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Department of Physical Therapy, Exercise, and Nutrition Sciences, State University of New York at Buffalo, Buffalo, New York 14214-3079
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Obesity is often associated with a reduced
ventilatory response and a decreased maximal exercise capacity. GABA is
a major inhibitory neurotransmitter in the mammalian central nervous
system. Altered GABAergic mechanisms have been detected in obese Zucker rats and implicated in their hyperphagic response. Whether altered GABAergic mechanisms also contribute to regulate ventilation and influence exercise capacity in obese Zucker rats is unknown and formed
the basis of the present study. Eight lean [317 ± 18 (SD) g]
and eight obese (450 ± 27 g) Zucker rats were studied at 12 wk of age. Ventilation at rest and ventilation during hypoxic (10%
O2) and hypercapnic (4% CO2) challenges were
measured by the barometric method. Peak O2 consumption
(
O2 peak) in response to a progressive
treadmill test to exhaustion was measured in a metabolic treadmill.
Ventilation and O2 peak were assessed
after administration of equal volumes of DMSO (vehicle) and the
GABAA receptor antagonist bicuculline (1 mg/kg). In lean animals, bicuculline administration had no effect on ventilation and
O2 peak. In obese rats, bicuculline
administration significantly (P < 0.05) increased
resting ventilation (465 ± 53 and 542 ± 72 ml · kg
1 · min1 for control
and bicuculline, respectively), ventilation during exposure to hypoxia
(899 ± 148 and 1,038 ± 83 ml · kg1 · min1 for control
and bicuculline, respectively), and
O2 peak (62 ± 3.7 and 67 ± 3.5 ml · kg0.75 · min1 for
control and bicuculline, respectively). However, in obese Zucker rats,
ventilation in response to hypercapnia did not change after bicuculline
administration (608 ± 96 vs. 580 ± 69 ml · kg1 · min1). Our
findings indicate that endogenous GABA depresses ventilation and limits
exercise performance in obese Zucker rats.
respiration; exercise; 
-aminobutyric acid; bicuculline; obesity
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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RECENT INVESTIGATORS have established important links between altered central neural pathways and regulation of obesity. There is, however, a lack of studies investigating whether altered neural mechanisms also influence control of breathing in obesity. The obese Zucker rat, a model of morbid obesity, presents many of the same deficits noted in obese humans, including reduced lung function, increased chest wall limitations, blunted ventilatory responses, and reduced exercise capacity (2, 9, 22, 34). Reduced ventilation in response to hypoxic or hypercapnic exposures is observed in some obese humans and in obese Zucker rats (22, 33, 34, 39). The underlying mechanisms responsible for the depressed ventilatory responses in obesity are unknown but are thought to represent part of the pathogenesis of obesity hypoventilation syndrome (OHS) (33, 39).
GABA, a major inhibitory neurotransmitter in the mammalian central nervous system (CNS) (4), is known to reduce resting ventilation, ventilation during hypoxic exposure, and metabolic function (13, 18, 20, 27). During hypoxic challenges, brain GABA levels increase (19, 37) and have been shown to exert an inhibitory modulatory effect during the late hypoxic ventilatory response (16, 27, 37). Despite elevations in brain GABA levels during hypercapnic challenges (15), the role of GABA as a neuromodulator of the hypercapnic ventilatory response is less well established, although a study did note that hypothalamic GABAergic mechanisms are involved (30).
The obese Zucker rat presents accelerated synthesis of GABA in the hypothalamus and brain stem (28) and possesses altered brain GABAergic mechanisms that contribute to their overeating (7, 28). The role of GABA in mediating breathing control or exercise regulation in obesity has, to our knowledge, not been previously investigated. Whether altered GABAergic mechanisms modulate ventilation and exercise capacity in obese Zucker rats is unknown and formed the basis of our study.
Because obese Zucker rats are known to possess altered brain
GABAergic mechanisms, we hypothesized that ventilation and maximal exercise capacity in obese Zucker rats would also be modulated by a
GABAergic mechanism. Because GABA is known to inhibit respiratory activity predominantly via GABAA ionic receptors
(12), bicuculline, a selective GABAA receptor
antagonist, was used to investigate whether endogenous GABA
modulates ventilation at rest, ventilation during hypoxic exposure,
ventilation during hypercapnic exposure, and peak O2
consumption (O2 peak) in obese Zucker
rats. Studies were conducted after administration of equal volumes of vehicle (DMSO) or bicuculline. The agents were given in a
blinded-randomized design with 72 h of recovery between successive
ventilatory or O2 peak tests. A
parallel study design was used, with lean age-matched Zucker rats
serving as controls.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. The studies were performed on eight lean (Fa/?) and eight obese (fa/fa) age-matched male Zucker rats. Animals were purchased from Vassar College (Poughkeepsie, NY) at 4 wk of age. One lean and one obese rat were housed per cage. Ambient temperature was maintained at 21°C, and an artificial 12:12-h light-dark cycle was set. The light period began at 7 AM. Standard laboratory chow (Ralston Purina, St. Louis, MO) and water were provided ad libitum. All protocols were approved by the Institutional Animal Care and Use Committee of the State University of New York at Buffalo. Animals underwent testing at 12 wk of age.
Pulmonary ventilation.
Breathing pattern was recorded by the barometric technique of
plethysmography (22, 24, 34). A cylindrical Plexiglas chamber with a volume of 4 liters was used for the measurement of
breathing pattern. The rat was placed in the chamber within a
restrainer that did not allow backward rotation. A flow of gas through
the chamber was provided by a wall-mounted compressed air source
(during the preliminary habituation period and for washout; see
Experimental protocol) or from pressurized gas tanks (BOC
Gases). Inlet flow was regulated by a flowmeter (Dwyer Instruments, Michigan City, IN) and maintained steady at 1.5 l/min during
measurement of gas exchange but raised to 4 l/min for a few minutes to
aid washin at the time of changeover of the gas mixture. The chamber was completely sealed after momentary interruption of the flow through
it, and the oscillations in pressure caused by breathing were recorded
by a sensitive pressure transducer (model PT5, Grass Instruments,
Quincy, MA). The signal was received and amplified by a Grass DC driver
(model 7PCPA) and displayed on an oscillographic strip-chart recorder
(model 7 polygraph, Grass Instruments). An average of 80 breaths was
recorded on chart paper at a speed of 10 mm/s. Injection and withdrawal
of 0.3-ml volumes were performed 
12 times during the recording, for
calibration purposes. Barometric pressure to the nearest 1 h was
obtained from the Internet posting of the US Weather Bureau located at
the Buffalo International Airport.
30 successive breaths. Pulmonary ventilation
(E and E/kg) was also calculated (E = VT × f) and expressed at body
temperature and water-saturated conditions (E in
ml/min BTPS and E/kg in
ml · kg1 · min1
BTPS). Colonic temperature was measured continuously from a
rectal probe (Tele-thermometer, Yellow Springs Instruments, Yellow
Springs, OH) and taken as representative of body temperature
(Tb). Chamber temperature and humidity were monitored by
means of a flow-through probe (Fisher Scientific, Pittsburgh, PA)
mounted within the chamber. The rat was placed into the chamber and
exposed to room air (21% O2-balance N2) for 30 min, hypoxia (10% O2, balance N2) for 20 min,
room air for 15 min, and hypercapnia (4% CO2-23%
O2-balance N2) for 10 min. Ventilatory patterns
were recorded at the end of 30 min in room air, at 10 and 20 min during
the hypoxic exposure, and at the end of the hypercapnic exposure.
O2 peak.
The exercise test to elicit peak aerobic activity
(O2 peak) was performed in a metabolic
treadmill (Columbus Instruments, Columbus, OH). To maintain a constant
flow rate, airflow through the metabolic treadmill was provided from
pressurized air tanks (BOC Gases). Flow was controlled by a flowmeter
(Dwyer Instruments) and maintained steady at 5 l/min throughout the
exercise test.
O2 peak were slightly different for
lean and obese rats. The treadmill slope was set at 20% for lean
animals and 10% for obese animals and remained constant throughout the
exercise test. After injection, each rat was placed into the metabolic
treadmill for 30 min before initiation of the exercise test. The
protocol for lean animals consisted of an initial speed of 10 m/min
followed by a 3 m/min increase in speed every 2 min until the animal
could no longer continue to run. Obese rats began at 10 m/min followed
by a 3 m/min increase every 3 min.
O2 uptake and
CO2 output.
O2 uptake (O2) and
CO2 output (CO2) were
measured in the barometric chamber or during the exercise test. The
concentrations of the chamber (barometric or treadmill) inflowing or
outflowing CO2 and O2 were monitored by
CO2 and O2 gas analyzers (models CD-3A and
S-3A/1, respectively, Ametek Applied Electrochemistry, Sunnyvale, CA)
arranged in series. The calibrations and linearities of the gas
analyzers were checked twice daily using certified calibration gases
(BOC gases). O2 and
CO2 were calculated from the
inflow-outflow O2 and CO2 differences
multiplied by the gas flow; the small error introduced by the
respiratory quotient less than unity was neglected (11).
Data are presented at STPD, corrected for the effective
mass exponent according to Refinetti (32), and expressed
in kilograms to the power of 0.75 (ml
O2 · kg0.75 · min1
STPD). Effective body mass (EBM) was calculated as 1.00 M0.75 and 0.86 M0.75 for lean and obese
animals, respectively (32). EBM was used to minimize
differences in adipose tissues between lean and obese rats.
O2 peak was expressed in absolute terms
(ml O2/min STPD) and in relative terms,
corrected for total body mass (ml O2 · kg1 · min1
STPD) and for EBM (ml
O2 · kg0.75 · min1
STPD).
Experimental protocol.
Animals were tested 30 min after a subcutaneous injection of equal
volumes (1 ml/kg) of DMSO (vehicle) or bicuculline (1 mg/kg). Bicuculline effects are noted within 10 min of injection and last for
>2 h in rodents (27, 38). The present studies were
carried out 30 min after injection and completed within 75 min of
injection. The solutions were prepared daily and placed in vials
labeled solutions I and II. The agents were given
in a blinded design and randomized order. The investigators involved in
the actual testing remained blinded to the contents of the vials until
the ventilatory and exercise tests were completed and analyzed.
Ventilation and exercise tests were performed on four separate
occasions with a 72-h recovery period between successive tests. Four
lean and four obese Zucker rats underwent ventilatory test on
days 1 and 4 and exercise test on days
7 and 10; the remaining four pairs underwent
ventilatory test on days 2 and 5 and exercise
test on days 8 and 11. Thus ventilatory and
exercise tests were completed within a 2-wk period. In an attempt to
minimize any stress during the study, all animals were habituated on
five separate occasions to the restraint device (80 min) and twice to
treadmill walking (10 m/min for 10 min) before the actual testing
period. To minimize any potential differences due to circadian rhythms,
each rat was injected and tested at exactly the same time on each
testing day.
Statistical analysis.
The planned comparisons with repeated-measures ANOVA under general
linear model in a one between (lean and obese) and two within (gases
and drugs) design were conducted to analyze all parameters. Body
weights of individual animals were averaged over the 2-wk experimental
period and tested by unpaired t-test between lean and obese
groups. Because of interactions among the three factors, the effects of
bicuculline on E, E/kg,
VT, VT/kg, f, Tb,
O2, CO2,
and O2 peak were subsequently tested as
a single group repeated measure with contrast transformation during
room air breathing, hypoxic exposure, hypercapnic exposure, and
exercise in lean and obese rats, separately. The contrast transformation is a useful approach when one level of the repeated measures is a control (i.e., DMSO) against which the others (i.e., bicuculline) are compared. In all cases, a difference at
P < 0.05 was considered statistically significant.
Values are means ± SD.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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At 12 wk of age, male obese Zucker rats weighed ~40% more than age-matched lean animals (450 ± 27 vs. 317 ± 18 g, P < 0.01, unpaired t-test).
Ventilatory parameters.
In lean animals compared with their control values (vehicle), all
ventilatory parameters (E, E/kg,
f, VT, and VT/kg) during room air breathing,
hypoxic challenges, and hypercapnic challenges were unaltered after
administration of bicuculline (Tables 1 and 2). E/kg, f, and
VT/kg during room air breathing, 10% hypoxic exposure, or
4% hypercapnic exposure are shown for individual animals in Fig.
1.
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E and E/kg) and
tidal volume (VT and VT/kg) after bicuculline administration. Bicuculline administration significantly increased resting ventilation by 17% compared with control values and was attributed to an increase in VT (Table 1). Similarly, the
ventilation during hypoxic exposures also increased in obese rats after
bicuculline administration. Bicuculline administration significantly
increased ventilation during hypoxic exposures by 15% and was also
attributed to an increase in tidal volume (Table 2).
E/kg, f, and VT/kg are shown for
individual animals in Fig. 1. These changes in ventilation after
bicuculline administration were not related to changes in metabolic
rates (Table 1). Ventilatory parameters measured in response to the
hypercapnic gas challenge were unaffected in the obese Zucker rats
after administration of bicuculline (Table 2, Fig. 1).
Tb was measured continuously throughout the ventilatory
measurements. After administration of bicuculline, lean Zucker rats revealed a small, but significant, drop (
0.2°C, P < 0.01) in Tb. In lean rats, decreased Tb
after bicuculline administration was noted in eight of eight paired
measurements during room air breathing, seven of eight observations
during hypoxia, and eight of eight observations during hypercapnia. In
contrast, Tb was not altered in obese Zucker rats by
bicuculline administration (Tables 1 and 2).
Exercise test (O2 peak).
Consistent with the ventilatory data,
O2 peak was unaltered after bicuculline
administration in lean animals compared with control values (Table
3, Fig.
2). In obese Zucker rats, however,
bicuculline administration increased
O2 peak. The average increase in
O2 peak for all eight obese animals after bicuculline administration was ~8% compared with control (62.2 ± 3.7 vs. 66.8 ± 3.5 ml · kg0.75 · min1,
P < 0.05, single-group repeated measures). The effect
of bicuculline administration on
O2 peak is shown graphically for
individual lean and obese animals in Fig. 2.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Our major findings can be summarized as follows. 1)
Antagonism of GABAA receptors does not change ventilation
at rest or during ventilatory challenges in lean Zucker rats.
2) Breathing at rest in obese Zucker rats is modulated by
endogenous GABA acting on GABAA receptors. 3)
Ventilation during hypoxic, but not hypercapnic, exposure is modulated
by endogenous GABA acting on GABAA receptors in obese
Zucker rats. 4) Antagonism of GABAA receptors in
obese, but not in lean, Zucker rats leads to increased
O2 peak.
GABA is the major inhibitory neurotransmitter in the mammalian CNS and
acts at ~25-40% of the synapses within the CNS
(4). GABA can exert its effect via ionotropic
(GABAA and GABAC) receptors to produce fast
synaptic inhibition or metabotropic (GABAB) receptors to
produce slow, prolonged inhibitory signals (6). GABA may be involved as a neurotransmitter in the generation, transmission, and
modulation of respiratory-related neural activities (12-14, 18, 20). In the present study, bicuculline, a selective
antagonist of GABAA receptors, was chosen, because previous
studies have shown that GABA inhibits respiratory activity mainly via
GABAA receptors (12). In GABAergic neurons,
GABAA receptors facilitate Cl flux into
neurons, resulting in hyperpolarization, whereas antagonism of
GABAA receptors by bicuculline will decrease
Cl flux, resulting in depolarization and increased
excitation (6, 18). Thus any effect noted in the present
study is restricted to a modulatory role exerted by endogenous GABA
acting specifically on GABAA receptors. GABAA
receptors are located throughout the neural axis and modulate numerous
systems. In the present study, bicuculline was injected systemically,
which consequently produced a widespread antagonistic action. Thus any
effect noted here cannot be localized to any specific system or brain
region. The goal of the present study, however, was to determine
whether GABAergic mechanisms regulate ventilation and exercise capacity
in obese Zucker rats. Clearly, additional experiments using a
reductionist approach are required to specifically identify those brain
areas that are directly responsible.
In the present study, baseline (DMSO) ventilatory and metabolic values (Table 1) for lean and obese rats are within the range of previously published values (22, 24). In the present study, comparisons of ventilation between lean and obese animals are complicated by the large differences in body weight and body composition. However, in the present study, our primary purpose was to assess the role of GABA in modulating ventilation. Thus lean and obese rats were used as their own control, such that weight differences between both groups are inconsequential.
In lean rats, bicuculline administration did not alter resting
ventilation, ventilation during hypoxic exposure, ventilation during
hypercapnic exposure, or O2 peak.
Indeed, in normal human subjects, increasing brain GABA concentration
by administration of vigabatrin, an agent that prevents the breakdown
of GABA, had no effects on resting ventilation or on chemical
ventilatory drive (10). Thus, consistent with the human
literature, GABA does not exert a significant effect on control of
respiration in normal-weight rats. In lean Zucker rats, however,
bicuculline administration did induce a small, but long-lasting,
decrease in Tb (Table 1), providing indirect evidence that
bicuculline's effect persisted during the entire testing period. At
the dose selected, no other side effect, such as bicuculline-induced
seizures or increased mortality (38), was noted.
In contrast, bicuculline administration elevated resting ventilation,
ventilation during hypoxic exposure, and
O2 peak in age-matched obese Zucker
rats. The obese Zucker rat presents accelerated synthesis of GABA in
the brain stem (28) and possesses altered brain GABAergic
mechanisms (7, 28). After 8 wk of chronic artificial
respiratory loading in rats, brain GABA levels are increased and
responsible for depressing ventilation (31). Thus the
increased chest wall loading or airway narrowing that is present in
obesity (2, 9) may represent a possible stimulus responsible for the altered GABAergic mechanisms. In the present study,
bicuculline administration significantly increased resting ventilation
in obese rats, which was attributed to an increase in VT
and not f. The selective effect on VT is consistent with previous reports indicating that direct exogenous central
administration of GABA or GABAA receptor agonist produces a
dose-dependent depression in respiratory amplitude with only minor
effects on f (14, 20). In obese Zucker rats, systemic
administration of bicuculline increased ventilation without any
observed changes in surrounding CO2 level, metabolic rate
(O2), or Tb. In anesthetized
dogs, Kneussl and colleagues (20) reported that centrally
administered GABA decreased ventilation and metabolic rate. In a second
study, Kneussl and colleagues (21) further showed,
however, that the reduction in metabolic rate was independent of the
central effects of GABA on respiration. Our results also support the
concept that GABAergic modulation of ventilation is independent of
metabolic rate or Tb.
During hypoxia, the respiratory drive is determined by a balance between the stimulation of peripheral chemoreceptors and the central depression of hypoxia on respiration (35). It has been postulated that the late phase of the ventilatory response to hypoxia is modulated by a variety of neurotransmitters, including GABA (18, 35). Brain GABA content is elevated during hypoxic (37) and hypercapnic exposures (15, 19). The rise in ventilation after treatment with bicuculline during hypoxia is consistent with previous studies in anesthetized cats (27), sedated newborn piglets (16), or anesthetized rats (35).
During hypercapnia, the respiratory drive is primarily determined by central chemoreceptors, which respond to changes in H+ concentration. In the present study, bicuculline administration had no effect on ventilation during 4% hypercapnia in lean and obese animals. It has been previously reported that intracerebroventricular administration of GABA did depress an increased ventilation during 10% CO2 exposure (13), indicating that the preexisting GABAergic modulation at rest was not directly mediated by GABAA receptors but compensated by central chemical drive or neutralized by increased CO2/H+ (15). The ventilation during hypercapnic exposure in lean and obese Zucker rats is not modulated by GABAA receptors.
Relative O2 peak
(ml · kg0.75 · min1) was
reduced in the obese animals compared with the lean animals (Table 2),
mirroring findings in obese humans (2). Bicuculline
administration led to an increase in
O2 peak in obese animals and lessened the difference between lean and obese animals. Thus endogenous GABA,
which tonically inhibits O2 peak in
obese animals, may partially account for their poor exercise capacity.
The underlying mechanism of GABAergic inhibition on
O2 peak is unknown. To our knowledge,
there has been no study specifically on the role of GABA in
O2 peak, but the effect of GABA on
running time to exhaustion in normal-weight rats was investigated in
two studies: muscimol, a GABAA receptor agonist, injected
directly into the posterior hypothalamus, significantly decreased
treadmill run time to exhaustion (29), whereas baclofen, a
GABAB receptor agonist, enhanced endurance time to
exhaustion (1). Does exercise contribute to an increase in
brain GABA content? Striatal GABA levels remain unchanged after
short-term exercise in rats (25), whereas whole brain GABA
content is reduced after prolonged exercise in rats (5).
Whether GABA levels during exercise in obese rats are different from
those in lean rats is unknown, and additional studies using
microdialysis in free-running rats are required to provide an answer.
The increase in O2 peak after
bicuculline administration may, however, be secondary to improved
ventilatory function. Although the respiratory system is not normally
considered a limiting factor to peak exercise, this may not be so in
certain pathological situations that affect the respiratory system,
such as aging, lung disease, and obesity (2, 36). The mass
loading due to fat deposition in and around the chest, coupled with the reduced ventilatory drive, may restrict ventilation during exercise. Thus we can speculate that, after bicuculline administration, the
increased respiratory drive resulted in the obese rats attaining a higher ventilation and a concomitant higher
O2 peak. At present, however, we have
no means of measuring ventilation during maximal exercise in obese
rats. Nevertheless, we conclude that reduced exercise capacity in obese
Zucker rats may be attributed to altered GABAergic mechanisms.
Significance. OHS is the combination of extreme obesity, somnolence, hypoventilation, arterial desaturation and hypercapnia, and pulmonary hypertension (33). The precise underlying pathophysiology of OHS is unclear and involves multiple factors, including impaired respiratory control, respiratory muscle weakness, abnormal respiratory load compensation, and chest wall limitations (3, 33, 39). The depressed chemical ventilatory drive is one recognized theory to explain the pathogenesis of OHS (33, 39). Although a role of GABA in OHS has not, to our knowledge, been previously proposed, the present results suggest that GABAergic tonic inhibition may be potentially responsible. In addition to GABA, complex interactions among the various neurotransmitters and neuromodulators involved in the etiology of obesity, such as leptin, neuropeptide Y, dopamine, opioids, adenosine, and several hormones (23), may directly or indirectly be involved in GABAergic regulation. Additional studies are required to address the role of GABAergic mechanisms in morbidly obese humans.
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ACKNOWLEDGEMENTS |
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The present study was supported by National Institute on Aging Grant AG-16048 and the American Lung Association. G. A. Farkas is the recipient of a Career Investigator Award from the American Thoracic Society.
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FOOTNOTES |
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Address for reprint requests and other correspondence: G. A. Farkas, Dept. of Physical Therapy, Exercise, and Nutrition Sciences, 405 Kimball Tower, University of Buffalo, 3435 Main St., Buffalo, NY 14214-3079 (E-mail: farkas{at}acsu.buffalo.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.
Received 3 April 2000; accepted in final form 1 December 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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) and
obese (
) Zucker rats in room air, 10% O2,
or 4% CO2. Solid line, line of identity. Symbols above
line of identity represent animals whose ventilatory parameters
increased after bicuculline administration; symbols below line
of identity represent animals whose ventilatory parameters
decreased after bicuculline administration.
