. Some of these effects may be transient (e.g., decreased O2 sensitivity of carotid body glomus cells) while others may be permanent (e.g., carotid body hypoplasia, loss of chemoafferent neurons). Whether the hyperoxic exposures routinely experienced by human infants in clinical settings are sufficient to alter respiratory control development remains an open question and requires further research. © 2020 American Physiological Society. Compr Physiol 10:597-636, 2020.

Ventilatory and carotid body responses to acute hypoxia in rats exposed to chronic hypoxia during the first and second postnatal weeks.

Chronic hypoxia (CH) during postnatal development causes a blunted hypoxic ventilatory response (HVR) in neonatal mammals. The magnitude of the HVR generally increases with age, so CH could blunt the HVR by delaying this process. Accordingly, we predicted that CH would have different effects on the respiratory control of neonatal rats if initiated at birth versus initiated later in postnatal development (i.e., after the HVR has had time to mature). Rats had blunted ventilatory and carotid body responses to hypoxia whether CH (12 % O2) occurred for the first postnatal week (P0 to P7) or second postnatal week (P7 to P14). However, if initiated at P0, CH also caused the HVR to retain the "biphasic" shape characteristic of newborn mammals; CH during the second postnatal week did not result in a biphasic HVR. CH from birth delayed the transition from a biphasic HVR to a sustained HVR until at least P9-11, but the HVR attained a sustained (albeit blunted) phenotype by P13-15. Since delayed maturation of the HVR did not completely explain the blunted HVR, we tested the alternative hypothesis that the blunted HVR was caused by an inflammatory response to CH. Daily administration of the anti-inflammatory drug ibuprofen (4 mg kg-1, i.p.) did not alter the effects of CH on the HVR. Collectively, these data suggest that CH blunts the HVR in neonatal rats by impairing carotid body responses to hypoxia and by delaying (but not preventing) postnatal maturation of the biphasic HVR. The mechanisms underlying this plasticity require further investigation.

Development of ventilatory chemoreflexes in Coturnix quail chicks.

Compared to mammals, little is known about the development of the respiratory control system in birds. In the present study, ventilation and metabolism were measured in Coturnix quail chicks exposed to room air, hypoxia (11 % O2), and hypercapnia (4% CO2) at 0-1, 3-4, and 6-7 days posthatching (dph). Mass-specific ventilation and metabolic rate tended to increase between 0-1 and 3-4 dph and then decrease again between 3-4 and 6-7 dph. The magnitude of the hypoxic ventilatory response (HVR) increased with age. The HVR also exhibited a biphasic shape in younger quail: after the initial increase in ventilation, ventilation declined back to (0-1 dph), or toward (4 dph), baseline. Older chicks (6-7 dph) had a "sustained HVR" in which ventilation remained high throughout the hypoxic challenge. The biphasic HVR did not appear to be caused by a decline in metabolic rate; although hypoxic hypometabolism was observed in quail chicks in all three age groups, the metabolic response appeared to occur more slowly than the biphasic HVR. The biphasic ventilatory response was also specific to hypoxia since the hypercapnic ventilatory response (HCVR) was characterized by a sustained increase in ventilation in all three age groups. The magnitude of the HCVR decreased with age. These results point to several similarities in the development of ventilatory chemorflexes between Coturnix quail and newborn mammals, including age-dependent (1) increases in the HVR, (2) transitions from a biphasic to a sustained HVR, and (3) decreases in the HCVR. Whether homologous mechanisms underlie these developmental changes remains to be determined.

Combined effects of intermittent hyperoxia and intermittent hypercapnic hypoxia on respiratory control in neonatal rats.

Chronic exposure to intermittent hyperoxia causes abnormal carotid body development and attenuates the hypoxic ventilatory response (HVR) in neonatal rats. We hypothesized that concurrent exposure to intermittent hypercapnic hypoxia would influence this plasticity. Newborn rats were exposed to alternating bouts of hypercapnic hypoxia (10% O2/6% CO2) and hyperoxia (30-40% O2) (5 cycles h-1, 24 h d-1) through 13-14 days of age; the experiment was run twice, once in a background of 21% O2 and once in a background of 30% O2 (i.e., "relative hyperoxia"). Hyperoxia had only small effects on carotid body development when combined with intermittent hypercapnic hypoxia: the carotid chemoafferent response to hypoxia was reduced, but this did not affect the HVR. In contrast, sustained exposure to 30% O2 reduced carotid chemoafferent activity and carotid body size which resulted in a blunted HVR. When given alone, chronic intermittent hypercapnic hypoxia increased carotid body size and reduced the hypercapnic ventilatory response but did not affect the HVR. Overall, it appears that intermittent hypercapnic hypoxia counteracted the effects of hyperoxia on the carotid body and prevented developmental plasticity of the HVR.

Developmental plasticity in the neural control of breathing.

The respiratory control system undergoes a diversity of morphological and physiological transformational stages during intrauterine development as it prepares to transition into an air-breathing lifestyle. Following birth, the respiratory system continues to develop and may pass through critical periods of heightened vulnerability to acute environmental stressors. Over a similar time course, however, the developing respiratory control system exhibits substantial capacity to undergo plasticity in response to chronic or repeated environmental stimuli. A hallmark of developmental plasticity is that it requires an interaction between a stimulus (e.g., hypoxia, hyperoxia, or psychosocial stress) and a unique window of development; the same stimulus experienced beyond the boundaries of this critical window of plasticity (e.g., at maturity), therefore, will have little if any appreciable effect on the phenotype. However, there are major gaps in our understanding of the mechanistic basis of developmental plasticity. Filling these gaps in our knowledge may be crucial to advancing our understanding of the developmental origin of adult health and disease. In this review, we: i) begin by clarifying some ambiguities in the definitions of plasticity and related terms that have arisen in recent years; ii) describe various levels of the respiratory control system where plasticity can (or has been identified to) occur; iii) emphasize the importance of understanding the mechanistic basis of developmental plasticity; iv) consider factors that influence whether developmental plasticity is permanent or whether function can be restored; v) discuss genetic and sex-based variation in the expression of developmental plasticity; and vi) provide a translational perspective to developmental plasticity.

Ventilatory and chemoreceptor responses to hypercapnia in neonatal rats chronically exposed to moderate hyperoxia.

Rats reared in hyperoxia hypoventilate in normoxia and exhibit progressive blunting of the hypoxic ventilatory response, changes which are at least partially attributed to abnormal carotid body development. Since the carotid body also responds to changes in arterial CO2/pH, we tested the hypothesis that developmental hyperoxia would attenuate the hypercapnic ventilatory response (HCVR) of neonatal rats by blunting peripheral and/or central chemoreceptor responses to hypercapnic challenges. Rats were reared in 21% O2 (Control) or 60% O2 (Hyperoxia) until studied at 4, 6-7, or 13-14days of age. Hyperoxia rats had significantly reduced single-unit carotid chemoafferent responses to 15% CO2 at all ages; CO2 sensitivity recovered within 7days after return to room air. Hypercapnic responses of CO2-sensitive neurons of the caudal nucleus tractus solitarius (cNTS) were unaffected by chronic hyperoxia, but there was evidence for a small decrease in neuronal excitability. There was also evidence for augmented excitatory synaptic input to cNTS neurons within brainstem slices. Steady-state ventilatory responses to 4% and 8% CO2 were unaffected by developmental hyperoxia in all three age groups, but ventilation increased more slowly during the normocapnia-to-hypercapnia transition in 4-day-old Hyperoxia rats. We conclude that developmental hyperoxia impairs carotid body chemosensitivity to hypercapnia, and this may compromise protective ventilatory reflexes during dynamic respiratory challenges in newborn rats. Impaired carotid body function has less of an impact on the HCVR in older rats, potentially reflecting compensatory plasticity within the CNS.

Chronic intermittent hyperoxia alters the development of the hypoxic ventilatory response in neonatal rats.

Chronic exposure to sustained hyperoxia alters the development of the respiratory control system, but the respiratory effects of chronic intermittent hyperoxia have rarely been investigated. We exposed newborn rats to short, repeated bouts of 30% O2 or 60% O2 (5 bouts h(-1)) for 4-15 days and then assessed their hypoxic ventilatory response (HVR; 10 min at 12% O2) by plethysmography. The HVR tended to be enhanced by intermittent hyperoxia at P4 (early phase of the HVR), but it was significantly reduced at P14-15 (primarily late phase of the HVR) compared to age-matched controls; the HVR recovered when individuals were returned to room air and re-studied as adults. To investigate the role of carotid body function in this plasticity, single-unit carotid chemoafferent activity was recorded in vitro. Intermittent hyperoxia tended to decrease spontaneous action potential frequency under normoxic conditions but, contrary to expectations, hypoxic responses were only reduced at P4 (not at P14) and only in rats exposed to higher O2 levels (i.e., intermittent 60% O2). Rats exposed to intermittent hyperoxia had smaller carotid bodies, and this morphological change may contribute to the blunted HVR. In contrast to rats exposed to intermittent hyperoxia beginning at birth, two weeks of intermittent 60% O2 had no effect on the HVR or carotid body size of rats exposed beginning at P28; therefore, intermittent hyperoxia-induced respiratory plasticity appears to be unique to development. Although both intermittent and sustained hyperoxia alter carotid body development and the HVR of rats, the specific effects and time course of this plasticity differs.

Role of TrkB during the postnatal development of the rat carotid body.

Brain-derived neurotrophic factor (BDNF) supports innervation of the carotid body by neurons projecting from the petrosal ganglion. Although carotid body glomus cells also express TrkB, BDNF's high affinity receptor, the role of BDNF in carotid body growth and O2 sensitivity has not been studied. Neonatal rats were treated with the TrkB antagonist K252a (100 µg kg(-1), i.p., b.i.d.) or vehicle on postnatal days P0-P6 and studied on P7. Carotid body volume was decreased by 35% after chronic K252a (P<0.001); a reduction in carotid body size was also elicited using the more selective TrkB antagonist ANA-12 (500 µg kg(-1), i.p., b.i.d.). In contrast, single-unit chemoafferent responses to 5% O2, measured in vitro, were unaffected by chronic K252a administration. Normoxic and hypoxic ventilation, measured by head-body plethysmography, were also normal after chronic K252a administration, but acute K252a administration produced a slower, deeper breathing pattern during the transition into hypoxia. These data suggest that BDNF regulates postnatal carotid body growth but does not influence the development of glomus cell O2 sensitivity.

Postnatal development of eupneic ventilation and metabolism in rats chronically exposed to moderate hyperoxia.

Newborn rats chronically exposed to moderate hyperoxia (60% O2) exhibit abnormal respiratory control, including decreased eupneic ventilation. To further characterize this plasticity and explore its proximate mechanisms, rats were exposed to either 21% O2 (Control) or 60% O2 (Hyperoxia) from birth until studied at 3-14 days of age (P3-P14). Normoxic ventilation was reduced in Hyperoxia rats when studied at P3, P4, and P6-7 and this was reflected in diminished arterial O2 saturations; eupneic ventilation spontaneously recovered by P13-14 despite continuous hyperoxia, or within 24h when Hyperoxia rats were returned to room air. Normoxic metabolism was also reduced in Hyperoxia rats but could be increased by raising inspired O2 levels (to 60% O2) or by uncoupling oxidative phosphorylation within the mitochondrion (2,4-dinitrophenol). In contrast, moderate increases in inspired O2 had no effect on sustained ventilation which indicates that hypoventilation can be dissociated from hypometabolism. The ventilatory response to abrupt O2 inhalation was diminished in Hyperoxia rats at P4 and P6-7, consistent with smaller contributions of peripheral chemoreceptors to eupneic ventilation at these ages. Finally, the spontaneous respiratory rhythm generated in isolated brainstem-spinal cord preparations was significantly slower and more variable in P3-4 Hyperoxia rats than in age-matched Controls. We conclude that developmental hyperoxia impairs both peripheral and central components of eupneic ventilatory drive. Although developmental hyperoxia diminishes metabolism as well, this appears to be a regulated hypometabolism and contributes little to the observed changes in ventilation.

Hyperoxia-induced developmental plasticity of the hypoxic ventilatory response in neonatal rats: contributions of glutamate-dependent and PDGF-dependent mechanisms.

Rats reared in hyperoxia exhibit a sustained (vs. biphasic) hypoxic ventilatory response (HVR) at an earlier age than untreated, Control rats. Given the similarity between the sustained HVR obtained after chronic exposure to developmental hyperoxia and the mature HVR, it was hypothesized that hyperoxia-induced plasticity and normal maturation share common mechanisms such as enhanced glutamate and nitric oxide signaling and diminished platelet-derived growth factor (PDGF) signaling. Rats reared in 21% O2 (Control) or 60% O2 (Hyperoxia) from birth until 4-5 days of age were studied after intraperitoneal injection of drugs targeting these pathways. Hyperoxia rats receiving saline showed a sustained HVR to 12% O2, but blockade of NMDA glutamate receptors (MK-801) restored the biphasic HVR typical of newborn rats. Blockade of PDGF-ß receptors (imatinib) had no effect on the pattern of the HVR in Hyperoxia rats, although it attenuated ventilatory depression during the late phase of the HVR in Control rats. Neither nitric oxide synthase inhibitor used in this study (nNOS inhibitor I and l-NAME) altered the pattern of the HVR in Control or Hyperoxia rats. Drug-induced changes in the biphasic HVR were not correlated with changes in metabolic rate. Collectively, these results suggest that developmental hyperoxia hastens the transition from a biphasic to sustained HVR by upregulating glutamate-dependent mechanisms and downregulating PDGF-dependent mechanisms, similar to the changes underlying normal postnatal maturation of the biphasic HVR.

Developmental hyperoxia alters CNS mechanisms underlying hypoxic ventilatory depression in neonatal rats.

Newborn mammals exhibit a biphasic hypoxic ventilatory response (HVR), but the relative contributions of carotid body-initiated CNS mechanisms versus central hypoxia on ventilatory depression during the late phase of the HVR are not well understood. Neonatal rats (P4-5 or P13-15) were treated with a nonselective P2 purinergic receptor antagonist (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, or PPADS; 125mgkg(-1), i.p.) to pharmacologically denervate the peripheral chemoreceptors. At P4-5, rats reared in normoxia showed a progressive decline in ventilation during a 10-min exposure to 12% O2 (21-28% decrease from baseline). No hypoxic ventilatory depression was observed in the older group of neonatal rats (i.e., P13-15), suggesting that the contribution of central hypoxia to hypoxic ventilatory depression diminishes with age. In contrast, rats reared in moderate hyperoxia (60% O2) from birth exhibited no hypoxic ventilatory depression at either age studied. Systemic PPADS had no effect on the ventilatory response to 7% CO2, suggesting that the drug did not cross the blood-brain barrier. These findings indicate that (1) CNS hypoxia depresses ventilation in young, neonatal rats independent of carotid body activation and (2) hyperoxia alters the development of CNS pathways that modulate the late phase of the hypoxic ventilatory response.

Chronic hyperoxia and the development of the carotid body.

Preterm infants often experience hyperoxia while receiving supplemental oxygen. Prolonged exposure to hyperoxia during development is associated with pathologies such as bronchopulmonary dysplasia and retinopathy of prematurity. Over the last 25 years, however, experiments with animal models have revealed that moderate exposures to hyperoxia (e.g., 30-60% O(2) for days to weeks) can also have profound effects on the developing respiratory control system that may lead to hypoventilation and diminished responses to acute hypoxia. This plasticity, which is generally inducible only during critical periods of development, has a complex time course that includes both transient and permanent respiratory deficits. Although the molecular mechanisms of hyperoxia-induced plasticity are only beginning to be elucidated, it is clear that many of the respiratory effects are linked to abnormal morphological and functional development of the carotid body, the principal site of arterial O(2) chemoreception for respiratory control. Specifically, developmental hyperoxia reduces carotid body size, decreases the number of chemoafferent neurons, and (at least transiently) diminishes the O(2) sensitivity of individual carotid body glomus cells. Recent evidence suggests that hyperoxia may also directly or indirectly impact development of the central neural control of breathing. Collectively, these findings emphasize the vulnerability of the developing respiratory control system to environmental perturbations.

Carotid body growth during chronic postnatal hyperoxia.

Rats reared in hyperoxia have smaller carotid bodies as adults. To study the time course and mechanisms underlying these changes, rats were reared in 60% O(2) from birth and their carotid bodies were harvested at various postnatal ages (P0-P7, P14). The carotid bodies of hyperoxia-reared rats were smaller than those of age-matched controls beginning at P4. In contrast, 7d of 60% O(2) had no effect on carotid body size in rats exposed to hyperoxia as adults. Bromodeoxyuridine (BrdU) and TdT-mediated dUTP nick end labeling (TUNEL) were used to assess cell proliferation and DNA fragmentation at P2, P4, and P6. Hyperoxia reduced the proportion of glomus cells undergoing cell division at P4; although a similar trend was evident at P2, hyperoxia no longer affected cell proliferation by P6. The proportion of TUNEL-positive glomus cells was modestly increased by hyperoxia. We did not detect changes in mRNA expression for proapoptotic (Bax) or antiapoptotic (Bcl-X(L)) genes or transcription factors that regulate cell cycle checkpoints (p53 or p21), although mRNA levels for cyclin B1 and cyclin B2 were reduced. Collectively, these data indicate that hyperoxia primarily attenuates postnatal growth of the carotid body by inhibiting glomus cell proliferation during the first few days of exposure.

Hypoxic ventilatory response of adult rats and mice after developmental hyperoxia.

Chronic postnatal hyperoxia attenuates the hypoxic ventilatory response (HVR) of rats. To determine whether the ability to detect deficits in the HVR depends on the degree of hypoxia, we assessed the HVR at several levels of hypoxia in adult rats reared in 60% O(2) for the first two postnatal weeks. Hyperoxia-treated rats exhibited smaller increases in ventilation than control rats at 12% O(2) (30±8 vs. 53±4% baseline, mean±SEM; P=0.02) but not at 10% O(2) (83±11 vs. 96±14% baseline; P=0.47). Interestingly, 10% O(2) was used as the test gas in the only study to assess HVR in mice exposed to developmental hyperoxia, and that study reported normal HVR (Dauger et al., Chest 123 (2003), 530-538). Therefore, we assessed the HVR at 12.5% O(2) in adult mice reared in 60% O(2) for the first two postnatal weeks. Hyperoxia-treated mice exhibited smaller increases in ventilation (28±7 vs. 58±8% baseline; P<0.01) and smaller carotid bodies than control mice. We conclude that hyperoxia impairs the HVR in both rats and mice, but this effect is most evident at moderate levels of hypoxia.

Recovery of carotid body O2 sensitivity following chronic postnatal hyperoxia in rats.

Chronic postnatal hyperoxia blunts the hypoxic ventilatory response (HVR) in rats, an effect that persists for months after return to normoxia. To determine whether decreased carotid body O(2) sensitivity contributes to this lasting impairment, single-unit chemoafferent nerve and glomus cell calcium responses to hypoxia were recorded from rats reared in 60% O(2) through 7d of age (P7) and then returned to normoxia. Single-unit nerve responses were attenuated by P4 and remained low through P7. After return to normoxia, hypoxic responses were partially recovered within 3d and fully recovered within 7-8d (i.e., at P14-15). Glomus cell calcium responses recovered with a similar time course. Hyperoxia altered carotid body mRNA expression for O(2)-sensitive K(+) channels TASK-1, TASK-3, and BK(Ca), but only TASK-1 mRNA paralleled changes in chemosensitivity (i.e., downregulation by P7, partial recovery by P14). Collectively, these data do not support a role for reduced O(2) sensitivity of individual chemoreceptor cells in long-lasting reduction of the HVR after developmental hyperoxia.

Potentiation of the hypoxic ventilatory response by 1 day of hyperoxia in neonatal rats.

The O(2) sensitivity of the neonatal rat carotid body is increased after 1 day in moderate hyperoxia (60% O(2)) (Donnelly et al., 2009). We investigated whether this enhanced peripheral chemosensitivity increases the hypoxic ventilatory response (HVR) and tested the hypothesis that this plasticity is mediated by the superoxide anion. Neonatal rats (7 d old) were injected with saline or MnTMPyP, a superoxide scavenger, and placed into 60% O(2) for 23-28h. Baseline ventilation was reduced and the acute HVR (12% O(2)) was enhanced in hyperoxia-treated rats relative to age-matched controls; MnTMPyP did not block these effects. An additional group of rats was studied after only 30min in 60% O(2). This shorter exposure had no effect on normoxic ventilation or the HVR. We conclude that 1 d, but not 30min, of 60% O(2) augments the HVR of neonatal rats and that production of the superoxide anion does not contribute to this plasticity.