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Department of Comparative Biosciences and Center for Neuroscience, University of Wisconsin, Madison, Wisconsin 53706
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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To investigate models
of plasticity in respiratory motor output, we determined the effects of
chronic unilateral phrenicotomy and/or exercise on time-dependent
responses to episodic hypoxia in the contralateral phrenic nerve.
Anesthetized (urethane), ventilated, and vagotomized rats were
presented with three, 5-min episodes of isocapnic hypoxia (11%
O2), separated by 5 min of hyperoxia (50% O2).
Integrated phrenic (and hypoglossal) nerve discharge were recorded
before and during each hypoxic episode, for the first 5 min after the
first hypoxic episode, and at 30 and 60 min after the final episode. Of
36 rats, one-half were sedentary while the other one-half had free
access to a running wheel; each of these groups was split into three
subgroups: 1) unoperated, 2) chronic left
phrenicotomy (27-37 days), and 3) sham operated. Neither unilateral phrenicotomy nor running wheel activity influenced the short-term hypoxic phrenic response (during hypoxia) or long-term facilitation (posthypoxia). Posthypoxia frequency decline was exaggerated in phrenicotomized-sedentary rats relative to
unoperated-sedentary rats (change in burst frequency = 
23 ± 4 vs. 11 ± 5 bursts/min, respectively; 5 min posthypoxia;
P < 0.05), an effect that was eliminated by
spontaneous exercise. The results indicate that neither voluntary
running nor unilateral phrenicotomy has major effects on time-dependent
hypoxic phrenic responses, with the exception of an unexpected effect
of phrenicotomy on posthypoxia frequency decline in sedentary rats.
respiratory control; plasticity; hypoglossal
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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SEVERAL
TIME-DEPENDENT VENTILATORY responses are elicited by hypoxia in
rats (14, 30), including 1) an acute increase in inspiratory neural activity observable within a single breath (11); 2) a progressive increase in nerve
amplitude over 1-2 min, followed by a similar progressive decrease
in amplitude when the stimulus is removed [short-term potentiation
(STP)] (33); 3) a concomitant progressive
decrease in nerve burst frequency during the first minute of hypoxia
[short-term depression (STD)] (30) followed by
4) an abrupt decrease in burst frequency, below baseline
values, during the first 5 min after the stimulus is removed
[posthypoxia frequency decline (PHFD)] (2, 5); and 5) long-term facilitation (LTF), an enhancement of
respiratory activity that persists for 1 h or more after episodic
chemoafferent activation (1, 2, 24). LTF and PHFD
depend, at least in part, on the activation of serotonergic and
2-adrenergic receptors, respectively (1, 2,
23). Recently, it has become clear that some of these
time-dependent responses can be modified by perturbations of the system
such as cervical dorsal rhizotomy (18) or chronic
intermittent hypoxia (19). We were interested in
investigating other, similar models of plasticity in time-dependent hypoxic ventilatory responses.
Our working hypothesis is that compensatory responses after neural injury or repetitive system activation arise from a general mechanism involving monoaminergic nervous system function. In this study, we investigated unilateral phrenicotomy as a model of neural injury. Unilateral phrenicotomy paralyzes the ipsilateral hemidiaphragm, and, under resting conditions, the contralateral hemidiaphragm and other accessory inspiratory muscles increase their activity to maintain adequate ventilatory output (12, 31). During periods of increased respiratory muscle recruitment (e.g., exercise), it may become difficult to meet ventilatory demands. A functional deficit such as that caused by phrenicotomy necessitates increased respiratory drive to the remaining respiratory muscles, a process we propose would be facilitated by increased activity in descending monoaminergic pathways. On the basis of activity-dependent mechanisms, the descending monoaminergic pathways could become more robust as a result of an upregulation of rate-limiting enzymes (e.g., tryptophan hydroxylase) and a strengthening of nerve terminals and their connections.
There is evidence that selective lesions induce long-lasting compensatory changes in neural circuitry that enhance the recruitment of intact respiratory musculature (20, 28). Cervical dorsal rhizotomy increases serotonergic innervation in the phrenic motor nucleus and enhances serotonin-dependent LTF of phrenic motor output after episodic hypoxia (18). In addition, chronic thoracic dorsal rhizotomy (TDR) increases the concentrations of serotonin and dopamine in cervical spinal cord segments associated with the phrenic motor nucleus of adult goats (25, 26). TDR eliminates sensory afferent feedback from the chest wall, thus compromising the ability of the intercostal musculature to contribute to breathing efforts, especially during periods of increased respiratory drive (e.g., exercise) (27). An upregulation of monoamine function in the phrenic motor nucleus could enhance diaphragmatic performance and offset the loss of intercostal function caused by the denervation. As yet, however, there is no direct demonstration of a causal, compensatory link.
In the present study, we investigated the effect of a selective neural injury on hypoxic ventilatory responses by examining the effect of chronic unilateral phrenicotomy on the phrenic nerve response to hypoxia in anesthetized rats. Specifically, we examined the effects of chronic unilateral phrenicotomy on the acute response to hypoxia, STP, STD, PHFD, and LTF of phrenic and hypoglossal nerve activity after hypoxia. We hypothesized that chronic unilateral phrenicotomy would upregulate serotonergic innervation of the contralateral cervical spinal cord, therefore enhancing contralateral phrenic LTF. Hypoglossal motor output was monitored as a comparison with the (intact) phrenic response.
Because exercise can increase the concentrations of central nervous system monoamines (22), one-half of the phrenicotomized animals were given voluntary access to running wheels. We hypothesized that the increased respiratory drive necessary for exercise might enhance compensatory responses to phrenicotomy.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental groups.
Thirty-six male rats (364-454 g; Harlan Sprague Dawley colony 205, Madison, WI) were randomly separated into six equal groups. Sedentary
groups included (each n = 6): 1) unilateral
(right) phrenicotomy, 2) sham-operated and 3)
unoperated rats. Identical groups (each n = 6) were
allowed continuous access to a running wheel (outfitted with a magnetic
revolution counter from which distance traveled per day was recorded;
Fisher Scientific, Pittsburgh, PA). Rats were familiarized with the
wheels for 2 wk before phrenicotomy. Phrenicotomy and sham surgery did
not appear to compromise the rats' ability or desire to exercise on
the running wheels, and, by the time experiments were conducted ~4 wk
later, the rats had reached a steady state of revolutions per day (Fig.
1). We did not attempt to induce greater
running through caloric restriction (8). All rats were
housed separately and maintained under 12:12-h light-dark conditions.
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Surgical preparation. Twenty-seven to thirty-seven days before acute experiments, phrenicotomies and sham operations were conducted under pentobarbital sodium anesthesia (55 mg/kg ip) after anesthetic induction with isoflurane. A ventral neck incision was made, and the muscles were gently separated and retracted to expose the phrenic nerve on the right side of the animal. The nerve was isolated and sectioned, and a small segment (1-2 mm) removed to discourage regrowth from the nerve stump. Phrenic nerve section was confirmed by visualizing changes in abdominal and rib cage movements associated with breathing. An equal number of sham surgeries were conducted in which the phrenic nerve was isolated but not cut. Rats recovered easily from both surgical procedures.
Experimental preparation.
On the day of an experiment, rats were initially anesthetized with
isoflurane (2.5-3.0% in 50% O2-balance
N2) and then slowly converted to urethane anesthesia (1.6 g/kg iv in water vehicle) over a period of 15-30 min. The adequacy
of anesthesia was assessed regularly by testing visual reflexes and
blood pressure responses to toe pinch. Supplemental urethane was
administered as needed through a catheter implanted in a femoral vein.
A slow infusion of sodium bicarbonate (5.0%) and lactated Ringer
solution (50:50, 1.7 ml · kg
1 · h1) was
initiated 1-2 h after induction of anesthesia to maintain acid-base and fluid balance.
Experimental protocols.
After completion of the experimental preparation, 60 min were allowed
for the nerve signals to stabilize in hyperoxia (inspired O2 fraction = 0.50; arterial
PO2 >150 Torr) and normocapnia
(PaCO2 ~3 Torr above the CO2 apneic
threshold; see Table 1). Baseline nerve
activity was achieved by manipulating inspired CO2 and
respiratory pump rate and/or volume while monitoring end-tidal
CO2 levels until both phrenic and hypoglossal nerve
activity attained low but stable levels of activity. The
CO2 thresholds for hypoglossal vs. phrenic nerve activity
were nearly the same in these rats (near 39 Torr for both nerves),
unlike the results found in cats (16). The protocol began
with a baseline arterial blood sample (0.3 ml drawn into a 0.5-ml
heparinized glass syringe; unused blood was returned to the animal).
All subsequent blood samples were compared with this initial baseline
value. Baseline nerve activity was recorded, followed by three, 5-min
episodes of isocapnic hypoxia (inspired O2 fraction
0.13-0.14), separated by 5 min of hyperoxic recovery. In all
cases, data reported during an hypoxic episode were collected from the
first hypoxic episode of a series.
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Data analysis. Peak amplitudes and frequency (bursts/min) of phrenic and hypoglossal nerve activity were averaged over 50 bursts for each recorded data point or in 20-s bins during the first 5 min of the first hypoxic episode and during the first 5 min after the hypoxic episode. Averaged amplitude data were then normalized as a percent change from baseline (prestimulus control) activity and as a change, expressed as the percentage of the (CO2-stimulated) maximum nerve activity. The latter form of normalization obviates concerns about expressing data in terms of the percent increase above an arbitrary (low) baseline value (13). Statistical analyses were conducted by using repeated-measures two-way ANOVA and paired t-tests with the Bonferroni correction for multiple comparisons. Differences were considered significant if P < 0.05. Values are presented as means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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There was no significant difference between sham-operated and unoperated animals in any of our analyses. Therefore, these data were pooled in all figures and are regarded as a single group for purposes of discussion.
Phrenic and hypoglossal burst amplitudes are expressed as a percentage
change from prehypoxic baseline values in Fig.
2. Burst amplitude increased acutely in
both neurograms at the onset of hypoxia. However, the increase in
hypoglossal burst amplitude during hypoxia reached twice the magnitude
of phrenic burst amplitude (a maximum increase of 194 ± 27% in
the hypoglossal neurogram vs. a maximum increase of 109 ± 17% in
the phrenic neurogram; P < 0.0001). Hypoglossal burst
amplitude was also significantly elevated above phrenic burst amplitude
for the first 3 min after the hypoxic stimulus was removed
(P < 0.008), but both had returned to prehypoxic
baseline levels at 5 min posthypoxia. To minimize normalization
artifacts caused by variable baseline nerve activities, mean data were
also expressed as a change from baseline, expressed as a percentage of
the CO2-stimulated nerve burst amplitude (data not shown).
Analyzed in this way, the results were qualitatively similar:
hypoglossal nerve burst amplitude was significantly greater than
phrenic nerve burst amplitude during and after hypoxia,
indicating that hypoglossal nerve activity is affected more profoundly
by isocapnic hypoxia than phrenic activity in urethane-anesthetized rats.
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Chronic phrenicotomy and/or exercise had no effects on phrenic nerve
activity during hypoxia. Figure
3A illustrates mean changes from baseline of nerve burst frequency during the 5-min hypoxic episode. Burst frequency increased acutely and then decreased significantly to a new steady-state level even though the stimulus was
unchanged (i.e., STD; P < 0.05). No significant
differences were detected between any of the treatment groups
consisting of 1) unoperated-sedentary rats, 2)
phrenicotomized-sedentary rats, 3) unoperated-exercised
rats, and 4) phrenicotomized-exercised rats. Mean phrenic
burst amplitude, expressed as percent changes from baseline values,
increased similarly in all treatment groups (Fig. 3B);
similar results were obtained when expressed as percentage of maximal
nerve activity (not shown).
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On termination of the hypoxic stimulus, there was a significant
decrease in respiratory nerve burst frequency below prestimulus control
values in all treatment groups, representing the PHFD (Fig.
4A; P < 0.001). In unoperated-sedentary animals, nerve burst frequency
decreased by 6.5 ± 4.6 bursts/min 1 min after the hypoxic stimulus was removed and by 11.5 ± 5.3 bursts/min 5 min
posthypoxia. PHFD was enhanced by chronic phrenicotomy in sedentary
rats, resulting in a greater decline in nerve burst frequency. Burst
frequency in phrenicotomized-sedentary rats decreased by 12.5 ± 2.1 bursts/min at 1 min and by 23.5 ± 4.0 bursts/min at 5 min
after the hypoxic stimulus was removed (P < 0.04 relative to sedentary controls). In animals that exercised after
phrenicotomy, an exaggerated PHFD was not apparent. In these
phrenicotomized-exercised rats, nerve burst frequency decreased by
9.5 ± 1.8 bursts/min at 1 min and by 9.5 ± 2.8 bursts/min
at 5 min after termination of the hypoxic stimulus. PHFD in animals
treated with phrenicotomy and exercise was significantly different from
animals treated with phrenicotomy alone (P < 0.05) but
was not significantly different from unoperated-sedentary and
unoperated-exercised animals.
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Phrenic nerve burst amplitude progressively decayed toward baseline at the termination of the hypoxic episode (i.e., STP; Fig. 4B). There were no differences in STP between unoperated and phrenicotomized-exercised rats. However, in phrenicotomized-exercised rats, phrenic nerve burst amplitude was significantly elevated relative to phrenicotomized-sedentary rats (P < 0.02) when expressed as percent change from baseline (16 ± 9% above baseline vs. 32 ± 22% below baseline 5 min posthypoxia, respectively). When these data were expressed as a change in percent of the CO2-stimulated maximal nerve burst amplitude, the results were similar (P < 0.01).
Thirty and sixty minutes after the third and final hypoxic episode, LTF
was evident in both phrenic and hypoglossal motor output. Phrenic and
hypoglossal nerve burst amplitudes are expressed as percent changes
from prestimulus baseline values in Fig.
5. Sixty minutes after the final hypoxic
episode, phrenic burst amplitude was increased by 46 ± 5% and
hypoglossal burst amplitude was increased by 26 ± 14% (average
of all 4 treatment groups; both P < 0.0001). Frequency
also exhibited a small, but significant, increase 30 and 60 min
posthypoxia (P < 0.05; Fig. 5C). There were
no significant differences between any of the treatment groups,
illustrating that chronic phrenicotomy and/or exercise had no
significant effects on LTF of phrenic or hypoglossal nerve amplitude.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We found no evidence to support the hypothesis that chronic
(unilateral) phrenicotomy enhances LTF of contralateral phrenic motor
output. Instead, the data suggest that chronic phrenicotomy exaggerates
PHFD, an effect that is offset by 1 mo of spontaneous exercise.
Furthermore, unilateral phrenicotomy exaggerated the posthypoxia return
of phrenic burst amplitude to baseline values (i.e., decreased STP), an
effect similarly offset by exercise. These results imply a complex
interplay between phrenicotomy and exercise in a mechanism possibly
associated with 2-adrenergic receptor activation
(2).
Phrenic and hypoglossal motor output: responses to hypoxia. In these studies, we recorded hypoglossal nerve activity as an indicator of changes in respiratory motor output not specifically associated with phrenic activity. Previous studies in cats (4) and rabbits (3) have shown that hypoglossal motor output is preferentially stimulated by hypoxia compared with phrenic motor output, suggesting that ventilatory drive is heterogeneously distributed among respiratory-related motoneuron pools. Recording from the phrenic and hypoglossal nerves of cats is problematic, however, because the CO2 apneic threshold for nerve activity is higher in the hypoglossal nerve (10). Thus, for any given level of CO2, hypoglossal motor output is stimulated more by hypoxia than phrenic motor output when analyzed as a percent change from (a lower) baseline nerve activity. In the present study, the CO2 apneic thresholds for phrenic and hypoglossal motor output were virtually identical. This allowed us the unique opportunity to compare hypoglossal and phrenic motor output in response to hypoxia without the confounding effects of variable CO2 apneic thresholds. Our results in rats confirm that the hypoglossal nerve is more responsive to hypoxia both during and immediately after the hypoxic exposure. This finding suggests that inputs to respiratory-related motoneuron pools may be heterogeneous in response to a given stimulus.
STD. STD of nerve burst frequency within an hypoxic episode (14, 30) was unaltered by phrenicotomy and/or chronic spontaneous exercise. STD of burst frequency was present in all treatment groups. This contrasts with Hayashi et al. (14), who observed STD of phrenic burst frequency during carotid sinus nerve stimulation but not during hypoxia in anesthetized rats. The difference between the two studies (both conducted in our laboratory) can probably be attributed to alterations in the gas-delivery system. A slow time course of hypoxic gas delivery, caused by low flow rates through long tubes, could effectively mask STD by blunting the acute increase in frequency that accompanies the onset of hypoxia. The present study coupled higher flow rates with shorter tubes than those used by Hayashi et al. to minimize gas dilution and maximize the speed of hypoxic gas delivery. These modifications resulted in an acute increase in burst frequency in response to hypoxia, followed by a gradual reduction in burst frequency toward a new steady-state level, similar to that observed after carotid sinus nerve stimulation (14).
PHFD and STP.
PHFD is a time-dependent decrease in nerve burst frequency below
initial baseline values after exposure to 5-min of moderate to severe
hypoxia. STP is a progressive increase in nerve burst amplitude during
the first 1-2 min of hypoxia as well as a progressive decrease in
burst amplitude when hypoxia ceases. PHFD can be blocked by electrical
lesions of the ventrolateral pons in the A5 noradrenergic area
(5). The response is also sensitive to
2-adrenergic-receptor antagonists (2),
although there is controversy surrounding this issue (6).
Chronic unilateral phrenicotomy enhanced the PHFD of phrenic and
hypoglossal motor output and blunts STP of phrenic burst amplitude
after hypoxic exposure. These effects suggests that unilateral
phrenicotomy alters the mechanism underlying PHFD and STP in rats,
possibly through denervation-induced changes in the noradrenergic
nervous system.
2-receptors in regions of the
brain and spinal cord relevant to respiratory control could be involved in the enhanced PHFD observed after phrenicotomy. Similarly,
2-receptors are upregulated in dorsal root ganglia after
peripheral nerve injury (34). Further experiments are
needed to determine whether 2-receptor densities
increase in neural structures relevant to the generation of respiratory
rhythm or in spinal segments affected by phrenicotomy.
One month of chronic voluntary exercise completely blocks the
exaggerated PHFD and the blunted STP of phrenic burst amplitude (posthypoxia) caused by chronic phrenicotomy, indicating that physical
activity can alter injury induced plasticity. Spontaneous exercise may
affect monoaminergic function directly, helping to offset the effects
of phrenicotomy on PHFD and STP. In the literature, chronic exercise
has inconsistent effects on resting central nervous system levels of
monoamines (22). Monoamines increase, decrease, or remain
unaltered depending on the type and duration of exercise and whether
the exercise was spontaneous or forced. For example, whole brain
norepinephrine concentrations increased in rats trained (forced)
to swim regularly for 17 wk (29). The synthesis and metabolism of brain stem serotonin also exhibited a significant increase after 4 wk of regular swimming (9). This increase was evident even 1 wk after termination of the training protocol. In
contrast, rats that ran voluntarily for 7 wk showed no significant increase in brain tissue serotonin levels (15), raising
the possibility that increased brain monoamine levels in rats trained (forced) to exercise may be caused by factors other than exercise per
se (e.g., stress hormones).
LTF. LTF of respiratory motor output is a long-lasting enhancement of phrenic and hypoglossal nerve burst amplitude and frequency observed after episodic exposure to isocapnic hypoxia (20, 30). LTF was unaffected by chronic phrenicotomy and/or exercise. This finding does not rule out the possibility that chronic phrenicotomy and/or exercise might enhance LTF under different circumstances. For example, it was difficult to control the distance and intensity of the rats physical activity because they exercised spontaneously. Exercise intensity could have been increased through dietary restriction (8) or a "forced" exercise regime. Alternatively, bilateral phrenicotomy would have completely denervated the diaphragm, increasing the overall functional deficit and, perhaps, the ensuing compensatory response. In addition, we conducted all experiments 1 mo after phrenicotomy. This recovery period was chosen on the basis of previous studies that demonstrated monoaminergic system alterations after 1 mo of recovery from cervical dorsal rhizotomy (18). Had the experiments been conducted at a different time postphrenicotomy, different findings may have been obtained.
Comparison with previous LTF studies. Overall, both LTF of phrenic and hypoglossal motor output and PHFD were reduced compared with previous studies on Sprague-Dawley rats (1, 17). This "blunted" short- and long-term response to hypoxia may be attributable to fundamental genetic differences between rat substrains used in different studies. Earlier experiments used Sprague-Dawley rats obtained from Sasco (Madison, WI) (1), whereas the present study used Sprague-Dawley rats obtained from Harlan. Morphological differences exist between the noradrenergic innervation of the spinal cord in Sasco vs. Harlan Sprague-Dawley rats (7, 32). In Sasco Sprague-Dawley rats, the locus coeruleus projects to the ventral horn (ipsilaterally), and in Harlan Sprague-Dawley rats, the locus coeruleus projects to the dorsal horn (bilaterally). This striking difference suggests that locus coeruleus neurons serve different physiological functions in these two substrains of rats and raises the possibility that other anatomic and, possibly, functional differences exist.
In summary, we discovered an unexpected model of ventilatory plasticity in respiratory motor output (exaggerated PHFD after 1 mo of recovery from unilateral phrenicotomy). Although our experimental preparation is unphysiological (anesthetized, paralyzed, vagotomized, ventilated rat) it allows us to examine and manipulate monoamine-dependent plasticity in the central nervous system in a way that is currently difficult in an awake, behaving mammal. We hypothesize that PHFD participates as part of a complex "push-pull" system with other forms of plasticity (e.g., LTF) that operate via different mechanisms to regulate ventilatory drive. This study illustrates that the balance between the two can be shifted, sometimes in favor of the inhibitory (possibly noradrenergic) mechanism (unilateral phrenicotomy) or against it (spontaneous exercise).| |
ACKNOWLEDGEMENTS |
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We thank Brad Hodgeman and Colleen Weinfurt for excellent technical assistance.
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FOOTNOTES |
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This study was supported by National Heart, Lung, and Blood Institute Grants HL-36780 and HL-53319 and by Neuroscience Training Program Grant GM-07507.
Address for reprint requests and other correspondence: K. B. Bach, Dept. of Comparative Biosciences, Univ. of Wisconsin, 2015 Linden Dr. West, Madison, WI 53706.
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.
Received 8 February 2000; accepted in final form 23 June 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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) in
phrenic and hypoglossal nerve amplitudes from unoperated-sedentary
rats. Values are means ± SE. Hypoxia was administered at
time 0 and maintained for 5 min, at which time data were
collected for another 5 min after hypoxia. Hypoglossal nerve burst
amplitude (
) is nearly twice as responsive to hypoxia
as phrenic nerve burst amplitude (
). Changes in nerve
burst amplitude are expressed as percent change from prehypoxic
baseline values. Because the CO2 apneic thresholds were the
same, data normalization in this way will not differentially affect the
curves. *Hypoglossal nerve response is significantly different from
phrenic nerve burst amplitude, both during and after hypoxia,
P < 0.01.
; n = 12), and
phrenicotomized-sedentary (
; n = 6)
rats. Changes in burst frequency are expressed as change from
prehypoxic baseline values. No significant difference was seen in
short-term depression between any treatment groups. No significant
differences in phrenic burst amplitudes (B) were observed in
any treatment groups (expressed as percent change from prehypoxic
baseline values). *Values at 5 min were significantly different from
values at 50 s in all experimental groups, P < 0.05.
