| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Adelaide Institute for Sleep Health, Repatriation General Hospital, Daw Park, South Australia 5041; 2 Department of Physiology, University of Adelaide, Adelaide, South Australia 5005; and 3 School of Medicine, Flinders University, Bedford Park, South Australia 5042, Australia
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Obstructive sleep apnea (OSA)
is more common in men than in women for reasons that are unclear. The
stability of the respiratory controller has been proposed to be
important in OSA pathogenesis and may be involved in the gender
difference in prevalence. Repetitive hypoxia elicits a progressive rise
in ventilation in animals [long-term facilitation (LTF)]. There is
uncertainty whether LTF occurs in humans, but if present it may
stabilize respiration and possibly also the upper airway. This study
was conducted to determine 1) whether LTF exists during
wakefulness in healthy human subjects and, if so, whether it is more
pronounced in women than men and 2) whether inspiratory pump
and upper airway dilator muscle activities are affected differently by
repetitive hypoxia. Twelve healthy young men and ten women in the
luteal menstrual phase were fitted with a nasal mask and intramuscular
genioglossal EMG (EMGgg) recording electrodes. After 5 min of rest,
subjects were exposed to ten 2-min isocapnic hypoxic periods (~9%
O2 in N2, arterial O2 saturation ~80%) separated by 2 min of room air. Inspired minute ventilation (
I) and peak inspiratory EMGgg activity were
averaged over 30-s intervals, and respiratory data were compared
between genders during and after repetitive hypoxia by using ANOVA for
repeated measures. I during recovery
from repetitive hypoxia was not different from the resting level and
not different between genders. There was no facilitation of EMGgg
activity during or after repetitive hypoxia. EMGgg activity was reduced
below baseline during recovery from repetitive hypoxia in women. In
conclusion, we have found no evidence of LTF of ventilation or upper
airway dilator muscle activity in healthy subjects during wakefulness.
gender; genioglossus muscle; obstructive sleep apnea
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
OBSTRUCTIVE SLEEP APNEA (OSA) is more common in men than in women (36). The reason for this gender difference is currently unknown; however, it is potentially related to differences in central respiratory control, upper airway neuromuscular control, or upper airway anatomy. Several studies have compared the airway anatomy in healthy men and women and reported that the cross-sectional area of the pharynx is larger in men than in women (8, 9, 19). However, only one study has corrected for the difference in body size between genders, and this study did not find a gender difference in pharyngeal cross-sectional area (9). The resting activity of the upper airway dilator muscles has been implicated in the pathogenesis and high male prevalence of OSA; however, the activity of the largest airway dilator, the genioglossus, has been reported to be similar between men and women (13, 26, 35) in all but one study (27). The central control of respiration may also play a role in the pathogenesis of OSA because the airway is more prone to collapse during periods of low respiratory drive (5, 25). Theoretically, it would seem that if periods of low drive were prevented and respiratory cycling minimized, then the upper airway would be stabilized and airway collapse less likely.
Long-term facilitation (LTF) is the progressive increase in
inspired minute ventilation (I) that persists for
minutes to hours after cessation of a repetitive hypoxic
stimulus. LTF is a centrally mediated, serotonin-dependent process
(4) that has been shown to exist in various awake animals
(1, 10, 23, 33). LTF not only prevents periods of low
drive but also could, at least theoretically, minimize respiratory
cycling and therefore stabilize the upper airway. There is disagreement
in the literature regarding the existence of LTF in humans (2, 3,
20, 21, 31). These studies have been predominantly conducted in
men, and thus far there have been no gender comparisons of LTF in
humans. Progesterone is a known respiratory stimulant that increases
not only resting ventilation (11) but also the hypoxic
ventilatory response (32). Recently, LTF has been
reported to be greater in diestrus than estrus in female rats
(37). It is therefore possible that LTF may be influenced
by female sex hormones and may be different between genders. If LTF
were more readily elicited or more pronounced in women than in men,
then it could provide partial protection from respiratory cycling in women and may help protect them from further sleep-disordered breathing events.
LTF is seen in both the hypoglossal and phrenic motoneurons in animals
(4). It would therefore appear likely that the
genioglossus muscle activity would increase during and after repetitive
hypoxia. However, the genioglossus has been reported to be depressed
during repetitive hypoxia in healthy male subjects, whereas diaphragm activity and ventilation were not different from the resting level (no
LTF) (20). However, there is evidence to suggest that
repetitive hypoxia may augment upper airway dilator activity. Aboubakr
et al. (2) reported that repetitive hypoxia during sleep
in patients with partial upper airway obstruction results in a
progressive reduction of upper airway resistance (Rua) without changing
I (2). It is therefore possible
that the genioglossus muscle may be facilitated or depressed during
repetitive hypoxia. The response of the genioglossus may differ between
genders because other respiratory depressants (alcohol and
benzodiazepines) that cause selective depression of genioglossus or
hypoglossal nerve activity (7, 15) do not depress the
genioglossus as much in women as men (15), and the
depression is reduced in male cats when pretreated with progesterone
(29).
We therefore conducted the present study to determine 1) whether LTF of ventilation occurs in healthy men and/or women and 2) whether depression or facilitation of genioglossus and diaphragm muscles occurs during repetitive hypoxia and whether this is the same in both genders.
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Subjects.
Twelve men and thirteen women gave informed written consent and
participated in the study. All subjects were healthy nonsmokers with normal lung function (spirometry and body plethysmography) and did
not take any regular medication, including the oral contraceptive pill.
Subject characteristics are displayed in Table
1. Female subjects had regular menstrual
cycles not longer than 35 days and were tested in the luteal
menstrual phase (days 20-24) as confirmed by plasma
progesterone levels (ACS:180 Progesterone assay, Chrion Diagnostics,
Chrion Healthcare, Victoria, Australia). Three women were subsequently
found to be anovulatory (plasma progesterone <7 nmol/l in the luteal
phase), and their results were excluded from the analysis. The study
was approved by the Research and Ethics Committee of the Repatriation
General Hospital (Daw Park, South Australia).
|
Equipment and measurements.
Subjects wore a nasal mask (Gel mask, Respironics, Murraysville, PA)
with a two-way non-rebreathing valve attached (series 2600, Hans
Rudolph, Kansas City, MO). On the inspiratory side, the breathing valve
was connected to a pneumotachograph (model PT36, Erich Jaeger,
Würzburg, Germany) and a Gatlin-shaped valve system (series
2440C, Hans Rudolph) for delivery of inspiratory gases. The
Gatlin-shaped valve consisted of one output port attached to the
pneumotachograph and four inputs, three of which were connected to foil
bags (300 liters, Scholle Industries, Adelaide, Australia) containing
the following inspiratory gas mixes: 50% O2 in
N2, 100% N2, and 9% O2 in
N2. The fourth port was open to room air. Each port could
be rapidly occluded or opened with a pneumatically driven solenoid
valve and balloon. Only one input port was open at a time, and all
changes between ports were conducted during expiration. The inspiratory
flow signal (pneumotachograph) was electronically integrated to give
inspiratory tidal volume (VT). Inspiratory
(TI), expiratory (TE) and total breath
(TT) times were determined from the flow signal, and
I was calculated on a breath-by-breath basis.
Mask pressure (Pmask) and end-tidal PO2 and PCO2
(PETO2 and
PETCO2, respectively) were measured
continuously from the mask (Pmask: model 78342A, Hewlett
Packard, Andover, MI; PETCO2 and
PETO2: POET II model 602-3, Criticare
Systems Waukesha, WI).
Protocol. Subjects presented to the laboratory in the morning after a light breakfast without caffeine. They were instrumented (as described above) and lay supine with one pillow. Maximal EMG activity of the genioglossus muscle was determined by performing three of each of the following maneuvers: swallows, deep sniffs, and maximal tongue protrusions against the top teeth. Care was taken to ensure that all subjects gave maximal efforts during the tongue protrusions by strong verbal encouragement and ensuring a plateau in muscle activity was reached before each maneuver was ceased.
After these maneuvers, subjects were given earphones through which they listened to the radio and were instructed to relax, keep their eyes open, stay awake, and breathe only through their nose. They were informed that during hypoxia they might experience slight dizziness or breathlessness but that these responses were normal and so to remain relaxed. After 5 min of baseline room air breathing, subjects were exposed to ten 2-min episodes of hypoxia separated by 2 min of room air. The hypoxic gas was 9% O2 in N2 blended with room air, as necessary via a three-way tap, to maintain SaO2 at 80%. Each hypoxic period was initiated with three breaths of 100% N2 to cause a rapid fall in SaO2 and terminated with one breath of 50% O2. Isocapnia was maintained during and after repetitive hypoxia by manually bleeding CO2 into the inspiratory tubing. Subjects breathed room air for a further 25 min after the tenth hypoxic period before the maximal EMG maneuvers were repeated. The highest activity recorded during the maneuvers was taken to be the maximal activity of the genioglossus. The EMG activity was then expressed as a percentage of maximal activity by scaling the moving-time-averaged EMG between electrical zero and the maximum activity level. This well-established technique (22) allowed the genioglossal EMG signals to be averaged within and between subjects and compared between genders.Data analysis and statistical procedures.
Breaths that were contaminated with movement artifact, swallows, sighs,
or sleep were removed from analysis. All variables were averaged at
30-s intervals to condense the 70 min of breath-by-breath data. Resting
variables were determined from the average of the 5 min immediately
before the start of the repetitive hypoxia. Anthropometric and resting
characteristics were compared between men and women by two-sample
Student's t-tests. The maintenance of isocapnia was
assessed with an ANOVA for repeated measures on
PETCO2 data for the entire protocol. All
measured variables (I, VT,
TT, TE, TT, phasic and tonic EMG
activity of the genioglossus and diaphragm, SaO2,
Pepi, Pmask, peak inspiratory flow, Rua, Rna,
and Rph) were compared between men and women with two-way ANOVA for
repeated measures, including the Greenhouse-Geisser correction for
multisample asphericity (18). Separate ANOVAs were used to
1) detect LTF or depression (data during the second minute
of normoxia between hypoxic exposures and during recovery after the
tenth hypoxic exposure analyzed) and 2) detect
"roll-off" during repetitive hypoxia (data during the
second minute of each hypoxic exposure analyzed). LTF was also
calculated in the manner described by Babcock and Badr
(3). This involved determining whether the
I was >10% above the resting level at 5 and 20 min after the tenth hypoxic exposure.
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Adequate ventilatory and diaphragm EMG data were obtained in all 22 subjects. One of either the Pmask or Pcho pressure signals was inadequate in five subjects (large drift in 3 subjects and catheter failure in 2 subjects), so all pressure and resistance data were excluded in these subjects. The genioglossal signal was poor in two subjects (intermittent signal in 1 subject and complete signal loss in the other subject mid protocol). Analysis of the genioglossus and diaphragm muscle activity was therefore limited to 20 subjects.
Resting data.
The 12 men and 10 women studied did not differ in terms of age, body
mass index, or lung function (Table 1). Although resting I was not different between genders, there were
significant differences in breathing pattern, VT, and
PETCO2 at rest (Table 2). The low
PETCO2 in women with equivalent
I is likely to be due to the elevated plasma
progesterone level in the 10 women studied (22.4 ± 1.1 nmol/l).
The resting level of genioglossal activity did not differ between
genders, and Pepi, Pcho, and Rua were also not
different between men and women (Table 2).
|
Repetitive isocapnic hypoxia.
SaO2 at rest, during or after repetitive isocapnic
hypoxia did not differ between genders (Fig.
1). There were no time or gender × time interaction effects for PETCO2 during
and after hypoxia, indicating adequate maintenance of isocapnia (Fig.
1).
|
I during the hypoxic periods did
not differ between men and women, and there was no gender × time
interaction effect. Similarly, the normoxic ventilation between hypoxic
exposures and during recovery was not different between genders (Fig.
1). There was no significant change of I over
time during normoxic periods of the protocol, indicating that no
depression or facilitation of ventilation occurred in either gender.
There were also no gender differences in VT,
TI, TE, and TT during the hypoxic
periods, or in the normoxic periods during or after repetitive hypoxia, indicating that these variables also showed no facilitation or depression (Fig. 1). When the I data were
analyzed by the method described by Babcock and Badr
[(3); see METHODS] to determine whether
individual subjects demonstrated LTF, we found that one male and one
female subject fit their criteria for LTF of ventilation. None of the
anovulatory women fitted this criteria for LTF of ventilation.
Rua and genioglossus and diaphragm muscle responses were more variable
than the I data; however, the same patterns
existed. There were no gender differences or gender × time
interaction effects in any of these variables during the hypoxic
periods or in the 2-min normoxic periods between hypoxic exposures.
However, after the tenth hypoxic exposure, the inspiratory phasic
genioglossus muscle activity was lower than baseline in women and lower
in women than in men (Fig. 2). This
occurred despite unchanged I, diaphragm muscle
activity, and Rua during this recovery time.
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
In this study, the ventilatory and respiratory muscles responses to repetitive eucapnic hypoxia were compared between healthy young men and women during wakefulness. We found that there was no LFT of ventilation, diaphragm, or genioglossus muscle activity during or after repetitive hypoxia. The genioglossus muscle activity was depressed in women during recovery from repetitive hypoxia; however, this was not apparent in men.
Resting gender differences.
Although resting I was not different between
genders, there were significant differences in the pattern of breathing
in the young men and women studied. Resting VT was lower in
women than in men; however, breathing frequency was higher in women because of lower TI and TE (Table 2).
PETCO2 was lower in women than in men,
consistent with the respiratory-stimulating effects of progesterone.
Previous gender comparisons of breathing at rest report that women in
the follicular menstrual phase have lower I and
VT than men but equal breathing frequency and arterial PCO2 (14, 28, 34). In women during
the luteal menstrual phase, however, ventilation has been reported to
be higher than in the follicular phase, such that ventilation is not
different compared with men (14, 34). The findings of the
present study are consistent with these previous studies. The
relevance, if any, of these differences in resting breathing pattern to
the present study and to the high male prevalence of sleep-disordered breathing syndromes is uncertain. There were no gender differences in
the resting genioglossus muscle activity or Rua.
LTF of ventilation. LTF of ventilation is the prolonged increase in ventilation after repetitive stimulation of the carotid bodies that has been proposed to stabilize breathing patterns. Although LTF has been extensively studied in various animal models, there have been relatively few studies in humans. In the early 1990s, there were two abstract reports from the same laboratory, one showing LTF in 14 healthy volunteers (31) and the second showing LTF in 14 OSA patients but not in 5 healthy controls (21). Since these initial reports, McEvoy et al. (20) studied 11 male volunteers during wakefulness and failed to find evidence of LTF. These three studies all used the same "2 min on-2 min off" hypoxia protocol, causing desaturation to ~80-85%. More recently, Babcock and Badr (3) have used a "3 min on-5 min off" hypoxia protocol (inspired O2 fraction = 8%) during sleep in healthy subjects and reported no LTF of ventilation in the group although some individuals appeared to demonstrate LTF. These authors commented that the presence or absence of LTF in an individual subject appeared to be related to whether the subjects snored and had inspiratory flow limitation (LTF existed in snorers). More recently, the same laboratory has conducted a similar study in OSA patients (2) with optimal or suboptimal continuous positive airway pressure (to allow inspiratory flow limitation) levels during sleep. Using the same 3 min on-5 min off protocol, the authors were unable to demonstrate LTF in either continuous positive airway pressure condition. In the present study, we have again failed to find evidence of LTF of ventilation in men during wakefulness and this observation has been extended to awake women. Given the results of this and the previous studies, we believe that it likely that LTF does not exist or that is quite rare in healthy humans when exposed to repetitive hypoxia of a few minutes duration and at physiologically significant levels. However, it is possible that neural facilitation and hypoxic depression occur simultaneously in humans such that ventilation appears neither facilitated nor depressed. Such a counterbalance concept has been suggested to explain the lack of long-term depression after episodic hypercapnia (6). The negative findings in these human studies contrast the many awake animal studies (1, 10, 23, 33) and may be related to species differences.
Genioglossus and diaphragm muscle activity and Rua. The genioglossus and diaphragm muscles both show inspiratory phasic activity that increases during respiratory stimulation and decreases with generalized respiratory depression. These relative changes in muscle activity are often proportional, suggesting that the hypoglossal and phrenic motoneuron outputs are coupled. However, there are situations when the activity of the two muscles differ. These include after alcohol (15) and benzodiazepene (17) ingestion in humans and after anesthesia and cyanide brain hypoxia in animals (30). Repetitive eucapnic hypoxia has previously been reported to also cause preferential depression of genioglossal activity in healthy men during wakefulness without altering diaphragmatic activity (20). In the present study of normal individuals during wakefulness, there was a statistically significant reduction in genioglossus muscle activity after the tenth hypoxic exposure in women but not in men. Given the variable nature of genioglossus EMG signals, power calculations were performed to determine the minimum detectable difference of genioglossus activity in both men and women. These calculations revealed that with the coefficient of variation of genioglossal activity measured at rest in the 10 women studied, a change in genioglossal activity below 87% of the resting level could be detected with 80% power (hence the power was adequate). In men, however, the coefficient of variation in genioglossal activity was almost twice that of women (20.9 in men, 12.8 in women) such that only changes below 79% of baseline could be detected with 80% power. It is therefore possible that the nonsignificant result in men was the result of type II error. However, it must be noted that the genioglossal data in men did not appear to show a trend toward depression during the 5- and 20-min recovery times despite being below baseline for the last three hypoxic episodes.
Repetitive (20) and sustained (24) isocapnic hypoxia has been shown to disproportionately suppress genioglossal compared with diaphragm activity. Why the present findings differ from the earlier studies using repetitive hypoxia (20) is uncertain. The present protocol was almost identical to that previous study with the exception that the hypoxic gas used in our study was a 9% O2 in N2 gas compared with an 11% O2 gas in the earlier study. Despite this, the level of hypoxemia was similar between studies (85% SaO2 in the earlier study and 82% in the present study), probably reflecting the fact that the earlier study was conducted at moderate altitude. In the earlier study, each hypoxic period was terminated with one breath of 100% O2, whereas in the present study each hypoxic period was terminated with one breath of 50% O2. We believe that unlikely that these differences would result in the different findings between studies. If anything, the subjects in the present protocol would be likely to experience more central depression because of the lower SaO2 levels achieved. There are some differences in the subject characteristics between studies, with the 11 subjects used in the earlier study having a mean age of 36 yr. This is noticeably older than our subjects (mean of 25 yr) and may contribute to the inability in this study to detect a reduction in genioglossal activity in men if this phenomenon is, at least in part, age related. Therefore, it is possible that the inability to demonstrate depression of the respiratory phasic genioglossal activity in the men in the present study results from either the high variability of the genioglossus in these men and/or the age of the experimental subjects. Previous studies in humans during non-rapid eye movement sleep (2, 3) have indicated that Rua decreases after repetitive hypoxia perhaps, implying facilitation of upper airway dilator muscles, although muscle activity was not measured in either study. Data from this and a previous study in wakefulness (20) do not support relative augmentation of genioglossal activity with repetitive hypoxia in healthy human subjects.Methodological considerations. There are several important methodological issues to consider when interpreting these results. First, some forms of neuroplasticity are protocol specific, and the results of this study do not preclude the possibility that other protocols may elicit LTF in human volunteers. Second, the development of LTF is not always instantaneous with some studies demonstrating a gradual increase in ventilation (12) after cessation of repetitive hypoxia. Thus, although previous human data do not appear to show such a slow increase in ventilation, the possibility remains that LTF occurred after completion of the study. Age alters LTF in a gender-dependant manner in rats (37, 38). The subjects studied in the present study were relatively young (25 yr), and if similar age and gender interactions occur in humans, then it is possible that older adults may demonstrate LTF that is different between men and women.
The level of inspired O2 was adjusted in the present study to target an SaO2 of 80% in both men and women. If the hypoxic ventilatory response was different between men and women, then one gender may have received a lower O2 concentration in the inspirate than the other. However, SaO2 andI were not different between genders, indicating
that the stimuli for LTF was probably not different between genders.
An additional consideration regards the recording of genioglossal and
diaphragmatic EMGs. The electrical activity of any muscle may not
represent the functional changes in muscle force or movement. If
the electromechanical coupling of the genioglossus and diaphragm muscle
differed between genders, then any EMG comparison would be of limited
significance regarding muscle force generation or perhaps upper airway
caliber. However, we are unaware of any data showing a gender
difference in electromechanical coupling of upper airway dilator
muscles. The surface recording of diaphragm muscle activity can be
confounded by activation of abdominal muscles during respiration;
however, we placed the diaphragm EMG electrodes in positions to
minimize abdominal muscle contamination.
Finally, this study was conducted during wakefulness, which limits the
significance of the findings with regard to sleep-disordered breathing.
However, we believe that if a fundamental difference in the control of
ventilation or development of LTF existed during wakefulness, it would
likely be of importance with regard to the control of breathing during
sleep. Previous investigators have suggested (3) that
serotonin-mediated LTF of ventilation may depend on the level of raphe
neuron activity. The activity of raphe neurons is near maximal during
wakefulness, possibly making further release of serotonin and therefore
LTF difficult to elicit. This would not, however, explain the apparent
inability to demonstrate LTF of ventilation during sleep in humans
(2, 3).
In summary, we have found no evidence of LTF of ventilation or of
genioglossal or diaphragm muscle activity in healthy men or women
during wakefulness. The present findings in awake men and women are
consistent with previous reports in awake men (20), sleeping normal subjects (3), and OSA patients
(2) and suggest that LTF of ventilation is either absent
or at least very difficult to elicit in humans. The genioglossus muscle
was depressed in women during recovery from repetitive hypoxia, as has
previously been shown in men (20). Our results do not
support the hypothesis that different ventilatory or respiratory muscle
responses to repetitive hypoxia could explain the gender difference in
OSA and other related sleep breathing disorders.
| |
ACKNOWLEDGEMENTS |
|---|
We acknowledge the technical assistance of Robin Woolford of the Biomedical Engineering Department of the Repatriation General Hospital (Daw Park, Australia).
| |
FOOTNOTES |
|---|
This study was supported by National Health and Medical Research Council of Australia Grant 138403.
Address for reprint requests and other correspondence: A. Jordan, Sleep Disorders Program, Div. of Sleep Medicine, 221 Longwood Ave., RFB-486, Boston, MA 02115 (E-mail: ajordan{at}rics.bwh.harvard.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.
August 30, 2002;10.1152/japplphysiol.00135.2002
Received 21 February 2002; accepted in final form 26 August 2002.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Aaron, EA,
and
Powell FL.
Effect of chronic hypoxia on hypoxic ventilatory response in awake rats.
J Appl Physiol
74:
1635-1640,
1993.
2.
Aboubakr, SE,
Taylor A,
Ford R,
Siddiqi S,
and
Badr MS.
Long-term facilitation in obstructive sleep apnea patients during NREM sleep.
J Appl Physiol
91:
2751-2757,
2001.
3.
Babcock, MA,
and
Badr MS.
Long-term facilitation of ventilation in humans during NREM sleep.
Sleep
21:
709-716,
1998.
4.
Bach, KB,
and
Mitchell GS.
Hypoxia-induced long-term facilitation of respiratory activity is serotonin dependent.
Respir Physiol
104:
251-260,
1996.
5.
Badr, MS.
Effect of ventilatory drive on upper airway patency in humans during NREM sleep.
Respir Physiol
103:
1-10,
1996.
6.
Baker, TL,
Fuller DD,
Zabka AG,
and
Mitchell GS.
Respiratory plasticity: differential actions of continuous and episodic hypoxia and hypercapnia.
Respir Physiol
129:
25-35,
2001.
7.
Bonora, M,
St John WM,
and
Bledsoe TA.
Differential elevation by protriptyline and depression by diazepam of upper airway respiratory motor activity.
Am Rev Respir Dis
131:
41-45,
1985.
8.
Brooks, LJ,
and
Strohl KP.
Size and mechanical properties of the pharynx in healthy men and women.
Am Rev Respir Dis
146:
1394-1397,
1992.
9.
Brown, IG,
Zamel N,
and
Hoffstein V.
Pharyngeal cross-sectional area in normal men and women.
J Appl Physiol
61:
890-895,
1986.
10.
Cao, KY,
Zwillich CW,
Berthon-Jones M,
and
Sullivan CE.
Increased normoxic ventilation induced by repetitive hypoxia in conscious dogs.
J Appl Physiol
73:
2083-2088,
1992.
11.
Dempsey, JA,
Olson EB,
and
Skatrud JB.
Hormones and neurochemicals in the regulation of breathing.
In: Handbook of Physiology. The Respiratory System. Control of Breathing. Bethesda, MD: Am. Physiol. Soc, 1986, vol. II, p. 181-221, sect. 3, pt. 1, chapt. 7.
12.
Fuller, DD,
Baker TL,
Behan M,
and
Mitchell GS.
Expression of hypoglossal long-term facilitation differs between substrains of Sprague-Dawley rat.
Physiol Genomics
4:
175-181,
2001.
13.
Jordan, AS,
Catcheside PG,
O'Donoghue FJ,
Saunders NA,
and
McEvoy RD.
Selected Contribution: Genioglossus muscle activity at rest and in response to brief hypoxia in healthy men and women.
J Appl Physiol
92:
410-417,
2002.
14.
Jordan, AS,
Catcheside PG,
Orr RS,
O'Donoghue FJ,
Saunders NA,
and
McEvoy RD.
Ventilatory decline after hypoxia and hypercapnia is not different between healthy young men and women.
J Appl Physiol
88:
3-9,
2000.
15.
Krol, RC,
Knuth SL,
and
Bartlett D, Jr.
Selective reduction of genioglossal muscle activity by alcohol in normal human subjects.
Am Rev Respir Dis
129:
247-250,
1984.
16.
Lansing, R,
and
Savelle J.
Chest surface recording of diaphragm potentials in man.
Electroencephalogr Clin Neurophysiol
72:
59-68,
1989.
17.
Leiter, JC,
Knuth SL,
Krol RC,
and
Bartlett D, Jr.
The effect of diazepam on genioglossal muscle activity in normal human subjects.
Am Rev Respir Dis
132:
216-219,
1985.
18.
Ludbrook, J.
Repeated measurements and multiple comparisons in cardiovascular research.
Cardiovasc Res
28:
303-311,
1994.
19.
Martin, SE,
Mathur R,
Marshall I,
and
Douglas NJ.
The effect of age, sex, obesity and posture on upper airway size.
Eur Respir J
10:
2087-2090,
1997.
20.
McEvoy, RD,
Popovic RM,
Saunders NA,
and
White DP.
Effects of sustained and repetitive isocapnic hypoxia on ventilation and genioglossal and diaphragmatic EMGs.
J Appl Physiol
81:
866-875,
1996.
21.
McNamara, SG,
Aarts MJ,
Becker H,
Cao K,
Polo OJ,
and
Sullivan CE.
Ventilatory responses to repetitive hypoxia in subjects with obstructive sleep apnea (Abstract).
Am J Respir Crit Care Med
151:
A100,
1995.
22.
Mezzanotte, WS,
Tangel DJ,
and
White DP.
Waking genioglossal electromyogram in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism).
J Clin Invest
89:
1571-1579,
1992.
23.
Mitchell, GS,
Powell FL,
Hopkins SR,
and
Milsom WK.
Time domains of the hypoxic ventilatory response in awake ducks: episodic and continuous hypoxia.
Respir Physiol
124:
117-128,
2001.
24.
Okabe, S,
Hida W,
Kikuchi Y,
Kurosawa H,
Midorikawa J,
Chonan T,
Takishima T,
and
Shirato K.
Upper airway muscle activity during sustained hypoxia in awake humans.
J Appl Physiol
75:
1552-1558,
1993.
25.
Onal, E,
Burrows DL,
Hart RH,
and
Lopata M.
Induction of periodic breathing during sleep causes upper airway obstruction in humans.
J Appl Physiol
61:
1438-1443,
1986.
26.
Pillar, G,
Malhotra A,
Fogel R,
Beauregard J,
Schnall R,
and
White DP.
Airway mechanics and ventilation in response to resistive loading during sleep: influence of gender.
Am J Respir Crit Care Med
162:
1627-1632,
2000.
27.
Popovic, RM,
and
White DP.
Influence of gender on waking genioglossal electromyogram and upper airway resistance.
Am J Respir Crit Care Med
152:
725-731,
1995.
28.
Regensteiner, JG,
Pickett CK,
McCullough RE,
Weil JV,
and
Moore LG.
Possible gender differences in the effect of exercise on hypoxic ventilatory response.
Respiration
53:
158-165,
1988.
29.
St John, WM,
Bartlett D, Jr,
Knuth KV,
Knuth SL,
and
Daubenspeck JA.
Differential depression of hypoglossal nerve activity by alcohol. Protection by pretreatment with medroxyprogesterone acetate.
Am Rev Respir Dis
133:
46-48,
1986.
30.
St John, WM,
and
Bledsoe TA.
Comparison of respiratory-related trigeminal, hypoglossal and phrenic activities.
Respir Physiol
62:
61-78,
1985.
31.
Stewart, D,
Berthon-Jones M,
McNamara S,
Grunstein R,
and
Sullivan C.
Ventilatory responses to repetitive hypoxia in normal males (Abstract).
Am J Respir Crit Care Med
149:
A260,
1994.
32.
Tatsumi, K,
Pickett CK,
Jacoby CR,
Weil JV,
and
Moore LG.
Role of endogenous female hormones in hypoxic chemosensitivity.
J Appl Physiol
83:
1706-1710,
1997.
33.
Turner, DL,
and
Mitchell GS.
Long-term facilitation of ventilation following repeated hypoxic episodes in awake goats.
J Physiol
499:
543-550,
1997.
34.
White, DP,
Douglas NJ,
Pickett CK,
Weil JV,
and
Zwillich CW.
Sexual influence on the control of breathing.
J Appl Physiol
54:
874-879,
1983.
35.
White, DP,
Edwards JK,
and
Shea SA.
Local reflex mechanisms: influence on basal genioglossal muscle activation in normal subjects.
Sleep
21:
719-728,
1998.
36.
Young, T,
Palta M,
Dempsey J,
Skatrud J,
Weber S,
and
Badr S.
The occurrence of sleep-disordered breathing among middle-aged adults (see comments).
N Engl J Med
328:
1230-1235,
1993.
37.
Zabka, AG,
Behan M,
and
Mitchell GS.
Selected Contribution: Time-dependent hypoxic respiratory responses in female rats are influenced by age and by the estrus cycle.
J Appl Physiol
91:
2831-2838,
2001.
38.
Zabka, AG,
Behan M,
and
Mitchell GS.
Serotonin-dependent long-term facilitation of respiratory motor output decreased with age in male rats.
J Physiol
531:
509-514,
2001.
This article has been cited by other articles:
|
|
 |
|
  D. S. Lee, M. S. Badr, and J. H. Mateika Progressive augmentation and ventilatory long-term facilitation are enhanced in sleep apnoea patients and are mitigated by antioxidant administration J. Physiol., November 15, 2009; 587(22): 5451 - 5467. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Mateika and G. Narwani Intermittent hypoxia and respiratory plasticity in humans and other animals: does exposure to intermittent hypoxia promote or mitigate sleep apnoea? Exp Physiol, March 1, 2009; 94(3): 279 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. McGuire, J. L. Tartar, Y. Cao, R. W. McCarley, D. P. White, R. E. Strecker, and L. Ling Sleep fragmentation impairs ventilatory long-term facilitation via adenosine A1 receptors J. Physiol., November 1, 2008; 586(21): 5215 - 5229. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. McGuire, C. Liu, Y. Cao, and L. Ling Formation and maintenance of ventilatory long-term facilitation require NMDA but not non-NMDA receptors in awake rats J Appl Physiol, September 1, 2008; 105(3): 942 - 950. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wadhwa, C. Gradinaru, G. J. Gates, M. S. Badr, and J. H. Mateika Impact of intermittent hypoxia on long-term facilitation of minute ventilation and heart rate variability in men and women: do sex differences exist? J Appl Physiol, June 1, 2008; 104(6): 1625 - 1633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Tadjalli, J. Duffin, Y. M. Li, H. Hong, and J. Peever Inspiratory activation is not required for episodic hypoxia-induced respiratory long-term facilitation in postnatal rats J. Physiol., December 1, 2007; 585(2): 593 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mahamed and G. S. Mitchell Sleep Apnoea & Hypertension: Physiological bases for a causal relation: Is there a link between intermittent hypoxia-induced respiratory plasticity and obstructive sleep apnoea? Exp Physiol, January 1, 2007; 92(1): 27 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P. Harris, A. Balasubramaniam, M. S. Badr, and J. H. Mateika Long-term facilitation of ventilation and genioglossus muscle activity is evident in the presence of elevated levels of carbon dioxide in awake humans Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R1111 - R1119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Jordan, A. Wellman, J. K. Edwards, K. Schory, L. Dover, M. MacDonald, S. R. Patel, R. B. Fogel, A. Malhotra, and D. P. White Respiratory control stability and upper airway collapsibility in men and women with obstructive sleep apnea J Appl Physiol, November 1, 2005; 99(5): 2020 - 2027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. McGuire, Y. Zhang, D. P. White, and L. Ling Phrenic long-term facilitation requires NMDA receptors in the phrenic motonucleus in rats J. Physiol., September 1, 2005; 567(2): 599 - 611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. McGuire and L. Ling Ventilatory long-term facilitation is greater in 1- vs. 2-mo-old awake rats J Appl Physiol, April 1, 2005; 98(4): 1195 - 1201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. C. McKay, W. A. Janczewski, and J. L. Feldman Episodic hypoxia evokes long-term facilitation of genioglossus muscle activity in neonatal rats J. Physiol., May 15, 2004; 557(1): 13 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Mateika, C. Mendello, D. Obeid, and M. S. Badr Peripheral chemoreflex responsiveness is increased at elevated levels of carbon dioxide after episodic hypoxia in awake humans J Appl Physiol, March 1, 2004; 96(3): 1197 - 1205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. McGuire, Y. Zhang, D. P. White, and L. Ling Chronic intermittent hypoxia enhances ventilatory long-term facilitation in awake rats J Appl Physiol, October 1, 2003; 95(4): 1499 - 1508. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
) and women
(n = 10; 
). Values are means ± SE. There was a significant effect of gender on
PETCO2. There was no significant change in
PETCO2 over time in either gender. There
were no other significant gender or gender × time interaction
effects.
