Vol. 85, Issue 4, 1260-1266, October 1998
Augmenting expiratory neuronal activity in sleep and
wakefulness and in relation to duration of expiration
John
Orem
Department of Physiology, School of Medicine, Texas Tech University
Health Sciences Center, Lubbock, Texas 79430
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ABSTRACT |
Augmenting expiratory cells
(n = 23) were recorded in the rostral
medulla of five cats in sleep and wakefulness. The
objective was to determine the relationship of their activity to the
duration of expiration (TE)
and, particularly, to TE in
rapid-eye-movement (REM) sleep, when expirations are short and may even
cause fractionated breathing. Correlation analysis (Kendall's 
)
showed no consistent relationship in any state between the
breath-by-breath mean activity of augmenting expiratory cells and
TE. This result contradicts predications of an inverse relationship between augmenting expiratory activity and TE. Some cells (11 of 23) were more active in REM than in non-REM sleep and were active
during fractionated breathing. This suggests that fractionated
breathing in REM sleep is caused by short expiratory phases and not by
intermittent inhibition of an ongoing inspiration.
brain stem respiratory neurons; fractionations; Bötzinger
cells; rapid-eye-movement sleep; cats
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INTRODUCTION |
IN THIS STUDY, we recorded the activity of augmenting
expiratory cells in the rostral medulla during sleep and wakefulness in
the cat. Some of these cells have widespread inhibitory actions that
are essential in models of rhythmogenesis (4, 6, 23), and they
purportedly determine the late phase of expiration. Theory predicts,
and it has been observed in rats, that they discharge in an augmenting
pattern to achieve high rates during long expirations, whereas their
bursts are truncated or even absent during short expirations (e.g.,
Ref. 21). The duration of expiration
(TE) is typically short during
rapid-eye-movement (REM) sleep in the cat (19), and one would predict,
therefore, that augmenting expiratory cells should be inactive or
silent in that state. One objective of the present work was to test
this idea.
Another objective was to determine whether augmenting expiratory cells,
like some inspiratory cells (14, 15), are excited in REM sleep.
Inhibitory effects on the respiratory system in REM sleep are well
known. For example, the atonia of the state can cause changes in airway
resistance and chest wall compliance. There are also excitatory effects
about which less is known. It is not known, for example, whether
central respiratory neurons are in general excited or what the
mechanism is for the increased rate of breathing in that state.
A third objective was to learn more about the erratic pattern of
breathing characteristic of REM sleep. In particular, inspiratory efforts sometimes occur as a series of rapid and brief efforts, as if a
single breath were fractionated into several parts (13). It has been
proposed that this fractionated pattern of breathing is the result of a
descending inhibition associated with pontogeniculooccipital waves
(13). Alternatively, it may be that fractionated breaths are brief but
complete respiratory cycles in which both phases, inspiratory and
expiratory, are present. If the latter is the case, then expiratory
neurons should discharge during the brief breaks in inspiratory
activity that are seen during fractionated breathing.
The results show that the prediction of a positive relationship between
TE and the discharge rate of
augmenting expiratory cells is not supported, that some augmenting
expiratory cells are excited in REM sleep and may account in part for
the pattern of breathing in that state, and that fractionated breathing
in REM sleep is the result of short, but complete, respiratory cycles.
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METHODS |
Electrodes for recording electroencephalographic (EEG) and
electromyographic (EMG) activity were implanted in five adult cats. In
addition, tracheal fistulas were created, and a headcap was attached to
the skull.
Surgical procedures.
The animals were anesthetized with acepromazine maleate (2.5 mg) and
ketamine (30 mg/kg) and 1-5% halothane in oxygen. A midline incision was made from below the cricoid cartilage to just above the
suprasternal notch, and the sternothyroid, sternohyoid, and sternomastoid muscles were retracted to expose the trachea. The trachea
was opened longitudinally for a length of five cartilaginous rings. The
cut edges of the rings were sewn to the skin on the corresponding side
to create a fistula. The animals were placed in a stereotaxic frame,
and a midline incision was made to expose the dorsal skull. EEG
electrodes and 4-40 stainless steel electrodes were threaded into
the skull and secured with dental cement.
EMG electrodes (Teflon-coated multistranded stainless steel wires;
Cooner no. AS 632) were implanted in the nuchal muscles. EEG and EMG
electrode wires and a prefabricated headcap with a connector and with
standoffs for head restraint were fixed to the skull with dental
cement. The animals were allowed to recover for at least 1 mo before
experimentation. All procedures were approved by the Institutional
Animal Care and Use Committee.
Experimental procedures.
After recovery from surgery, the animals were adapted to the
experimental apparatus. For this they were placed in a veterinary cat
bag, and their heads were restrained by attachment of the headcap to a
modified stereotaxic apparatus. The animals either could assume a
sphinx position or could be semiprone on their left or right side.
Generally, a week or more of daily 2-h adaptation sessions were
required before the animals would sleep in the laboratory.
After adaptation and in a second operation under general anesthesia (as
above), a small craniotomy (~5 mm diameter) was made in the occipital
bone. The craniotomy allowed passage of microelectrodes through the
cerebellum into the brain stem.
To consolidate sleep to the daytime hours when recordings were made,
the animals were housed overnight in a cold (0°C) environment.
For recording of intratracheal pressures, a small Silastic tube was
inserted through the fistula into the trachea. This tube was connected
to a pressure transducer. In two of five animals in the study, the
trachea was intubated with an 18-Fr endotracheal tube, and pressures
within the tube and instantaneous airflow rates were measured. Only
four augmenting expiratory cells were recorded from these two animals.
Accordingly, the results were obtained primarily from animals that
breathed normally through the upper airways rather than through an
endotracheal tube. EEG and EMG activity and intratracheal pressures
(PT5A volumetric pressure transducer, Grass Instruments) were recorded
on an analog tape recorder (Hewlett-Packard) and on a chart recorder
(MT9500, Astro-Med). The EEG was band-pass filtered [1-35
cycles/s (cps)] and amplified (wideband alternate current
preamplifiers, Grass Instruments). EMG signals from the nuchal muscles
were led to a high-impedance probe (Grass HP511) and to an amplifier
(Grass P511) set to pass frequencies from 300 to 10,000 cps.
Tungsten microelectrodes (impedances 1-10 M
) were used to
record single medullary respiratory neurons. The microelectrodes were
mounted to a hydraulic microdrive and driven through the cerebellum and
into the medulla. Signals were led to a high-impedance probe (Grass
HIP511) and to a preamplifier (Grass P511) and were recorded on the
Astro-Med and analog tape recorders.
The recording sessions lasted ~4 h. Non-REM (NREM) and REM sleep and
wakefulness were defined on the basis of standard EEG criteria.
Data analysis.
All analyses were performed off-line. Data were played back from the
tape recorder into a PS/2 486 computer with a LabWindows data-acquisition system (National Instruments). Cycle-triggered histograms and the signal strength and consistency of the respiratory component of the activity of a cell
(
2 values) were determined for
each cell. Procedures for constructing cycle-triggered
histograms and calculating the
2 value of the activity of a
cell have been published (18). The 2 values can vary from 0.0 to
1.0. The respiratory component can vary in different states; the
2 values used to categorize the
cells in this study were obtained from activity occurring during
relaxed wakefulness or NREM sleep. Discharge rates of the cell and the
duration of inspiration (TI) and TE were calculated breath by
breath in wakefulness and in NREM and REM sleep. Discharge rates were
calculated from interspike intervals of <300 ms, an arbitrary value
chosen to exclude intervals during the inactive phase of the cells.
Rank order and Pearson product-moment correlation coefficients were
calculated to determine the relationship between
TE and the mean discharge rate
of the cells breath by breath.
Histology.
After fixation in Formalin (10%), frozen sections (40-80 µm in
thickness) of the medulla were cut, stained with cresyl violet, and
examined for evidence of microelectrode penetrations.
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RESULTS |
Characteristics of augmenting expiratory cells.
Twenty-three augmenting expiratory cells were recorded in five adult
cats. They were located in the ventral respiratory group from the
retrofacial nucleus to 1-2 mm rostral to the obex. Their activity
augmented throughout expiration and ceased at the onset of inspiration.
Eleven had a distinct period of activity at the end of inspiration or
beginning of expiration (Fig. 1, see also Ref. 10, 20, 24). The 2 values
of the cells varied from 0.45 to 0.94 and averaged 0.74 ± 0.16 (SD). Average discharge rates in NREM sleep varied from 4.5 to 64.6 cps.
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Fig. 1.
Discharge profiles of 2 augmenting expiratory cells in
rapid-eye-movement (REM) and non-REM (NREM) sleep.
A: cell had an augmenting discharge
pattern in both NREM and REM sleep. Discharge rate is plotted as a
function of time from onset of inspiration at time
0 to end of expiration. Plots are averages of
n breaths as indicated. Note greater
rate of rise of activity and higher discharge rates in REM sleep
compared with NREM sleep. B: cell
discharged at inspiration-to-expiration transition, paused, and then
augmented throughout expiration. This profile was compressed but is
evident in REM sleep. Approximately one-half (11 of 23) of cells in
this study showed this bimodal profile. cps, Cycles/s.
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Behavior of augmenting expiratory cells in REM sleep.
Eleven cells were more active in REM than in NREM sleep (Figs.
2-4).
Other cells were either less active in REM sleep
(n = 9) or had similar mean rates in
both states (n = 3) (Fig. 2, Tables 1 and 2).
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Fig. 2.
Discharge rates of augmenting expiratory cells in wakefulness and REM
sleep normalized to discharge rates in NREM sleep. Solid lines plot
results for cells that were significantly more active in REM than in
NREM sleep. No. of lines showing relationship of discharge rates in
wakefulness to those in NREM sleep are fewer than for relationship
between NREM and REM sleep because no data in wakefulness were
available for 3 cells. Dotted lines show data for cells that were
significantly less active in REM than in NREM sleep or for cells the
discharges rates of which were not different in the two states. Again,
here data are incomplete and no. of lines for NREM sleep-wakefulness
relationship do not correspond to no. of lines for NREM-REM sleep
relationship. This figure shows diverse behaviors of augmenting
expiratory cells in REM sleep.
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Fig. 3.
Transition from NREM to REM sleep showing an increase in discharge rate
of an augmenting expiratory cell in REM sleep. Note that this cell is
active during even very short expirations in REM sleep. EEG,
electroencephalogram; Ptr, tracheal pressure. Negative pressures
(inspiration) signaled by upward deflections.
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Fig. 4.
Activity of an augmenting expiratory cell in REM sleep
(A) and in wakefulness
(B). Note that cell discharges in
association with each positive (downward) Ptr deflection (expiration)
during rapid and erratic breathing in REM sleep. In wakefulness
(B), cell is silent or only weakly
active during expiratory events associated with body movements (note
artifacts on EEG) and during a swallow (arrow). Expiratory efforts at
beginning of this episode are large and produce large voltage changes
that cause oscillation of amplifier. Those episodes in which there are
expiratory efforts were commonly seen as part of a sequence that
comprised also an augmented breath and swallows.
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The group of cells that was more active in REM sleep discharged at a
mean rate of 55.4 ± 23.5 cps in that state, compared with a rate of
38.2 ± 18.4 cps in NREM sleep. The average ratio of REM activity to
NREM activity was 1.54 ± 0.40. Coefficients of variation of
discharge rates were greater in REM sleep (0.39 ± 0.17) than in
NREM sleep (0.25 ± 0.23). The group average
2 value was 0.82 ± 0.15 (Table 1). These cells were active during all expirations in REM sleep,
regardless of whether the breathing pattern was regular or irregular
(Fig. 4). The activation was sustained throughout REM sleep, but there
was much variability, and, on some breaths, rates were equivalent to
those in NREM sleep (Fig. 5).
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Fig. 5.
Breath-by-breath mean discharge rate of an augmenting expiratory cell
in wakefulness (W) and NREM and REM sleep. Note sustained activation
and breath-to-breath variation in activity of cell in REM sleep.
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Nine cells were significantly less active in REM sleep than in NREM
sleep. The average discharge rate of this group of cells in NREM sleep
was 24.9 ± 19.5 cps and decreased to 13.7 ± 18.3 cps in REM
sleep. The average ratio of REM activity to NREM activity across cells
was 0.46 ± 0.31. The coefficients of variation of the discharge
rates were greater in REM sleep (1.84 ± 1.52) than in NREM sleep
(0.31 ± 0.28). The group average
2 value was 0.65 ± 0.14 (Table 2).
Three cells had similar discharge rates in REM sleep (44.9 ± 12.7 cps) and NREM sleep (45.5 ± 18.5 cps). Their average
2 value was 0.75 ± 0.7, and
coefficients of variation of their discharge rates were greater in REM
sleep (0.43 ± 0.01 cps) than in NREM sleep (0.15 ± 0.02 cps).
Activity of augmenting expiratory cells during active expirations in
wakefulness.
Large expiratory intratracheal pressures sometimes occurred on arousal
and were associated with movement of the animal. These movements
generally preceded an augmented breath (e.g., Fig.
6). Some augmenting expiratory cells
(n = 5) were intensely active during
these movements associated with large expiratory pressures, and they
were active also during swallowing (Fig. 6), whereas others
(n = 10) were not (Fig. 4). In eight
cases, these movements were not observed.
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Fig. 6.
Activity of an augmenting expiratory cell in wakefulness. This cell,
unlike cell in Fig. 4, discharged intensely during movements in arousal
preceding an augmented breath. Cell discharged also during swallows
(arrow).
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Comparisons between augmenting expiratory cells with increased
activity in REM sleep and other augmenting expiratory cells.
Cells that had higher discharge rates in REM sleep had significantly
(t-test,
P < 0.05) higher
2 values than did cells that
were less active or unchanged in that state. The coefficient of
variation of the activity in REM sleep was also significantly less for
cells that were more active in that state than for other cells. The
mean discharge rate in NREM sleep tended to be higher for the cells
that were more active in REM than in NREM sleep (38.2 vs. 24.9 cps),
but this difference was not significant at the 0.05 level.
Only 1 of the 11 cells that were more active in REM sleep, but 4 of the
9 cells that were less active in that state, discharged during active
expirations in wakefulness. The number of cases is too small for
statistical analysis of this association; nevertheless, the results
suggest a relationship between behaviors in REM sleep and during active
expirations.
Early expiratory bursting was not related to the direction of the
change in cellular discharge from NREM to REM sleep. Approximately one-half of the cells (5 of 11) that were more active in REM sleep and
one-half of the cells (5 of 9) that were less active in REM sleep had
early expiratory peaks in their cycle-triggered histograms.
Relationship between mean discharge rate of augmenting expiratory
cells and TE.
Kendall's rank order coefficient () was calculated to determine the
relationship between the mean discharge rate of the cells and
TE breath by breath. A total of
64 values were calculated from samples in wakefulness and NREM and
REM sleep.
In REM sleep, 10 of 23 cells showed a small but significant
relationship. In five cases the relationship was positive, which indicates that expirations with longer durations were associated with
higher discharge rates; in five cases the relationship was negative.
Values of varied from 0.16 to 0.48 and averaged 0.25. These small
but significant correlations between discharge rate and
TE were found in 4 of 11 cells
that were more active in REM sleep and 6 of 9 cells that were less
active in REM sleep. Five of six correlations of the latter cells were
positive, whereas only one of four correlations of the former cells was
positive. One cell with comparable rates in NREM and REM sleep showed a significant negative correlation. Figures 3 and 4 illustrate an augmenting expiratory cell that was active during even very short expirations in REM sleep.
Mixed results were obtained also for correlations in NREM sleep. Seven
of twenty-two cells for which there were NREM sleep data showed
significant correlations: five correlations were positive, and two were
negative. The average value of the significant correlations in NREM
sleep was 0.29.
Six of nineteen cells studied in wakefulness showed significant
correlations between mean discharge rate and
TE. All but one of these six
significant correlations were negative. The average value of the
significant correlations in wakefulness was 0.31.
Linear regression lines of discharge rate as a function of
TE were determined from data
across states for each of the 23 cells (Fig.
7). The slopes were in some cases negative
and in others positive. This result followed from the behaviors of the
cells in REM sleep: cells that were more active in REM sleep, when
TE is short, had primarily
negative correlations to the TE
(Fig. 7C). Cells less active in REM
sleep had mostly positive correlations. (Fig.
7B).
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Fig. 7.
Relationship between duration of expiration
(TE) and discharge rate of all
cells (A) and of cells that were
more (B) or less
(C) active in NREM than in REM
sleep. Regression lines (y = ax + b) were constructed from data from
single cells across all states. Slopes across population of all cells
were variously positive and negative
(A), but slopes were generally
positive for cells that were more active in NREM than in REM sleep
(B) and were generally negative for
cells that were more active in REM than in NREM sleep
(C). This resulted from the fact
that expirations in NREM sleep were longer than expirations in REM
sleep.
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DISCUSSION |
Characteristics of rostral augmenting expiratory cells.
The cells in this study were located in the rostral medulla. This area
contains respiratory motoneurons that innervate upper airway muscles
and propriobulbar as well as bulbospinal respiratory neurons. Some
rostral augmenting expiratory cells have widespread inhibitory actions
on other respiratory neurons, including phrenic motoneurons and
augmenting and decrementing expiratory and inspiratory cells in both
the dorsal and ventral medullary respiratory groups (5, 9, 11). Other
rostral augmenting expiratory cells excite expiratory premotoneurons in
the caudal brain stem (2, 9), and there are projections back to the
region of rostral augmenting expiratory cells from this caudal area
(26). Thus there are several different types of cells with augmenting
expiratory patterns in the rostral medulla.
Augmenting expiratory cells in the rostral medulla display different
discharge patterns during active expirations. Some are inactive during
sneezing (17) or during expiratory efforts induced by chemical
stimulation of caudal expiratory premotoneurons in anesthetized animals
(3). In contrast, other studies find that rostral expiratory neurons
are active during vomiting (12) and coughing (25). In the present
study, some rostral augmenting expiratory cells were active during
active expirations, and others were not. The augmenting expiratory
cells that are active during active expiration may be motor, premotor,
or pre-premotor cells, and those that are inactive may be part of the
network that produces rhythmogenesis.
The three-phase theory.
A current theory contends that the respiratory cycle comprises three
phases: an inspiratory phase and an early and a late expiratory phase
(22). According to this theory,
TE depends on activity in the
third phase. The theory contends that shortening of expiration occurs
by reducing or eliminating the late expiratory phase. (e.g., Ref. 21).
Augmenting expiratory cells are members of the class of cells that
define the late expiratory phase. As stated by Parkes et al. (21),
there should be "elimination of the stage II (late expiratory) phase
of expiration as seen in the membrane potential changes in all classes
of respiratory neurone, and in the loss of discharge in stage II
expiratory neurones, as the respiratory rate increases" (Ref. 21, p.
136).
In the present study, Kendall's and Pearson's product-moment
correlation coefficients were calculated to determine the relationship between TE and the mean
discharge rate of augmenting expiratory cells. Pearson's
product-moment correlation coefficients were calculated on the combined
data from wakefulness and NREM and REM sleep. These showed
relationships that followed from the behaviors of the cells in REM
sleep. If a cell was more active in REM sleep than in NREM sleep, the
correlation to TE was negative;
if the cell was less active in REM sleep, the correlation was positive. This result could be interpreted as partial support of the three-phase theory. Additional support comes from observation that five of nine
cells that were less active in REM sleep showed a small but significant
positive correlation between mean discharge rate and TE within REM sleep. However,
this interpretation does not explain why correlations between the
activity of other augmenting expiratory cells and
TE were negative or not
significant.
Values of were calculated within states for each cell. Most values were not significant. This indicates that there was not a
monotonic relationship between the discharge rate of a cell and
TE. Of the values that were
significant, 11 were positive (the direction predicted by the
three-phase theory) and 12 were negative. The values of significant
correlations were small (0.2-0.3). These cannot be interpreted in
the same way as Pearson product-moment correlation coefficients, but
the possible range of values, like correlation coefficients, is
1.0 to +1.0, indicating complete disagreement and complete
agreement, respectively, in the rank order of the two variables.
Because most values were not significant and because significant
values were evenly divided between those showing a positive and
those showing a negative relationship, we conclude that the predictions
of the three-phase theory cannot be supported by our observations. On a
qualitative basis alone, it is difficult to see how the persistence of
augmenting expiratory neuronal activity during extremely rapid and
irregular breathing in REM sleep (Fig. 4) can be reconciled with the
predictions of the three-phase theory.
Fractionations.
Diaphragmatic activity in REM sleep appears at times interrupted or
fractionated (13). It was originally proposed that these interruptions
were the result of a phasic descending inhibition that was related to
the occurrence of pontogeniculooccipital waves and that bypassed
medullary respiratory neurons to affect directly phrenic motoneurons
(13). Subsequent studies have found that fractionations can occur in
the absence of pontogeniculooccipital waves and that they can have
significant depressive effects on ventilation (7, 8). Although we did
not record the activity of the diaphragm in this study, intratracheal
pressures (and/or airflow traces) showed patterns consistent
with fractionations. These patterns were rapid alternations from
negative (inspiratory) to positive (expiratory) pressures (Fig.
4A). Augmenting expiratory cells
discharged during these reversals of inspiratory pressures even when
they were very brief. This suggests that fractionations may be
extremely rapid breathing during which respiratory cycles are complete,
progressing rapidly through all the phases of inspiration and
expiration and involving respiratory cells of all types, including augmenting expiratory cells.
Excitatory effects on the respiratory system in REM sleep.
The variable that distinguished augmenting expiratory cells that were
more active in REM sleep from those that were less active was the
2 value of their activity. All
of the cells in this study except one had
2 values 
0.5, but cells that
were more active in REM than in NREM sleep had significantly higher
2 values than did cells that
were less active in REM sleep. The 2 values of some of the
augmenting expiratory cells are among the highest we have seen in
recordings of many different types of respiratory neurons in chronic
animals. The meaning of the association of high
2 values with activation in REM
sleep is not known.
This is the first evidence of excitation of augmenting expiratory
neurons in REM sleep. Previous studies have shown that augmenting and
late inspiratory neurons increase their discharge rates in REM sleep,
compared with NREM sleep (14, 15), and that diaphragmatic EMG activity
has a greater rate of rise in that state (16). This excitation may be a
compensatory response to changes in compliance and resistance of the
respiratory system during REM sleep, or it may result from
state-specific processes that cause excitation throughout the nervous
system. The increase in the activity of some augmenting expiratory
cells in REM sleep may explain the increase in rate of breathing and in
the rate of rise of inspiratory activity in that state. If the
augmenting expiratory cells that are excited in REM sleep are those
that have widespread inhibitory actions, then they may cause more rapid
breathing because of strong inhibition of inspiratory cells and then
postinhibitory rebound excitation of the same cells. Indeed,
simulations of a network model have found that increased augmenting
expiratory activity causes an increase in inspiratory activity (1),
just as has been observed in previous studies (14, 15).
Conclusions.
Augmenting expiratory cells in the rostral medulla are a heterogeneous
group that includes cells that are excited in REM sleep. Their mean
discharge rates are poorly related or unrelated to the
TE. The activity of some of them
indicates that fractionated breathing consists of inspirations
alternating rapidly with brief expirations. The oscillator in REM sleep
has an inspiratory bias (the
TI/TE
ratio is large), and inspiratory neurons have a greater rate of rise of
activity that may be caused in part by brief but intense augmenting
expiratory activity.
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ACKNOWLEDGEMENTS |
Drs. Edward H. Vidruk, Cary Anderson-Culbertson, and Thomas E. Dick
assisted with the recordings and consulted on the interpretation of the
results. Jonathan Rude and Carrie Hines Sherman provided technical
assistance, and Becky J. Tilton cared for the animals.
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FOOTNOTES |
This study was supported by National Heart, Lung, and Blood Institute
Grant HL-21257.
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. §1734 solely to indicate this fact.
Address for reprint requests: J. Orem, Dept. of Physiology, School of
Medicine, Texas Tech Univ. HSC, Lubbock, TX 79430 (E-mail:
phyjmo{at}ttuhsc.edu).
Received 27 March 1998; accepted in final form 7 June 1998.
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Abstract
Introduction
