Sleep and maturation of eucapnic ventilation and CO2 sensitivity in the premature primate

The effects of sleep state and postnatal maturation on steady-state CO2 sensitivity, "inspiratory drive" (VT/TI), and the inspiratory "duty cycle" (TI/Ttot) were examined in nine unanesthetized premature Macaca nemestrina in the first 3 wk of life. Minute volume (VE) in room air was less in NREM sleep than in the awake state but there were no differences in VE, VT/TI, or TI/Ttot between REM and NREM sleep. VE and VT/TI corrected for body weight increased in REM and NREM sleep with postnatal maturation whereas TI/Ttot did not vary. Concomitant with this increase in room air VE and VT/TI, an increase in CO2 sensitivity (delta V/delta Paco2) with postnatal maturation was documented in NREM sleep. CO2 sensitivity was similar between REM and NREM states at each postnatal age. The increase in VE following inhalation of 2-5% CO2 was mediated by an increase in VT/TI, whereas TI/Ttot remained constant. The differences in the effect of sleep on CO2 sensitivity between neonates and adults are discussed and possible mechanisms for the observed developmental increase in CO2 sensitivity are proposed.     

Effect of high-intensity exercise on the VE-VCO2 relationship

The intrinsic relationship between ventilation (VE) and carbon dioxide output (VCO2) is described by the modified alveolar ventilation equation VE = VCO2 k/PaCO2(1-VD/VT) where PaCO2 is the partial pressure of CO2 in the arterial blood and VD/VT is the dead space fraction of the tidal volume. Previous investigators have reported that high-intensity exercise uncouples VE from VCO2; however, they did not measure the PaCO2 and VD/VT components of the overall relationship. In an attempt to provide a more complete analysis of the effects of high-intensity exercise on the VE-VCO2 relationship, we undertook an investigation where five subjects volunteered to perform three steady-state tests (SS1, SS2, SS3) at 60 W. One week after SS1 each subject was required to perform repeated 1-min bouts of exercise corresponding to a work rate of approximately 140% of maximal oxygen uptake (VO2max). Two and 24 h later the subjects performed SS2 and SS3, respectively. This exercise intervention caused PaCO2 during SS2 and SS3 to be regulated (P less than 0.01) approximately 4 Torr below the control (SS1) value of 38.8 Torr. Additionally, significant alterations were noted for VCO2 with corresponding values of 1.15 (SS1), 1.10 (SS2), and 1.04 (SS3) l/min. No changes were noted in either VD/VT or VE. In summary, it seems reasonable to suggest that the disproportionate increase in VE with respect to VCO2 noted in earlier work does not reflect an uncoupling. Rather the slope of the VE-VCO2 relationship is increased in a predictable manner as described by the modified alveolar ventilation equation.     

Effect of a single breath of 100% oxygen on respiration in neonates during sleep

To determine the effect of a single breath of 100% O2 on ventilation, 10 full-term [body wt 3,360 +/- 110 (SE) g, gestational age 39 +/- 0.4 wk, postnatal age 3 +/- 0.6 days] and 10 preterm neonates (body wt 2,020 +/- 60 g, gestational age 34 +/- 2 wk, postnatal age 9 +/- 2 days) were studied during active and quiet sleep states. The single-breath method was used to measure peripheral chemoreceptor response. To enhance response and standardize the control period for all infants, fractional inspired O2 concentration was adjusted to 16 +/- 0.6% for a control O2 saturation of 83 +/- 1%. After 1 min of control in each sleep state, each infant was given a single breath of O2 followed by 21% O2. Minute ventilation (VE), tidal volume (VT), breathing frequency (f), alveolar O2 and CO2 tension, O2 saturation (ear oximeter), and transcutaneous O2 tension were measured. VE always decreased with inhalation of O2 (P less than 0.01). In quiet sleep, the decrease in VE was less in full-term (14%) than in preterm (40%) infants (P less than 0.001). Decrease in VE was due primarily to a drop in VT in full-term infants as opposed to a fall in f and VT in preterm infants (P less than 0.05). Apnea, as part of the response, was more prevalent in preterm than in full-term infants. In active sleep the decrease in VE was similar both among full-term (19%) and preterm (21%) infants (P greater than 0.5). These results suggest greater peripheral chemoreceptor response in preterm than in full-term infants, reflected by a more pronounced decrease in VE with O2. The results are compatible with a more powerful peripheral chemoreceptor contribution to breathing in preterm than in full-term infants.     

An evaluation of ventilation in dystrophic Syrian hamsters

Ventilatory responses of 10 control and 10 dystrophic male hamsters to air, hypercapnia, and hypoxia were evaluated at four ages (40, 70, 100, and 140 days). Tidal volume (VT), frequency (f), minute ventilation (VE) as well as inspiratory and expiratory time of awake animals were measured with a plethysmograph. There was a small increase of VT in both groups with age. Although there was no change of f in the control group with age, there was a progressive decrease in f (means +/- SE: 92 +/- 8, 97 +/- 9, 74.5 +/- 10, and 68 +/- 8 breaths/min) in the dystrophic group. Consequently VE on air decreased in the dystrophic group. Both groups showed similar responses to hypoxia (13 and 10% O2) and hypercapnia (3, 5, and 8% CO2) at 40 days. By 70 days the hypercapnic, but not hypoxic, response of the dystrophic animals was significantly decreased compared with that of the control group (at 8% CO2, VE = 47.4 +/- 4.1 vs. 75.7 +/- 7.6 ml/min, P less than 0.01). At both 100 and 140 days the response of the dystrophic group to CO2 was flat; i.e., the slope VE vs. fractional concentration of inspired CO2 was close to zero, and the hypoxic responses were greatly diminished. Because hamsters increase VE in response to CO2 primarily by increasing VT, the data suggest that dystrophic hamsters are unable to increase VT at a very early age, presumably due to muscle weakness. The normal response of hamsters to hypoxia, which is primarily to increase f, appears to be maintained for a longer time.     

Effects of early hypoxia on breathing pattern in rabbit pups before and after vagotomy

We examined the influence of vagal pulmonary receptors exerted on the breathing pattern and inspiratory activities of phrenic nerve and intercostal electromyograms (EMG) during hypoxia in rabbit pups. Animals in their second week of life were anaesthetized with ketamine (50 mg/kg) and acepromazine (3 mg/kg) and tracheostomized. While they breathed spontaneously, we recorded tidal volume (VT), integrated phrenic activity (PHR), integrated external intercostal EMG (INT), and blood pressure (BP). To prevent secondary ventilatory depression, animals were exposed to 12% O2 (balanced with N2) for no longer than 5 min before and after vagotomy. All measurements were taken from 1 min following the onset of hypoxic exposure until the end of the run. During hypoxia, VT, PHR, and INT increased in intact rabbit pups. There was an almost immediate decrease in BP that was maintained during the total period of hypoxia exposure. Hypoxia resulted in inconsistent changes in inspiratory (TI) and expiratory (TE) time in intact animals. Following vagotomy, PHR, INT, VT, BP, and TE responses were the same as in intact animals. However, TI significantly decreased in all animals. In response to hypoxia with and without vagal feedback, INT increased less than PHR in most cases. Qualitatively similar effects of hypoxia were observed in an adult rabbit. The results reveal that the increase in VT and the shortening of TI in response to hypoxia do not depend on vagal feedback in rabbits during the early postnatal period. In fact TI shortening was significant only without vagal feedback.     

Decline in peripheral chemoreceptor excitatory stimulation during acute hypoxia in the lamb

Chemoreceptor function was studied in eight 2- to 3-day-old unanesthetized lambs to sequentially assess hypoxic chemoreflex strength during an 18-min exposure to hypoxia [inspired O2 fraction (FIO2) = 0.08]. The immediate ventilatory (VE) drop in response to five breaths of pure O2 was measured at 3, 7, and 15 min during hypoxia. Each lamb was studied again at 10-11 days of age. At 2-3 days of age VE increased, with the onset of hypoxia, from 658 +/- 133 (SD) ml.min-1 X kg-1 to a peak of 1,124 +/- 177 ml.min-1 X kg-1. A dampening of the VE response then occurred, with a mean decline in VE of 319 ml.min-1 X kg-1 over the 18-min hypoxia period. Each pure O2 test (Dejours test) resulted in an abrupt fall in VE (delta VEDejours). This VE drop was 937 +/- 163, 868 +/- 244, and 707 +/- 120 ml.min-1 X kg-1 at 3, 7, and 15 min of hypoxia, respectively. Comparing the three O2 tests, delta VEDejours was significantly decreased by 15 min, indicating a loss of about one-fourth of the O2 chemoreflex drive during hypoxia. Testing at 10-11 days of age revealed a smaller VE decline during hypoxia. O2 tests at the beginning and end of the hypoxic period were not significantly different, indicating a smaller loss of hypoxic chemoreflex drive in the more mature animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of centrally administered gamma-aminobutyric acid on metabolic function

gamma-Aminobutyric acid (GABA) content of the brain increases during hypoxia and hypercapnia and GABA by itself is a central ventilatory depressant and may depress metabolism as well. Therefore the effect of centrally administered GABA by ventriculocisternal perfusion on O2 consumption (VO2) and CO2 production (VCO2) was studied in pentobarbital-anesthetized dogs. GABA (30 mM) in mock cerebrospinal fluid (CSF) was perfused for 15 min at the rate of 1.0 ml/min followed by perfusion with mock CSF alone. Body temperature, perfusion pressure, and CSF pH were kept constant. Minute ventilation (VE) was kept constant mechanically. Under these conditions, VO2, VCO2, alveolar ventilation (VA), and relative pulmonary dead space volume (VD/VT) were measured. During perfusion with 30 mM GABA, mean VO2 (+/- SE) decreased from 96.5 +/- 3.3 to 81.9 +/- 5.1 ml/min, VCO2 from 72.1 +/- 3.8 to 60.7 +/- 3.0 ml/min, and VA from 1.7 +/- 0.1 to 1.3 +/- 0.1 l/min. VD/VT increased from 0.55 +/- 0.02 to 0.65 +/- 0.01. Perfusion with mock CSF alone restored these parameters to initial levels within 15 min. We conclude that centrally administered GABA depresses VO2 and VCO2. This reduction in metabolic function is independent of the central modulatory effects of GABA on respiration.     

Development of CO2 sensitivity: effects of gestational age, postnatal age, and sleep state

To determine the independent effects of sleep state, gestational age, and postnatal age on eucapnic ventilation and steady-state CO2 sensitivity, nine premature (146 +/- 3 days) and eight full-term (168 +/- 2 days) monkeys, Macaca nemestrina, from accurately timed conceptions were studied serially over the first 3 wk of life. Minute volume (VE)/kg,tidal volume (VT)/kg, and respiratory frequency were quantitated during rapid-eye-movement sleep (REM) and nonrapid-eye-movement sleep (NREM)in room air and when animals were breathing varied concentrations of cO2 in 21% O2. Eucapnic VE/kg and CO2 sensitivity [(deltaVE/kg)/delta PaCO2] increased progressively with advancing postnatal age during NREM sleep in grouped term and premature animals. CO2 sensitivity was not significantly different between REM and NREM sleep except in full-term animals at the highest postconceptual age studied (189 +/- 2 days) when [(delta VE/kg)/delta PaCO2] was lower in REM sleep than in NREM sleep (209 +/- 54 vs. 301 +/- 71 ml.min-1.kg-1.Torr-1; P less than 0.05, paired-t test). Gestational age had no measurable effect on eucapnic ventilation or CO2 sensitivity. These results support the hypothesis that REM sleep-induced depression of CO2 sensitivity develops in the neonatal monkey with advancing postconceptual age.     

Threshold levels of maternal nicotine impairing protective responses of newborn rats to intermittent hypoxia.

Experiments were carried out to determine the threshold level of maternal nicotine that impairs protective responses of rat pups to hypoxia. From days 6 or 7 of gestation, pregnant rats received either vehicle or nicotine (1.50, 3.00, or 6.00 mg of nicotine tartrate. kg body wt(-1).day(-1)) or vehicle continuously via a subcutaneous osmotic minipump. On postnatal days 5 or 6, pups were exposed to a single period of hypoxia produced by breathing an anoxic gas mixture (97% N(2) or 3% CO(2)) and their time to last gasp was determined, or they were exposed to intermittent hypoxia and their ability to autoresuscitate from hypoxic-induced primary apnea was determined. Perinatal exposure to nicotine did not alter the time to last gasp or the total number of gasps when the pups were exposed to a single period of hypoxia. The number of successful autoresuscitations on repeated exposure to hypoxia was, however, decreased in pups whose dams had received either 3.00 or 6.00 mg of nicotine tartrate/kg body wt; these dosage regimens produced maternal serum nicotine concentrations of 19 +/- 6 and 35 +/- 8 ng/ml, respectively. Thus our experiments define the threshold level of maternal nicotine that significantly impairs protective responses of 5- to 6-day-old rat pups to intermittent hypoxia such as may occur in human infants during episodes of prolonged sleep apnea or positional asphyxia.     

Limitation of lower limb VO(2) during cycling exercise in COPD patients.

Patients with chronic obstructive pulmonary disease (COPD) usually stop exercise before reaching physiological limits in terms of O(2) delivery and extraction. A plateau in lower limb O(2) uptake (VO(2)) and blood flow occurs despite progression of the imposed workload during cycling in some patients with COPD, suggesting that maximal capacity to transport O(2) had been reached and that it had been extracted in the peripheral exercising muscles. This study addresses this observation. Symptom-limited incremental cycle exercise was performed by 14 men [62 +/- 11 (SD) yr] with severe COPD (forced expiratory volume in 1 s = 35 +/- 7% of predicted value). Leg blood flow was measured at each exercise step with a thermodilution catheter inserted in the femoral vein. This value was multiplied by two to account for both working legs (Q(LEGS)). Arterial and femoral venous blood was sampled at each exercise step to measure blood gases. Leg O(2) consumption (VO(2LEGS)) was calculated according to the Fick equation. Total body VO(2) (VO(2TOT)) was measured from expired gas analysis, and tidal volume (VT) and minute ventilation (VE) were derived from the flow signal. In eight patients, VO(2LEGS) kept increasing in parallel with VO(2TOT) as external work rate was increasing. In six subjects, a plateau in VO(2LEGS) and Q(LEGS) occurred during exercise (increment of <3% between 2 consecutive increasing workloads) despite the increase in workload and VO(2TOT) [corresponding mean was 110 +/- 38 ml (11 +/- 4%)]. These six patients also exhibited a plateau in O(2) extraction during exercise. Peak exercise work rate was higher in the eight patients without a plateau than in the six with a plateau (51 +/- 10 vs. 40 +/- 13 W, P = 0.043). VT, VE, and dyspnea were significantly greater at submaximal exercise in patients of the plateau group compared with those of the nonplateau group. These results show that, in some patients with COPD, blood flow directed to peripheral muscles and O(2) extraction during exercise may be limited. We speculate that redistribution of cardiac output and O(2) from the lower limb exercising muscles to the ventilatory muscles is a possible mechanism.     

Effect of caffeine on ventilatory responses to hypercapnia, hypoxia, and exercise in humans

The effect of oral caffeine on resting ventilation (VE), ventilatory responsiveness to progressive hyperoxic hypercapnia (HCVR), isocapnic hypoxia (HVR), and moderate exercise (EVR) below the anaerobic threshold (AT) was examined in seven healthy adults. Ventilatory responses were measured under three conditions: control (C) and after ingestion of either 650 mg caffeine (CF) or placebo (P) in a double-blind randomized manner. None of the physiological variables of interest differed significantly for C and P conditions (P greater than 0.05). Caffeine levels during HCVR, HVR, and EVR were 69.5 +/- 11.8, 67.8 +/- 10.8, and 67.8 +/- 10.9 (SD) mumol/l, respectively (P greater than 0.05). Metabolic rate at rest and during exercise was significantly elevated during CF compared with P. An increase in VE from 7.4 +/- 2.5 (P) to 10.5 +/- 2.1 l/min (CF) (P less than 0.05) was associated with a decrease in end-tidal PCO2 from 39.1 +/- 2.7 (P) to 35.1 +/- 1.3 Torr (CF) (P less than 0.05). Caffeine increased the HCVR, HVR, and EVR slopes (mean increase: 28 +/- 8, 135 +/- 28, 14 +/- 5%, respectively) compared with P; P less than 0.05 for each response. Increases in resting ventilation, HCVR, and HVR slopes were associated with increases in tidal volume (VT), whereas the increase in EVR slope was accompanied by increases in both VT and respiratory frequency. Our results indicate that caffeine increases VE and chemosensitivity to CO2 inhalation, hypoxia, and CO2 production during exercise below the AT.     

Ventilatory and metabolic adaptations to walking and cycling in patients with COPD.

To test the hypothesis that in chronic obstructive pulmonary disease (COPD) patients the ventilatory and metabolic requirements during cycling and walking exercise are different, paralleling the level of breathlessness, we studied nine patients with moderate to severe, stable COPD. Each subject underwent two exercise protocols: a 1-min incremental cycle ergometer exercise (C) and a "shuttle" walking test (W). Oxygen uptake (VO(2)), CO(2) output (VCO(2)), minute ventilation (VE), and heart rate (HR) were measured with a portable telemetric system. Venous blood lactates were monitored. Measurements of arterial blood gases and pH were obtained in seven patients. Physiological dead space-tidal volume ratio (VD/VT) was computed. At peak exercise, W vs. C VO(2), VE, and HR values were similar, whereas VCO(2) (848 +/- 69 vs. 1,225 +/- 45 ml/min; P < 0. 001) and lactate (1.5 +/- 0.2 vs. 4.1 +/- 0.2 meq/l; P < 0.001) were lower, DeltaVE/DeltaVCO(2) (35.7 +/- 1.7 vs. 25.9 +/- 1.3; P < 0. 001) and DeltaHR/DeltaVO(2) values (51 +/- 3 vs. 40 +/- 4; P < 0.05) were significantly higher. Analyses of arterial blood gases at peak exercise revealed higher VD/VT and lower arterial partial pressure of oxygen values for W compared with C. In COPD, reduced walking capacity is associated with an excessively high ventilatory demand. Decreased pulmonary gas exchange efficiency and arterial hypoxemia are likely to be responsible for the observed findings.     

Effect of increased inspired CO2 on respiratory dead space in ponies

The objective of the present study was to determine the effect of elevated inspired CO2 on respiratory dead space (VD) of 12 normal, 8 carotid body-denervated (CBD), 7 hilar nerve-denervated (HND), and 6 CBD+HND ponies. The Fowler technique was used to determine VD on a breath-by-breath basis while the ponies breathed room air and inspired CO2 at 3 and 6%. During room air breathing, tidal volume (VT) and VD were greater in HND ponies than in normal and CBD ponies (P less than 0.05), and VT was less and VD/VT was greater after CBD than before CBD. For all groups. VD, VT, and breathing frequency (f) increased and VD/VT decreased significantly (P less than 0.01) with increasing inspired CO2. During CO2 breathing, VT and VD were higher (P less than 0.05) in the HND ponies than in all other groups, the decrease (P less than 0.05) in VD/VT was greatest in the CBD+HND group, and f was lower in the HND and HND+CBD than in the normal and CBD ponies. In addition, when inspired CO2 was increased from 0 to 6%, the decrease in VD/VT was greater and the increase in arterial PCO2 was less (P less than 0.05) after CBD than before CBD. For 70% of the ponies in all groups, VD increased linearly with increases in VT; for most of the remainder, VD tended to plateau at higher values of VT.     

Performance of runners and swimmers after four weeks of intermittent hypobaric hypoxic exposure plus sea level training.

This double-blind, randomized, placebo-controlled trial examined the effects of 4 wk of resting exposure to intermittent hypobaric hypoxia (IHE, 3 h/day, 5 days/wk at 4,000-5,500 m) or normoxia combined with training at sea level on performance and maximal oxygen transport in athletes. Twenty-three trained swimmers and runners completed duplicate baseline time trials (100/400-m swims, or 3-km run) and measures for maximal oxygen uptake (VO(2max)), ventilation (VE(max)), and heart rate (HR(max)) and the oxygen uptake at the ventilatory threshold (VO(2) at VT) during incremental treadmill or swimming flume tests. Subjects were matched for sex, sport, performance, and training status and divided randomly between hypobaric hypoxia (Hypo, n = 11) and normobaric normoxia (Norm, n = 12) groups. All tests were repeated within the first (Post1) and third weeks (Post2) after the intervention. Time-trial performance did not improve in either group. We could not detect a significant difference between groups for a change in VO(2max), VE(max), HR(max), or VO(2) at VT after the intervention (group x test interaction P = 0.31, 0.24, 0.26, and 0.12, respectively). When runners and swimmers were considered separately, Hypo swimmers appeared to increase VO(2max) (+6.2%, interaction P = 0.07) at Post2 following a precompetition taper and increased VO(2) at VT (+8.9 and +12.1%, interaction P = 0.007 and 0.006, at Post1 and Post2). We conclude that this "dose" of IHE was not sufficient to improve performance or oxygen transport in this heterogeneous group of athletes. Whether there are potential benefits of this regimen for specific sports or training/tapering strategies may require further study.     

Effects of inspiratory resistive load on respiratory control in hypercapnia and exercise

Eight healthy young men underwent two separate steady-state incremental exercise runs within the aerobic range on a treadmill with alternating periods of breathing with no load (NL) and with an inspiratory resistive load (IRL) of approximately 12 cmH2O.1-1.s. End-tidal PCO2 was maintained constant throughout each run at the eucapnic or a constant hypercapnic level by adding 0-5% CO2 to the inspired O2. Hypercapnia caused a steepening, as well as upward shift, relative to the corresponding eucapnic ventilation-CO2 output (VE - VCO2) relationship in NL and IRL. Compared with NL, the VE - VCO2 slope was depressed by IRL, more so in hypercapnic [-19.0 +/- 3.4 (SE) %] than in eucapnic exercise (-6.0 +/- 2.0%), despite a similar increase in the slope of the occlusion pressure at 100 ms - VCO2 (P100 - VCO2) relationship under both conditions. The steady-state hypercapnic ventilatory response at rest was markedly depressed by IRL (-22.6 +/- 7.5%), with little increase in P100 response. For a given inspiratory load, breathing pattern responses to separate or combined hypercapnia and exercise were similar. During IRL, VE was achieved by a greater tidal volume (VT) and inspiratory duty cycle (TI/TT) along with a lower mean inspiratory flow (VT/TI). The increase in TI/TT was solely because of a prolongation of inspiratory time (TI) with little change in expiratory duration for any given VT. The ventilatory and breathing pattern responses to IRL during CO2 inhalation and exercise are in favor of conservation of respiratory work.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of glutamate as the central neurotransmitter in the hypoxic ventilatory response.

Recent data suggest that the increase in ventilation during hypoxia may be related to the release of the excitatory amino acid neurotransmitter glutamate centrally. To further investigate this, we studied the effects of MK-801, a selective noncompetitive N-methyl-D-aspartate receptor antagonist, on the hypoxic ventilatory response in lightly anesthetized spontaneously breathing intact dogs. The cardiopulmonary effects of sequential ventriculocisternal perfusion (VCP) at the rate of 1 ml/min with mock cerebrospinal fluid (CSF, control) and MK-801 (2 mM) were compared during normoxia and 8 min of hypoxic challenge with 12% O2. Minute ventilation (VE), tidal volume (VT), and respiratory frequency (f) were recorded continuously, and hemodynamic parameters [heart rate (HR), blood pressure (MAP), cardiac output (CO), pulmonary arterial pressure, and pulmonary capillary wedge pressure] were measured periodically. Each dog served as its own baseline control before and after each period of sequential VCP under the two different O2 conditions. During 15 min of normoxia, there were no significant changes in the cardiopulmonary parameters with mock CSF VCP, whereas with MK-801 VCP for 15 min, VE decreased by approximately 27%, both by reductions in VT and f (17 and 9.5%, respectively). HR, MAP, and CO were unchanged. During 8 min of hypoxia with mock CSF VCP, VE increased by 171% associated with increased VT and f (25 and 125%, respectively). HR, MAP, and CO were likewise augmented. In contrast, the hypoxic response during MK-801 VCP was characterized by an increased VE of 84%, mainly by a rise in f by 83%, whereas the VT response was abolished. The cardiovascular excitation was also inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of almitrine on respiration in unanesthetized newborn rabbits

We previously demonstrated that almitrine, a peripheral chemoreceptor stimulant, increased tidal volume (VT), expired minute ventilation (VE), and respiratory frequency (f) and decreased inspiratory (TI) and expiratory time (TE) in sleeping adult cats. We now hypothesized that almitrine would induce an increase in ventilation in a young animal model. Respiration was studied by the barometric method in 11 unanesthetized New Zealand White rabbit pups between 3 and 6 days of age. Recordings were made in 0.21 FIO2 at base line and after cumulative intraperitoneal infusions of almitrine (2.5, 5.0, and 7.5 mg/kg). The chamber pressure deflection (proportional to VT after appropriate calculation) was computer sampled at 200 Hz. At least 100 breaths for each dose in each animal were analyzed. We found that a 7.5-mg/kg intraperitoneal dose of almitrine increased f to 135 +/- 9% (SE) of base line and decreased TE and TI to 72 +/- 8% and 79 +/- 8% of base line, respectively. Changes in VE, VT/TI, and VT were not significant. Recognizing that apnea is associated with inadequate ventilation and a prolonged TE (failure of the "inspiratory on-switch"), these results, particularly the increase in f and decrease in TE, suggest that almitrine might be useful in treating apnea in preterm infants.     

Neonatal thymulin gene therapy in nude mice: Effects on the morphology of the pituitary corticotrope population

The integrity of the thymus during early life is necessary for a proper maturation of the neuroendocrine system, including the adrenal axis. The thymic metallopeptide thymulin seems to be a central physiologic mediator of thymus-pituitary communication. Furthermore, neonatal thymulin gene therapy has been shown to prevent the typical alterations of gonadotrophic cell number and morphology and serum gonadotropin levels in nude female mice. In the present study we assessed the impact of athymia and the effect of neonatal thymulin gene therapy on the corticotropic cell population in nude mice. The effect of thymulin administration to adult nudes on their hypothalamic content of corticotropin-releasing hormone (CRH) and the adrenal content of corticosterone was also determined. We used an adenoviral vector expressing a synthetic gene for the thymic peptide thymulin (metFTS) termed RAd-FTS. On postnatal day 1 or 2, heterozygous (nu/+) and homozygous (nu/nu) pups of both sexes received a single bilateral i.m. injection of RAd-FTS or RAd-GFP, a control vector. On postnatal day 71, mice were bled and sacrificed, and their pituitaries were immediately dissected, fixed and immunostained for corticotropin. Morphometry was performed by means of an image-analysis system. The following parameters were calculated: volume density (VD: Σ cell area/reference area), cell density (CD: number of cells/reference area), and cell surface (CS: expressed in μm2). Serum thymulin levels were measured by a bioassay, and CRH as well as corticosterone were determined by IRMA and RIA, respectively. Neonatal thymulin gene therapy in the athymic mice restored their serum thymulin levels and increased corticotrope CD, VD and CS in both control and athymic mice. Athymic mice showed only a marginal reduction in corticotrope CD, VD and CS. In these mutants hypothalamic CRH content was slightly increased, whereas adrenal corticosterone tended to be lower. Thymulin administration to adult mice tended to reverse these changes. Our results suggest a possible modulating effect of thymulin on the corticotrope population and the adrenal gland, confirming the existence of a bidirectional thymus-pituitary-adrenal axis.     

Ventilation in newborn rats after gestation at simulated high altitude

Pregnant rats were kept at a simulated altitude of 4,500 m (PO2 91 Torr) for the whole of gestation and returned to sea level 1 day after giving birth. During pregnancy, body weight gain and food intake were approximately 30% less than in controls at sea level. Measurements were made on the 1-day-old (HYPO) pups after a few hours at sea level. In normoxia, ventilation (VE) measured by flow plethysmography was more (+17%) and O2 consumption (VO2) measured by a manometric method was less (-19%) than in control (CONT) pups; in HYPO pups VE/VO2 was 44% greater than in CONT pups. In acute hyperoxia, VE/VO2 of HYPO and CONT pups decreased by a similar amount (15-20%), indicating some limitation in O2 availability for both groups of pups in normoxia. However, VE/VO2 of HYPO pups, even in hyperoxia, remained above (+34%) that of CONT pups. HYPO pups weighed slightly less than CONT pups, their lungs were hypoplastic, and their hearts were a larger fraction of body weight. An additional group of female rats was acclimatized (8 days) to high altitude before insemination. During pregnancy, body weight gain and food intake of these females were similar to those of pregnant rats at sea level. Measurements on the 1-day-old pups of this group were similar to those of HYPO pups. We conclude that newborn rats born after hypoxic gestation present metabolic adaptation (low VO2) and acclimatization (high VE/VO2), possibly because of hypoxemia. Maternal acclimatization before insemination substantially alters maternal growth in hypoxia but does not affect neonatal outcome.     

Living high-training low increases hypoxic ventilatory response of well-trained endurance athletes.

This study determined whether "living high-training low" (LHTL)-simulated altitude exposure increased the hypoxic ventilatory response (HVR) in well-trained endurance athletes. Thirty-three cyclists/triathletes were divided into three groups: 20 consecutive nights of hypoxic exposure (LHTLc, n = 12), 20 nights of intermittent hypoxic exposure (four 5-night blocks of hypoxia, each interspersed with 2 nights of normoxia, LHTLi, n = 10), or control (Con, n = 11). LHTLc and LHTLi slept 8-10 h/day overnight in normobaric hypoxia (approximately 2,650 m); Con slept under ambient conditions (600 m). Resting, isocapnic HVR (DeltaVE/DeltaSp(O(2)), where VE is minute ventilation and Sp(O(2)) is blood O(2) saturation) was measured in normoxia before hypoxia (Pre), after 1, 3, 10, and 15 nights of exposure (N1, N3, N10, and N15, respectively), and 2 nights after the exposure night 20 (Post). Before each HVR test, end-tidal PCO(2) (PET(CO(2))) and VE were measured during room air breathing at rest. HVR (l. min(-1). %(-1)) was higher (P < 0.05) in LHTLc than in Con at N1 (0.56 +/- 0.32 vs. 0.28 +/- 0.16), N3 (0.69 +/- 0.30 vs. 0.36 +/- 0.24), N10 (0.79 +/- 0.36 vs. 0.34 +/- 0.14), N15 (1.00 +/- 0.38 vs. 0.36 +/- 0.23), and Post (0.79 +/- 0.37 vs. 0.36 +/- 0.26). HVR at N15 was higher (P < 0.05) in LHTLi (0.67 +/- 0.33) than in Con and in LHTLc than in LHTLi. PET(CO(2)) was depressed in LHTLc and LHTLi compared with Con at all points after hypoxia (P < 0.05). No significant differences were observed for VE at any point. We conclude that LHTL increases HVR in endurance athletes in a time-dependent manner and decreases PET(CO(2)) in normoxia, without change in VE. Thus endurance athletes sleeping in mild hypoxia may experience changes to the respiratory control system.