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Medical Service, John D. Dingell Veterans Affairs Medical Center, and Division of Pulmonary/Critical Care and Sleep Medicine, Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We hypothesized that long-term
facilitation (LTF) is due to decreased upper airway resistance (Rua).
We studied 11 normal subjects during stable non-rapid eye movement
sleep. We induced brief isocapnic hypoxia (inspired O2
fraction = 8%) (3 min) followed by 5 min of room air. This
sequence was repeated 10 times. Measurements were obtained during
control, hypoxia, and at 20 min of recovery (R20) for
ventilation, timing, and Rua. In addition, nine subjects were studied
in a sham study with no hypoxic exposure. During the episodic hypoxia
study, inspiratory minute ventilation (
I) increased
from 7.1 ± 1.8 l/min during the control period to 8.3 ± 1.8 l/min at R20 (117% of control; P < 0.05). Conversely, there was no change in diaphragmatic
electromyogram (EMGdia) between control (16.1 ± 6.9 arbitrary units) and R20 (15.3 ± 4.9 arbitrary units)
(95% of control; P > 0.05). In contrast, increased
I was associated with decreased Rua from 10.7 ± 7.5 cmH2O · l
1 · s during
control to 8.2 ± 4.4 cmH2O · l1 · s at
R20 (77% of control; P < 0.05). No change
was noted in I, Rua, or EMGdia during
the recovery period relative to control during the sham study. We
conclude the following: 1) increased I in
the recovery period is indicative of LTF, 2) the lack of increased EMGdia suggests lack of LTF to the diaphragm,
3) reduced Rua suggests LTF of upper airway dilators, and
4) increased I in the recovery period is
due to "unloading" of the upper airway by LTF of upper airway dilators.
peripheral chemoreceptors; unloading; upper airway; non-rapid eye movement sleep
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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VENTILATORY MOTOR OUTPUT IS an important determinant of upper airway patency during sleep. Induction of periodic breathing results in oscillation of ventilatory drive and ventilation with reciprocal changes in upper airway resistance (Rua) (15, 22, 33). Conversely, chemoreceptor stimulation with hypoxia or hypercapnia decreases Rua during wakefulness and sleep (7-9). Thus increased ventilatory drive exerts salutary effects on upper airway patency.
Increased ventilatory motor output may persist after removal of a
ventilatory stimulus. For example, brief peripheral chemoreceptor stimulation is followed by a transient elevated ventilatory motor output, referred to as short-term potentiation (6, 11,
13). Interestingly, repetitive hypoxia is followed by a
sustained increase in ventilatory motor output, referred to as
long-term facilitation (LTF) (20). This excitatory
mechanism occurs after repetitive stimulation of the carotid bodies as
ventilation returns to baseline over a long duration, up to several
hours (10). LTF has been observed in several animal models
(10, 12, 17, 18, 20, 21, 31) but not others
(16). The critical contribution of episodic hypoxia to the
genesis of LTF suggests potential relevance to sleep apnea syndrome.
However, studies investigating the occurrence of LTF in humans have
shown variable results. One study in awake humans demonstrated no
evidence of LTF (19). Conversely, we have shown that LTF
is elicited by repetitive hypoxia during sleep but only in subjects who
snore regularly and who have evidence of inspiratory flow limitation
(IFL) during sleep (2). In our model, LTF manifested as
increased inspiratory minute ventilation (I) and
amelioration of IFL lasting for 40-60 min during the recovery
period after hypoxia. Conversely, repetitive hypoxia in sleep apnea
patients resulted in decreased Rua during the recovery, albeit without
corresponding increase in I (1).
However, upper airway anatomy in sleep apnea patients may dampen
ventilatory LTF despite upper airway dilatation. Therefore, we
hypothesized that repetitive hypoxia during sleep is followed by a
period of decreased Rua in normal subjects (including those who snore). The purpose of this study was to determine the after effects of episodic hypoxic on Rua and ventilation during stable non-rapid eye
movement (NREM) sleep in humans.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
The Human Investigation Committee of the Wayne State University School of Medicine and the Detroit Veterans Affairs Medical Center approved the experimental protocol. Informed written consent was obtained from 11 healthy subjects free of daytime sleepiness, sleep disordered-breathing, or other medical disorders. The absence of sleep-disordered breathing was confirmed by sham studies in nine subjects. There were five men and six women with a mean age of 29.3 ± 7.7 yr (range 22-46 yr) and body mass index of 26.6 ± 4.6 kg/m2.Breathing Circuit
The subject was connected to the circuit with an airtight silicone rubber mask strapped and glued to the face to prevent leaks. The mask was connected to a plateau exhalation valve (Respironics, Pittsburgh, PA) via a heated pneumotachometer. The valve, which provides a continuous leak path in the breathing circuit and serves as an exhaust vent, was connected on the inspiratory line. Three cylinders containing 100% N2, 8% O2, or 100% O2 were connected to the inspiratory line. To maintain isocapnia, supplemental CO2 was added to the inspiratory line from an external source, and end-tidal PCO2 (PETCO2) was maintained at control levels.Measurements
Electroencephalograms (EEG), electrooculograms (EOG), and chin electromyograms (EMG) were recorded by using the international 10-20 system of electrode placement (EEG: C3-A2 and C4-A1; EOG: F7-A2 and F8-A2). Inspiratory airflow was measured by a heated pneumotachometer (model 3700A, Hans Rudolph, Kansas City, MO) attached to a pressure transducer (Validyne, Northridge, CA). Tidal volume (VT) was obtained from the electronic integration of the flow signal (model FV156 Integrator, Validyne, Northridge, CA). Supraglottic airway pressure was measured by using a transducer-tipped pressure catheter (model TC-500XG, Millar Instruments, Houston, TX). The hypopharyngeal position was confirmed by advancing the catheter tip for 2 cm after it disappeared behind the tongue. PETCO2 was measured by using air sampled continuously from the nasal mask by an infrared analyzer (model CD-3A, AEI Technologies, Pittsburgh, PA). Arterial O2 saturation (SaO2) was measured by a pulse oximeter (Biox 3700, Ohmeda). All signals were displayed on a polygraph recorder (model 7-D, Grass, West Warwick, RI) and recorded by using Biobench data acquisition software (National Instruments, Austin, TX) for further analysis (see below). Surface diaphragmatic EMG (EMGdia) was recorded by using two surface electrodes (3M Red Dot, 3M, St. Paul, MN) placed 2-4 cm above the right costal margin in the anterior axillary line. One pair was positioned at the percussed dullness at total lung capacity, and another pair was positioned at the point of percussed dullness at functional residual capacity. The electrode pair with the best signal-to-noise ratio was selected for analysis.Protocol
The study was conducted during regular sleep hours. Subjects lay in the supine position for the whole study. After reaching stable stage 2 or stage 3 sleep, the subjects breathed room air for 5 min (control period), followed by 3 min of hypoxic gas (8% O2); this sequence was repeated 10 times. Hypoxia was rapidly induced by having the subject breathe one or two breaths of 100% N2 followed by continuous 8% O2 for 3 min to maintain hypoxia (SaO2 80-84%). Care was taken to ensure that isocapnia was maintained throughout the hypoxia period by measuring PETCO2, and 5% CO2 was supplemented as needed. Hypoxia was abruptly terminated with one breath of 100% O2. The breathing pattern was monitored for 40 min of recovery after the 10th exposure to hypoxia (H10). To ensure that changes in the recovery period were not time-dependent effects per se, nine of the subjects underwent a sham study on a different night with the identical measurements but no intervention. The other two subjects declined to participate in future studies.Data Analysis
Sleep state. Wakefulness/sleep stage was scored according to standard criteria (22). The subjects were in stable stage 2 or stage 3 (slow wave % = 20-50%) sleep during the hypoxic exposures and data collection.
Selection of breaths.
The control period consisted of 3 min immediately preceding the first
hypoxic exposure. All breaths were used for determination of IFL. The
last 20 breaths were used for measurement of Rua and I. A similar duration was selected for 20 min of
recovery (R20). All breaths were used for determination of
IFL; the last 20 breaths were used for I and Rua
analysis. The criteria for selecting the recovery segment included a
similar sleep state to the control period and similar distribution of
various sleep waveforms. An independent observer matched the sleep
state between the control and the recovery period without knowledge of
the breathing in either segment.
Ventilation and timing. Inspiratory VT, inspiratory time (TI), total time for a breath (TT), breathing frequency, PETCO2, and SaO2 were calculated breath by breath during stable sleep during the first normoxic period (control period) and at 20 min after the H10 exposure (R20). Breaths for analysis were selected during a period of stable sleep with no evidence of an arousal, as confirmed by an independent observer who matched the sleep state precisely, without knowledge of breathing, between control and R20. A mean value for each variable was computed from 20 consecutive breaths. For the sham study, no hypoxia was induced. Data were sampled after 80 min of sleep; this duration was equal to the total duration of the repetitive hypoxia trials in the night 1 protocol. Accordingly, for the sham study, the recovery period (R20) was designated as 100 min from the beginning of the control period. All the data were normalized to the control period data for comparison.
Upper airway mechanics.
To ascertain changes in upper airway mechanics, a pressure-flow loop
was plotted for every breath in 20 breaths of the control period and 20 breaths each at R20. All breaths were averaged, and
composite pressure-flow loops were plotted for the control and
R20 periods for each subject. To generate a composite
pressure-flow plot of breaths with different duration, pressure and
flow were sampled at equally distributed points in inspiration and
expiration in each breath. Rua at a fixed flow (0.2 l/s) was computed
from each loop as a numeric representation of the slope of the linear part of the pressure-flow loop. Pressure-flow loops were also utilized to determine the presence of IFL in each subject by using a
flow loop of each breath. A 3-min segment of control was used to
determine the presence of IFL on a breath-by-breath basis. Flow
limitation was defined by the inspiratory flow reaching a plateau at
a maximal level (max) despite a
1-cmH2O decrease in the supraglottic (downstream)
pressure (5). Flow limitation was determined as a
dichotomous variable. The development of IFL indicates dissociation
between the driving downstream pressure and flow. Accordingly, the
effect of repetitive hypoxia on the severity of IFL was determined by
comparing the proportion of breaths with flow limitation and by
comparing max between the control and the recovery
period in subjects with IFL. A change in max can be
used as a surrogate for changing collapsibility.
EMGdia. The raw EMG signal was amplified, filtered with a band pass filter of 100-10,000 Hz (model 7-D polygraph, Grass), and full wave rectified. ECG artifacts were "blanked" with an ECG blanker (model SB-1, CWE). The processed signal was integrated with a moving-time averager with a time constant of 100 ms (model MA-821 RES, CWE). Phasic EMG activity was determined from the peak integrated activity of the moving time average and expressed in arbitrary units (au).
Statistical analysis.
A commercially available computer statistical package was used to
analyze the data (Sigma Stat 2.0, SPSS). I (as
percentage of control) at 20 min of recovery (I
R20) was chosen as the dependent variable because it
represents the presence or absence of LTF. The level of significance
was set at P < 0.05. Paired t-test was used
to compare values of variables between control and R20.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Figure 1 is a representative
polygraph record showing ventilation and upper airway mechanics during
control conditions (A), hypoxia (B), and at
R20 (C). Hypoxia resulted in increased flow and
a reduction of the magnitude of negative supraglottic pressure; this
effect persisted at R20. A representative pressure-flow
loop during control and posthypoxic recovery (R20) is shown
in Fig. 2. Note the change in slope and
the amelioration of the IFL during hypoxia and R20. Figure
3 and Table
1 summarize the results for the group.
Data are reported only from subjects with stable sleep or only minimal
fragmentation. During the hypoxic trials, arousal and
wakefulness occurred for 2.7 ± 2.6 min (out of 30 min), and no
periods of wakefulness were noted during the recovery period. Hypoxia
resulted in increased I from (7.1 ± 1.8 l/min)
to (9.1 ± 2.3 l/min) (128% of control); during the recovery
period, I remained elevated at 8.3 ± 1.8 l/min
(117% of control; P < 0.05). The increase in
I was due to increased VT from 0.42 ± 0.13 to 0.49 ± 0.09 liter (117% of control; P < 0.05) and VT/TI from 0.26 ± 0.09 to
0.32 ± 0.06 l/s (123% of control; P < 0.05).
However, inspiratory muscle activity did not increase because
EMGdia was 16.1 ± 6.9 au during control and 15.3 ± 4.9 au during recovery (95% of control; P > 0.05).
Similarly, the after effects of repetitive hypoxia on timing parameters
were not remarkable, because there was no significant change in
TI, TE, or TI/TT (Table
1).
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The ventilatory changes during the recovery period occurred in
association with decreased Rua from 10.7 ± 7.5 to 8.2 ± 4.4 cmH2O · l1 · s (77% of
control; P < 0.05). Similarly, Rua at
max decreased from 16.2 ± 12.0 to 12.3 ± 7.9 cmH2O · l1 · s (90% of
control; P = 0.07). When analysis was repeated after removal of one subject who demonstrated increased Rua at
max, a statistically significant decrease was noted
from 16.5 ± 12.6 to 11.8 ± 8.2 cmH2O · l1 · s (81% of
control; P = 0.02).
Seven subjects showed flow limitation during the control period
(89 ± 18% of the control breaths). The proportion of breaths with IFL did not change in the recovery period (71 ± 42% of
R20 breaths; P > 0.05); IFL was eliminated
only in one subject. The remaining four subjects had no breaths that
met the operational definition of IFL during the control or recovery
periods. The proportion of breaths with IFL for the whole group was
57 ± 47 and 48 ± 46% during control and R20,
respectively (P > 0.05). Similarly, there was no
change in max for breaths with IFL between control
(0.34 ± 0.03 l/s) and R20 (0.36 ± 0.03 l/s)
(P > 0.05).
The findings of the sham study differed from the repetitive hypoxia
study (Fig. 4). I and
VT during the recovery period were 94 and 100% of control,
respectively (P > 0.05). Similarly, there was no
significant change in Rua 102% of control (P > 0.05) or the proportion of breaths with flow limitation (61 ± 41%
during control and 62 ± 41% at R20;
P > 0.05). However, prolongation of TE
occurred (1.9 ± 0.3 s during the control period vs. 2.1 ± 0.3 s at R20; P < 0.05).
Therefore, respiratory frequency decreased (17.4 ± 1.7 breaths/min during control vs. 16.21 ± 0.1 breaths/min at
R20; P < 0.05; Table 1).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We showed reduced Rua and increased I in the
recovery period after repetitive hypoxic exposure, confirming the
development of LTF by repetitive hypoxia in sleeping humans.
Effects of LTF on Upper Airway Mechanics
We showed that repetitive hypoxia results in decreased Rua indicative of upper airway dilatation. One possible explanation for decreased Rua is passive dilatation secondary to increased thoracic inspiratory activity (32). Given that our data do not show increased diaphragmatic activity, passive upper airway dilatation requires LTF of the intercostal muscles with ensuing increased VT and increased caudal traction. This is consistent with data showing that intercostal muscles are more likely to demonstrate LTF after repetitive hypoxia than the diaphragm in cats (12). Accordingly, decreased Rua would be due to increase VT.Decreased Rua can also be explained by active upper airway dilatation
as a result of LTF of ventilatory motor output to upper airway dilators
(7, 8, 26). There is evidence in the literature that
repetitive hypoxia elicits LTF of ventilatory motor output to upper
airway dilators. Mateika and Fregosi (18) showed that repetitive hypoxia in vogotomized cats is followed by increased activity of the genioglossus and the alae nasae but not the diaphragm (18). Similarly, we showed that repetitive hypoxia in
snorers results in amelioration of IFL for 40-60 min after
termination of hypoxic exposure during NREM sleep (2).
Accordingly, increased VT during the recovery period would
be due to decreased Rua or "unloading" of the upper airway
(14, 28). Previous studies showed that unloading of the
upper airway in healthy individuals who snore, with the use of nasal
continuous positive airway pressure (14) or
He-O2 mixture during NREM sleep (28), results
in reduced total pulmonary resistance and increased VT and
I. This interpretation is also consistent with our
previous finding (2) that ventilatory LTF manifests mostly
in subjects with snoring and flow limitation. In summary, LTF of either
intercostal muscles or upper airway dilators can explain decreased Rua;
we cannot distinguish between these two possibilities on the basis of
our findings.
The present study corroborates our previous work demonstrating LTF
after episodic hypoxia in sleeping humans (2). There are,
nevertheless, two differences that should be mentioned. 1) We found that decreased Rua was associated with ventilatory LTF for the
whole group. In contrast, our previous study showed ventilatory LTF
only in subjects with IFL. One likely explanation is that the majority
of the subjects in the present study were snorers and had evidence of
IFL during eupneic breathing. 2) We noted that flow
limitation persisted during the recovery period despite decreased Rua
and increased I. This disproves our previous
suggestion (2), based on the flow profile only, that LTF
is associated with amelioration of flow limitation and demonstrates
dissociation between resistance and collapsibility (see below).
We were intrigued by the observation that decreased Rua was not
associated with increased max. The discrepancy
between the two indexes of upper airway mechanics suggests dissociation
between changes in caliber and changes in compliance. Several studies have demonstrated similar dissociation under several experimental paradigms. First, Rowley et al. (24, 25) showed, in a
feline preparation, that max is increased during
hypercapnia secondary to reduced critical closing pressure (Pcrit)
despite increased Rua. Second, there is evidence that stimulation of
pharyngeal dilators enlarges the lumen of the upper airway
(26), whereas evidence that upper airway dilators
"stiffen" the upper airway is still lacking. Third, our laboratroy
previously showed a similar dissociation during induced hypocapnia in
individuals who snore (4, 5); reduced ventilatory motor
output resulted in decreased max without change in
Rua. Finally, Aboubakr et al. (1) studied obstructive sleep apnea patients during sleep using a repetitive hypoxia protocol similar to the present study. The upper airway was
stabilized with nasal continuous positive airway pressure at a pressure
level preventing apnea and hypopnea while allowing IFL. Repetitive
hypoxia was followed by decreased Rua, indicative of upper
airway-dilating muscle recruitment. However, no change in
max was noted.
The aforementioned studies demonstrate that resistance and
collapsibility may be altered independently. Although the mechanism of
the dissociation between Rua and max cannot be
ascertained from our data, we interpret our finding as further support
of the notion that repetitive hypoxia elicits LTF of the pharyngeal dilators and not pump muscles. Thus stimulation of upper airway dilators may decrease Rua without necessarily increasing
max or collapsibility. We emphasize that our
interpretation is speculative in the absence of direct measurement of
pharyngeal collapsibility and upper airway-dilating muscle activity.
Limitations of Methods
Several limitations have to be considered for proper interpretation of our data. First, changes in sleep state might have caused a misinterpretation of the data. However, we analyzed data only when the sleep was in stable stage 2 or greater, with no evidence of changes in sleep state by Rechtschaffen and Kales criteria (23) or by transient arousals (29). The induction of hypoxia caused only a transient minimal change in the sleep state in 8 of 11 subjects, which lasted for <3 min of wakefulness for the whole duration of hypoxia. A subject who did not maintain sleep at stage 2 or deeper for the majority of the 140-min study was excluded from the study. The data reported here were from periods where there was no difference in sleep state.Second, we measured Rua as an index of upper airway caliber and
max as a surrogate for Pcrit and hence pharyngeal
collapsibility. According to the principles of flow in
collapsible tubes, max is a function of upstream
pressure, upstream resistance, and Pcrit of the collapsible segment.
Although Pcrit is not the sole determinant of max,
there is an inverse correlation between max and
Pcrit (higher max = lower Pcrit = less
collapsible upper airway) under most conditions. Therefore, we believe
that reasonable inferences regarding upper airway collapsibility can be
made from max. This conclusion needs to be confirmed
in the future by direct measurements of Pcrit under similar
experimental conditions.
We measured surface EMGdia as a marker of EMGdia activity. However, the surface location of the electrodes precludes precise determination of the inspiratory muscle. Thus we presume, but cannot be certain, that we measured EMGdia signals. Conversely, we did not measure pharyngeal muscle activity; instead, we used Rua to ascertain the net effect of muscle recruitment on upper airway caliber. We believe that this approach provides a better assessment of the mechanical function of all upper airway muscles rather than the readily accessible dilators. However, measurement of specific upper airway dilators is needed to confirm the effect of episodic hypoxia on upper airway neural control and dilation.
We noted that I during the control period differed
between the sham study and the repetitive hypoxia study. This
variability was not due to differences in eupneic breathing because the
proportion of breaths with IFL was similar between the sham study and
the repetitive hypoxia study. The main difference was a smaller number of subjects in the sham study. We interpret the difference in eupneic
control as a manifestation of night-to-night variability. However, it
had no impact on the recovery period given the marked difference
between the repetitive hypoxia and the sham study. Therefore, we
believe that the difference in response between the repetitive hypoxia
nights and the sham nights represented a true physiological response to
repetitive hypoxia per se and was not due to selection bias or
variability in control respiration.
Finally, we noted increased TE and reduced frequency during the sham study. This change seems to be a time-dependent phenomenon. Interestingly, this effect was less apparent (and not statistically significant) during repetitive hypoxia night. It is tempting to speculate that the preservation of respiratory frequency is another manifestation of LTF. However, this speculation requires experimental proof.
In summary, we have shown that episodic hypoxia during sleep in normal
subjects elicits LTF of ventilatory motor output manifested by
decreased Rua and increased I without increased
EMGdia, suggesting that the thoracic pump does not
demonstrate LTF.
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ACKNOWLEDGEMENTS |
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We thank Dr. James Rowley for critical review of the manuscript.
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FOOTNOTES |
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This work was supported by the Veterans Affairs Medical Service and the National Heart, Lung, and Blood Institute (NHLBI). M. S. Badr is a recipient of midcareer investigator award in patient-oriented research from the NHLBI (K24-HL-04174).
Address for reprint requests and other correspondence: M. S. Badr, Harper Hospital, 3990 John R. 3-Hudson, R-3923 Detroit, MI 48201 (E-mail: sbadr{at}intmed.wayne.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published March 1, 2002;10.1152/japplphysiol.00938.2001
Received 11 September 2001; accepted in final form 25 February 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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