Ventilatory responses to hypercapnia and hypoxia in heterozygous c-ret newborn mice

The c-ret proto-oncogene encodes a tyrosine-kinase receptor involved in survival and differentiation of neural crest cell lineages. Previous studies have shown that homozygous c-ret−/− mice die soon after birth and have impaired ventilatory responses to hypercapnia. Heterozygous c-ret+/− mice develop normally, but their respiratory phenotype has not been described in detail. We used whole-body flow plethysmography to compare baseline breathing and ventilatory and arousal responses to chemical stimuli in unrestrained heterozygous c-ret+/− newborn mice and their wild-type c-ret+/+ littermates at 10–12 h of postnatal age. The hyperpnoeic and arousal responses to hypoxia and hypercapnia were not significantly different in these two groups. However, the number and total duration of apnoeas and periodic breathing episodes were significantly higher in c-ret+/− than in c-ret+/+ pups during hypoxia and post-hypoxic normoxia. These results are further evidence that respiratory control at birth is heavily dependent on genes involved in the neural determination of neural crest cells.     

Platelet-activating factor receptor and respiratory and metabolic responses to hypoxia and hypercapnia

Activation of the platelet-activating factor receptor (PAFR) regulates neural transmission. A PAFR blocker reduced the peak hypoxic (pHVR) but not hypercapnic ventilatory (HCVR) responses in rats [Am. J. Physiol. 275 (1998) R604]. To further examine the role of PAFR in respiratory control, genotype-verified PAFR -/- and PAFR +/+ adult male mice underwent hypoxic and hypercapnic challenges. HCVR was similar in the two groups (p-NS). However, pHVR was significantly reduced in PAFR -/- mice (38 +/- 13% baseline [S.D.]) compared to PAFR +/+ mice (78 +/- 16% baseline; P < 0.001, ANOVA), with reduced tidal volume recruitments during pHVR. In addition, hypoxic ventilatory depression was attenuated in PAFR -/- mice (P < 0.01), and was primarily due to attenuation of the time-dependent decreases in oxygen consumption during sustained hypoxia (P < 0.01). Thus, PAFR expression/function modulates components of the acute ventilatory and metabolic adaptations to hypoxia but not to hypercapnia. Imbalances in PAFR activity may lead to maladaptive regulation of the tightly controlled metabolic-ventilatory relationships during hypoxia.     

Developmental plasticity of ventilatory control in zebrafish, Danio rerio

To determine whether development of ventilatory control in zebrafish (Danio rerio) exhibits plasticity, embryos were exposed to hypoxia, hyperoxia or hypercapnia for the first 7 days post-fertilization. Their acute reflex breathing responses to ventilatory stimuli (hypoxia, hypercapnia and external cyanide) were assessed when they had reached maturity (3 months or older). Zebrafish reared under hyperoxic conditions exhibited significantly higher breathing frequencies at rest (283+/-27min(-1) versus 212+/-16min(-1) in control fish); breathing frequency was unaffected in adult fish subjected to hyperoxia for 7 days. The respiratory responses of fish reared in hyperoxic water to acute hypoxia, hypercapnia or external cyanide were blunted (hypoxia, cyanide) or eliminated (hypercapnia). Adult fish exposed for 7 days to hyperoxia showed no change in acute responses to these stimuli. The respiratory responses to acute hypoxia, hypercapnia or external cyanide of fish reared under hypoxic or hypercapnic conditions were similar to those in fish reared under normal conditions. A subset of all fish examined exhibited episodic breathing; an analysis of breathing patterns demonstrated that fish reared under hypercapnic conditions had an increased tendency to display episodic breathing. The results of this study reveal that there is flexibility in the design and functioning of the embryonic or larval respiratory system in zebrafish.     

Increased ventilation and CO2 chemosensitivity in acetylcholinesterase knockout mice

To investigate the effects of a permanent excess of acetylcholine (AChE) on respiration, breathing and chemosensitivity were analyzed from birth to adulthood in mice lacking the AChE gene (AChE-/-), in heterozygotes, and in control wild-type (AChE+/+) littermates. Breathing at rest and ventilatory responses to brief exposures to hypoxia (10% O2) and hypercapnia (3-5% CO2) were measured by whole-body plethysmography. At rest AChE-/- mice show larger tidal volumes (VT, + 96% in adults), overall ventilation (VE, + 70%), and mean inspiratory flow (+270%) than wild-type mice, with no change in breathing frequency (fR). AChE-/- mice have a slightly blunted response to hypoxia, but increased VE and fR responses to hypercapnia. Heterozygous animals present no consistent alterations of breathing at rest and chemosensitivity is normal. Adult AChE-/- mice have an increased VE/VO2 and a marginally higher normalized VO2. The results suggest that the hyperventilation and altered chemosensitivity in AChE-/- mice largely reflect alterations of central respiratory control.     

Genes modulating chemical breathing control: lessons from mutant animals

Genetic factors influence breathing control. Respiratory phenotypes of mutant mice may help to better understand these factors. Congenital central hypoventilation syndrome (CCHS) is a rare disorder defined as failure of chemical control of breathing causing central alveolar hypoventilation, especially during sleep. A genetic basis for CCHS is supported by several arguments, mainly the identification, in a few CCHS patients, of heterozygous mutations of genes contributing to neural crest cell development, namely, genes involved in the endothelin and c-ret pathways. Furthermore, plethysmography studies of the respiratory phenotypes of newborn heterozygous mutant mice have shown that genes in both pathways are involved in breathing control at birth. Nevertheless, no single gene mutation in newborn mice reproduces the human CCHS phenotype. Avenues for future research into the genetics of CCHS include (i) testing of mutant newborn mice for genes in other pathways and (ii) use of microarrays to identify gene clusters that should be associated with abnormal chemical breathing control.     

Medullary serotonergic neurones modulate the ventilatory response to hypercapnia, but not hypoxia in conscious rats

Serotonergic neurones in the mammalian medullary raphe region (MRR) have been implicated in central chemoreception and the modulation of the ventilatory response to hypercapnia, and may also be involved in the ventilatory response to hypoxia. In this study, we ask whether ventilatory responses across arousal states are affected when the 5-hydroxytryptamine 1A receptor (5-HT_1A) agonist ( R )-(+)-8-hydroxy-2(di- n -propylamino)tetralin (DPAT) is microdialysed into the MRR of the unanaesthetized adult rat. Microdialysis of 1, 10 and 30 m m DPAT into the MRR significantly decreased absolute ventilation values     during 7% CO₂ breathing by 21%, 19% and 30%, respectively, in wakefulness compared to artificial cerebrospinal fluid (aCSF) microdialysis, due to decreases in tidal volume ( V _T) and not in frequency ( f ), similar to what occurred during non-rapid eye movement (NREM) sleep. The concentration-dependence of the hypercapnic ventilatory effect might be due to differences in tissue distribution of DPAT. DPAT (30 m m ) changed room air breathing pattern by increasing f and decreasing V _T. As evidenced by a sham control group, repeated experimentation and microdialysis of aCSF alone had no effect on the ventilatory response to 7% CO₂ during wakefulness or sleep. Unlike during hypercapnia, microdialysis of 30 m m DPAT into the MRR did not change the ventilatory response to 10% O₂. Additionally, 10 and 30 m m DPAT MRR microdialysis decreased body temperature, and 30 m m DPAT increased the percentage of experimental time in wakefulness. We conclude that serotonergic activity in the MRR plays a role in the ventilatory response to hypercapnia, but not to hypoxia, and that MRR 5-HT_1A receptors are also involved in thermoregulation and arousal.     

Chemosensory ventilatory responses in the mutant mice with Presbyterian hemoglobinopathy

The working hypothesis of this study was that chronically increased tissue oxygenation would facilitate respiratory endurance to chemical stimuli. We investigated the ventilatory responses to hypoxia and hypercapnia before and after carotid chemodenervation in the anesthetized, spontaneously breathing Presbyterian, which carry a low affinity variant of hemoglobin, and in wild-type mice. We found a dampening of all chemosensory responses in Presbyterian hemoglobinopathy. Particularly, the Presbyterian mouse with intact carotid body innervation was more vulnerable to hypoxia than the wild-type mouse, showing an accelerated decline in breathing frequency which was not counterbalanced by tidal respiration. We further found that chemodenervation in the Presbyterian mouse, performed in normoxia, led to respiratory arrest. The study shows enhanced susceptibility of respiration to hypoxia and indispensability of neural input from the carotid body for upholding the central respiratory controller's function in Presbyterian hemoglobinopathy. The study also suggests a relationship between hemoglobin-oxygen dissociation and respiration, which points to a metabolic, tissue oxygenation-linked component of respiratory regulation.     

Respiratory frequency response to progressive isocapnic hypoxia.

1. Ventilatory, tidal volume and frequency responses to progressive isocapnic hypoxia have been measured in twenty-nine healthy subjects by a rebreathing technique. 2. A strong correlation was found between ventilatory response to hypoxia (deltaVI/DELTASaO2) and frequency response to hypoxia (deltaf/deltaSaO2) (r=0-82, P less than 0-001). There was a lesser correlation between deltaV1/deltaSaO2 and tidal volume response (deltaVT/deltaSaO2) (r=0-50, P less than 0-01). These findings suggest that the wide range of ventilatory response to hypoxia among subjects is mainly determined by differences in frequency response and contrast with previous findings in studies of the response to progressive hypercapnia. 3. The breathing pattern during progressive hypoxia and hypercapnia was compared in ten subjects. Ventilation/tidal volume plots were constructed and patterns of response were further analysed in terms of inspiratory duration (TI), expiratory duration (TE) and mean inspiratory flow rate (VI). 4. Increments in ventilation during hypoxia were achieved with a greater respiratory frequency and a smaller tidal volume than during hypercapnia in eight of the ten subjects studied. In two subjects no difference in breathing pattern during hypoxia and hypercapnia was observed. 5. Changes in respiratory frequency during progressive hypoxia were achieved in all subjects by a progressive shortening of TI and TE. By contrast, TI remained constant during hypercapnia until VT had increased to 3-5 times the eupnoeic value; during hypercapnia the increase in frequency was achieved mainly by a progressive shortening of TE. 6. It is concluded that different mechanisms may be involved in altering respiratory frequency when ventilation is driven progressively by these different chemical stimuli.     

Ventilatory pattern and chemosensitivity in M1 and M3 muscarinic receptor knockout mice

Acetylcholine (ACh) acting through muscarinic receptors is thought to be involved in the control of breathing, notably in central and peripheral chemosensory afferents and in regulations related to sleep-wake states. By using whole-body plethysmography, we compared baseline breathing at rest and ventilatory responses to acute exposure (5 min) to moderate hypoxia (10% O(2)) and hypercapnia (3 and 5% CO(2)) in mice lacking either the M(1) or the M(3) muscarinic receptor, and in wild-type matched controls. M(1) knockout mice showed normal minute ventilation (V(E)) but elevated tidal volume (V(T)) at rest, and normal chemosensory ventilatory responses to hypoxia and hypercapnia. M(3) knockout mice had elevated V(E) and V(T) at rest, a reduced V(T) response slope to hypercapnia, and blunted V(E) and frequency responses to hypoxia. The results suggest that M(1) and M(3) muscarinic receptors play significant roles in the regulation of tidal volume at rest and that the afferent pathway originating from peripheral chemoreceptors involves M(3) receptors.     

Control of breathing in newborn mice lacking the beta-2 nAChR subunit

AIM: To study the ventilatory and arousal/defence responses to hypoxia in newborn mutant mice lacking the beta2 subunit of the nicotinic acetylcholine receptors. METHODS: Breathing variables were measured non-invasively in mutant (n = 31) and wild-type age-matched mice (n = 57) at 2 and 8 days of age using flow barometric whole-body plethysmography. The arousal/defence response to hypoxia was determined using behavioural criteria. RESULTS: On day 2, mutant pups had significantly greater baseline ventilation (16%) than wild-type pups (P < 0.02). Mutant pups had a decreased hypoxic ventilatory declines. Arousal latency was significantly shorter in mutant than in wild-type pups (133 +/- 40 vs. 146 +/- 20 s, respectively, P < 0.026). However, the duration of movement elicited by hypoxia was shorter in mutant than in wild-type pups (14.7 +/- 5.9 vs. 23.0 +/- 10.7 s, respectively, P < 0.0005). Most differences disappeared on P8, suggesting a high degree of functional plasticity. CONCLUSION: The blunted hypoxic ventilatory decline and the shorter arousal latency on day 2 suggested that disruption of the beta2 nicotinic acetylcholine receptors impaired inhibitory processes affecting both the ventilatory and the arousal response to hypoxia during postnatal development.     

Cardiorespiratory responses to hypoxia and hypercapnia at rest in vocalists

In order to clarify whether or not ventilatory and circulatory responses to hypoxia and hypercapnia at rest in male vocalists (n = 11) are identical to those of untrained subjects (n = 11), ventilatory responses to hypoxia (HVR) and hypercapnia (HCVR) were estimated as the slope of regression relating .VI to SaO(2) (Delta.VI/DeltaSaO(2)) or the slope factor (A) for the .VI-PETO(2) curve, and as the slope of regression relating .VI to PETCO(2) (Delta.VI/DeltaPETCO(2)), respectively. The respiratory frequency (f), tidal volume (VT), heart rate (HR), and blood pressure (BP) responses to hypoxia and hypercapnia were also estimated as the slope of the line calculated by linear regression related to SaO(2) and PETCO(2). Mean values of Delta.VI/DeltaSaO(2) and A as an index of hypoxic ventilatory response were lower in the vocalist group (0.39 +/- 0.25 l.min(-1).%(-1) and 76.8 +/- 55.7 l.min(-1).torr(-1)) than that in the control group (0.56 +/- 0.46 l.min(-1).%(-1) and 101.6 +/- 85.4 l.min(-1).torr(-1)), and there was no statistically significant difference. The Deltaf/DeltaSaO(2) was significantly (plt;0.05 ) lower in the vocalist group (-0.02 +/- 0.39 breaths.min(-1).%(-1)) than that in the control group (0.43 +/- 0.65 breaths.min(-1).%(-1)). In contrast, mean values of Delta.VI/DeltaPETCO(2) per body mass index were significantly (p<0.05) lower in the vocalist group (0.05 +/- 0.03 l.min(-1).torr(-1)) than those in the control group (0.10 +/- 0.06l.min(-1).torr(-1)). There were also significant differences in DeltaVT/DeltaPETCO(2) and Deltaf/DeltaPETCO(2) between the two groups (p<0.05). However, no significant differences in HR and BP responses to hypoxia and hypercapnia between the two groups were observed. These results suggest that the magnitude of ventilatory response, but not HR and BP, to hypoxia and hypercapnia at rest in vocalists is reduced by chronic vocal training, including breath control and elongation of phonation for long periods.     

Hypoxia impairs the arousal response to external resistive loading and airway occlusion during sleep

STUDY OBJECTIVES: Sustained hypoxia is a neurocognitive depressant, which has been shown to impair respiratory load sensation. Hypoxia has also been shown to impair arousal in animal models, but the effects of sustained hypoxia on arousal in humans have not been studied. The aim of this study was to assess the effects of sustained hypoxia on arousal from sleep in normal subjects. DESIGN: Twelve normal male subjects (age, 24.3 +/- 1.2 years; body mass index, 24.8 +/- 1.4 kg/m2) were studied during stable stage 2 non-rapid eye movement sleep on 2 separate nights 1 week apart. SETTING: Sleep physiology laboratory. PARTICIPANTS: Normal healthy volunteers. Interventions: Arousal responses to external resistive loads (18 cm H2O x L(-1) x sec(-1)) and occlusions were compared during room-air breathing following sustained normoxia and isocapnic hypoxia (SaO2 approximately 85%). Measurements and Results: Time to arousal and minimum esophageal pressure preceding arousal were measured. Time to arousal was significantly increased following hypoxia compared with normoxia for resistive loads (24.6 + 4.4 seconds vs. 12.6 +/- 1.9 seconds, p = .007) but not occlusions. Minimum esophageal pressure prior to arousal was more negative following hypoxia for both external loads (-16.8 +/- 1.2 vs. -13.5 +/- 1.3 cm H2O, p = .035) and occlusions (-19.6 +/- 2.2 vs. -15.1 +/- 1.5 cm H2O, p = .029). CONCLUSIONS: We conclude that sustained isocapnic hypoxia delays arousal to inspiratory loading during sleep and increases the respiratory arousal threshold. This has implications for disorders characterized by sustained nocturnal hypoxia, such as neuromuscular weakness, chronic obstructive pulmonary disease, obesity-hypoventilation syndrome, and severe obstructive sleep apnea.     

Arousal response to hypoxia in newborns: Insights from animal models

In newborns, the inability to initiate an arousal response to hypoxia is associated with apnea of prematurity, sudden infant death syndrome, and rare genetic disorders of respiratory control. Despite intensive research, the mechanisms of this response are poorly understood. This paper provides an overview of studies investigating the arousal response to hypoxia, with special emphasis on newborn mouse models. Mutant mouse models can provide valuable information regarding the pathogenesis of genetically determined disorders affecting arousal response to hypoxia, although data remain sparse. In mice, the arousal response to hypoxia emerges immediately after birth, when the ventilatory response to hypoxia is still immature. Habituation of the arousal response occurs after repeated hypoxic episodes. Newborn mice can learn to associate novel odors to hypoxia and respond to those odors by producing alerting responses, suggesting that the arousal response to hypoxia may be shaped by learning processes.     

Ventilation during air breathing and in response to hypercapnia in 5 and 16 month-old <Emphasis Type="Italic">mdx</Emphasis> and C57 mice

Previous studies have shown a blunted ventilatory response to hypercapnia in mdx mice older than 7 months. We test the hypothesis that in the mdx mice ventilatory response changes with age, concomitantly with the increased functional impairment of the respiratory muscles. We thus studied the ventilatory response to CO₂ in 5 and 16 month-old mdx and C57BL10 mice (n = 8 for each group). Respiratory rate (RR), tidal volume (VT), and minute ventilation (VE) were measured, using whole-body plethysmography, during air breathing and in response to hypercapnia (3, 5 and 8% CO₂). The ventilatory protocol was completed by histological analysis of the diaphragm and intercostals muscles. During air breathing, the 16 month-old mdx mice showed higher RR and, during hypercapnia (at 8% CO₂ breathing), significantly lower RR (226 ± 26 vs. 270 ± 21 breaths/min) and VE (1.81 ± 0.35 vs. 3.96 ± 0.59 ml min⁻¹ g⁻¹) (P < 0.001) in comparison to C57BL10 controls. On the other hand, 5 month-old C57BL10 and mdx mice did not present any difference in their ventilatory response to air breathing and to hypercapnia. In conclusion, this study shows similar ventilation during air breathing and in response to hypercapnia in the 5 month-old mdx and control mice, in spite of significant pathological structural changes in the respiratory muscles of the mdx mice. However in the 16 month-old mdx mice we observed altered ventilation under air and blunted ventilation response to hypercapnia compared to age-matched control mice. Ventilatory response to hypercapnia thus changes with age in mdx mice, in line with the increased histological damage of their respiratory muscles. J. Gayraud and S. Matecki contributed equally to this work     

Hypercapnia attenuates inspiratory amplitude and expiratory time responsiveness to hypoxia in vagotomized and vagal-intact rats

There is evidence for a “sensitive period” in respiratory development in rats around postnatal age (P) 12-13 d. Little is known about sex differences during that time. The purpose of this study was to assess the effect of sex on breathing development, specifically around the “sensitive period”. We used whole-body plethysmography to study breathing in normoxic, hypoxic and hypercapnic gases in non-anesthetized male and female neonatal rats from P10 to P15, juvenile (P30) and young adult (P90) rats. Compared to other neonatal ages, P12-13 male rats had significantly lower ventilation during normoxia, hypoxia, and hypercapnia. Compared to age-matched females, P12-13 male rats had lower ventilation in normoxia and hypoxia and a lower O₂ saturation during hypoxia. Circulating estradiol was greater in P12-13 male vs. female rats. Estradiol and ventilatory responses to hypoxia and hypercapnia were negatively correlated in neonatal male, but not female rats. Our results suggest that P10-15 includes a critical developmental period in male but not female rats.     

Sudden neonatal death in PACAP-deficient mice is associated with reduced respiratory chemoresponse and susceptibility to apnoea

Pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient mice are more prone to sudden death during postnatal weeks 1–3 than wild-type littermates. Given that PACAP is localized in brainstem regions associated with respiratory chemosensitivity, we examined whether PACAP-null neonates have reduced respiratory responses to hypoxia and hypercapnia. Using unrestrained, whole-body, flow-through plethysmography we found that, by postnatal day 4, the PACAP-null neonates had significantly reduced ventilation during baseline breathing, and blunted responses to both hypoxia (10% O₂–90% N₂) and hypercapnia (8% CO₂–92% air). To determine whether the respiratory phenotype of the PACAP-null mice may contribute to their greater neonatal mortality, we used ECG to examine respiration and cardiovascular function of littermates. We demonstrate that, under conditions that exacerbate mortality of knockout but not wild-type animals, PACAP-deficient mice experience prolonged apnoeas that precede atrio-ventricular block. Both apnoeas and atrio-ventricular block were absent in wild-type littermates. These data suggest that PACAP-deficiency results in higher neonatal mortality primarily as a result of respiratory control defects and raise the possibility that mutations in genes encoding components of the PACAP signalling pathways may contribute to neonatal breathing disorders in humans.     

Respiratory responses to hypercapnia and hypoxia in mice with genetic ablation of Kir5.1 (Kcnj16)

Inward rectifier (Kir) potassium channels contribute to the control of electrical activity in excitable tissues and their activity is modulated by many biochemical factors, including protons. Heteromeric Kir4.1-Kir5.1 channels are highly pH sensitive within the physiological range of pH changes and are strongly expressed by the peripheral chemosensors as well as in the brainstem pH-sensitive areas which mediate respiratory responses to changes in blood and brain levels of P(CO(2))/[H(+)]. In the present study, Kir5.1 knockout mice (Kir5.1(-/-)) were used to determine the role of these channels in the chemosensory control of breathing. We found that Kir5.1(-/-) mice presented with persistent metabolic acidosis and a clear respiratory phenotype. Despite metabolic acidosis, ventilation at rest and in hyperoxic hypercapnia were similar in wild-type and Kir5.1(-/-) mice. Ventilatory responses to hypoxia and normoxic hypercapnia were significantly reduced in Kir5.1(-/-) mice; however, carotid body chemoafferent responses to hypoxia and CO(2) were not affected. In the in situ brainstem-spinal cord preparations with denervated peripheral chemoreceptors, resting phrenic nerve activity and phrenic nerve responses to respiratory acidosis or isohydric hypercapnia were also similar in Kir5.1(-/-) and wild-type mice. In in situ preparations of Kir5.1(-/-) mice with intact peripheral chemoreceptors, application of CN(-) resulted in a significantly reduced phrenic nerve response, suggesting that the relay of peripheral chemosensory information to the CNS is compromised. We suggest that this compensatory modulation of the peripheral chemosensory inputs develops in Kir5.1(-/-) mice in order to counteract the effect of continuing metabolic acidosis on the activity of the peripheral chemoreceptors. These results therefore suggest that despite their intrinsic pH sensitivity, Kir4.1-Kir5.1 channels are dispensable for functional central and peripheral respiratory chemosensitivity.     

Ventilatory responses to acute hypoxia in neurokinin-1 receptor deficient mice

The regulatory effect of substance P on respiration is mediated via neurokinin (NK) receptors. While previous studies suggest that NK-1 receptors are involved, little is known about the role NK-2 receptors in ventilatory responses to hypoxia. Ventilatory responses to acute hypoxia (8% O2 in N2) were measured by indirect plethysmography in unanaesthetized, unrestrained NK-1 receptor gene deficient (NK-1-/-) and wild-type mice. In additional experiments mice were treated with an NK-2 receptor antagonist prior to hypoxic challenge. Resting ventilatory parameters were not different between groups. NK-1-/- mice displayed significantly greater shortening of expiratory time and higher increase of breathing frequency during hypoxia than wild-type mice. Treatment with the NK-2 receptor antagonist SR 48968 (1 mg/kg) resulted in a further shortening of inspiratory and expiratory time in NK-1-/- but not wild-type mice. These results demonstrate that both NK-1 and NK-2 receptors are involved in the modification of ventilation in response to acute hypoxia.     

Effect of hypoxia on ventilatory and arousal responses to CO2 during NREM sleep with and without flurazepam in young adults

We examined the ventilatory response to CO2 at two levels of oxygenation during wakefulness and sleep in healthy young adults before and after the ingestion of a single dose of 30 mg flurazepam. Progressive hypercapnia was produced at two levels of arterial O2 saturation (greater than 99 and 87%) by having subjects re-breathe from a tight-fitting face mask and a reservoir bag containing gas mixtures with two different O2 concentrations. Ventilation was measured with an inductive plethysmograph. O2 saturation was measured with an ear oximeter. Sleep was monitored using standard techniques by recording the electroencephalogram, eye movements, and chin electromyogram. During wakefulness, hypoxia increased the slope of the ventilatory response to CO2 and shifted the response slightly to the left. NREM sleep lowered the slope of the CO2 response under both hyperoxic and hypoxic conditions. The slope of the hyperoxic CO2 response curve was not affected by flurazepam during wakefulness or sleep. After administration of flurazepam to the subjects, the shift of the CO2 response curve to the left produced by hypoxia (additive effect) during NREM sleep was slightly less as compared to control, but hypoxia still increased the slope of the CO2 ventilatory response. During hypoxic hypercapnia, the PCO2 at arousal from sleep was significantly lower than during hyperoxic hypercapnia, but the level of ventilation at arousal during hypercapnia was similar in the control condition and after flurazepam. We conclude that (a) both natural and flurazepam-induced sleep depress ventilatory responses to hyperoxic and hypoxic hypercapnia and alter, in a complex fashion, the effects of hypoxia and hypercapnia on ventilation; and (b) hypoxia and hypercapnia interact as arousal stimuli in both natural and flurazepam-induced sleep.     

Respiratory plasticity after perinatal hypercapnia in rats

Environmental conditions during early life may have profound effects on respiratory control development. We hypothesized that perinatal hypercapnia would exert lasting effects on the mammalian hypercapnic ventilatory response, but that these effects would differ between males and females. Rats were exposed to 5% CO2 from 1 to 3 days before birth through postnatal week 2 and ventilation was subsequently measured by whole-body plethysmography. In both male and female rats exposed to perinatal hypercapnia, a rapid, shallow breathing pattern was observed for the first 2 weeks after return to normocapnia, but ventilation was unchanged. Acute hypercapnic ventilatory responses (3% and 5% CO2) were reduced 27% immediately following perinatal hypercapnia, but these responses were normal after 2 weeks of recovery in both sexes and remained normal as adults. Collectively, these data suggest that perinatal hypercapnia elicits only transient respiratory plasticity in both male and female rats. This plasticity appears similar to that observed after chronic hypercapnia in adult animals and, therefore, is not unique to development.