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1 Departamento de Fisiologia, Faculdade de Medicina de Ribeirão Preto and, 2 Departamento de Morfologia, Estomatologia e Fisiologia, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hypoxia causes
hyperventilation and decreases body temperature (Tb) and
metabolism [O2 consumption
(
O2)]. Because dopamine (DA) is
released centrally in response to peripheral chemoreceptor stimulation,
we tested the hypothesis that central DA mediates the ventilatory,
thermal, and metabolic responses to hypoxia. Thus we predicted that
injection of haloperidol (a DA D2-receptor antagonist) into
the third ventricle would augment hyperventilation and attenuate the
drop in Tb and O2 in
conscious rats. We measured ventilation, Tb, and
O2 before and after
intracerebroventricular injection of haloperidol or vehicle (5% DMSO
in saline), followed by a 30-min period of hypoxia exposure.
Haloperidol did not change Tb or
O2 during normoxia; however, breathing
frequency was decreased. During hypoxia, haloperidol significantly
attenuated the falls in Tb and
O2, although hyperventilation persisted.
The present study shows that central DA participates in the thermal and
metabolic responses to hypoxia without affecting hyperventilation,
showing that DA is not a common mediator of this interaction.
haloperidol; ventilation; body temperature; metabolism; awake rats
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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RESPIRATORY, THERMAL, and metabolic adjustments have been reported to attenuate changes in O2 supply during hypoxia (3). At first sight, these responses appear to occur in opposite directions, i.e., increases in ventilatory drive and decreases in metabolism and body temperature (Tb) (13). However, this impression may reflect the complexity of the still unknown mechanisms and neuromodulators involved in these responses.
Goiny et al. (16) reported dopamine (DA) accumulation in
the nucleus tractus solitarius (NTS) in response to peripheral chemoreceptor stimulation in rabbits and attributed this accumulation to the roll-off phenomenon of the biphasic ventilatory response to
hypoxia. This response consists of an early rise in ventilation () followed by a subsequent decline or roll-off from peak values (34). The roll-off is thought to be of central
origin because chemoreceptor output does not change during its
occurrence (32). In addition, Long and Anthonisen
(26) reported that systemic administration of haloperidol,
a DA D2-receptor antagonist that crosses the blood-brain
barrier, decreases the roll-off in awake cats, supporting the notion
that DA in the brain stem may influence sustained hypoxic hyperventilation.
No reports are available about the role of DA in the mediation of Tb reduction during hypoxia. However, several studies show that DA may be involved in thermoregulation, because agonists cause hypothermia (27, 30). If the roll-off of the hypoxic ventilatory response coincided with the drops in Tb and metabolism, the respiratory and metabolic interaction during hypoxia would no longer be conflicting and DA would be a potential candidate to play a role in this interaction. However, the biphasic ventilatory response to hypoxia is not a universal response. It is consistently found in neonates and anesthetized adult animals (34), but only conscious adult humans (10), cats (35), and squirrels (3) have been reported to exhibit this response. In addition, studies using systemic haloperidol could not exclude its effects on the periphery, specifically on the carotid bodies, where DA is released during hypoxia (17).
With the objective to elucidate the interaction between ,
Tb, and metabolism during hypoxia in awake rats, we tested
the hypothesis that central DA mediates simultaneously the ventilatory, thermal, and metabolic responses to hypoxia so that hyperventilation will be augmented and the reductions in Tb and metabolism
will be attenuated by haloperidol administration into the third ventricle.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Experiments were performed on adult male Wistar rats (Rattus norvegicus, Rodentia: Muridae) weighing 274.0 ± 12.0 g, housed at controlled temperature (25 ± 1°C), and exposed to a daily 12:12-h light-dark cycle. The animals were allowed free access to water and food. The rats used in this study were divided into five major groups: 1) central haloperidol injection (n = 7), 2) central vehicle injection (n = 5), 3) intravenous (IV) haloperidol injection (n = 5), 4) IV vehicle injection (n = 5), and 5) a control group (n = 8).Surgery
Animals were submitted to general anesthesia with intraperitoneal administration of 2,2,2-tribromoethanol (250 mg/kg; Aldrich, Milwaukee, WI). Rats of the central haloperidol and vehicle injection groups were fixed in a stereotaxic frame and implanted with a stainless steel guide cannula (0.7 mm OD) into the third ventricle (coordinates: anterior
0.4 mm, lateral 0 mm, dorsal 7.8-8.5 mm) for intracerebroventricular (ICV) administration. The displacement of
the meniscus in a water manometer ensured correct positioning of the
cannula in the third ventricle. The cannula was attached to the bone
with stainless steel screws and acrylic cement. A tight-fitting stylet
was kept inside the guide cannula to prevent occlusion. In the animals
of the IV haloperidol and vehicle injection groups, a catheter was
inserted into the femoral vein, tunneled subcutaneously, and
exteriorized through the back of the neck. Animals of all groups were
submitted to paramedian laparotomy for the insertion of a biotelemetry
capsule (model VM-FH, Mini-Mitter, Sunriver, OR) into the peritoneal
cavity. The wound was then closed, and the implanted capsule was used
for Tb measurement. At the end of the surgical procedures,
animals received 100,000 units of benzyl-penicillin. Only the latter
surgery was performed in the control group. Experiments were initiated
1 wk after surgeries in the ICV haloperidol or vehicle injection groups
and 2 days after surgeries in the IV haloperidol or vehicle injection
and control groups.
Determination of
were performed by the body
plethysmograph method (4).
During measurements, the flow was interrupted, the chamber was
sealed for short periods of time (~2 min), and the oscillations in
air temperature caused by breathing could be measured as pressure oscillations. This procedure was performed once during each time of
measurement. Signals from an air differential transducer (Validyne) were collected by a differential pressure signal conditioner (Gold), passed through an analog-to-digital converter, digitized in a
microcomputer equipped with data-acquisition software (Acquire 6600 data acquisition system, Gold Instrument Systems, Valley View, OH), and
then analyzed with data-analysis software (Windaq). Calibration for
volume was obtained during each experiment by injecting the animal
chamber with a known amount of air (1 ml) using a graduated syringe.
Two respiratory variables were measured, respiratory frequency (f) and
tidal volume (VT), the latter being calculated by the
formula VT = PT/PK × VK × [Tb × (PB PC)/Tb × (PB PC) TC × (PB PR)], where PT is the pressure deflection associated with each VT, PK is the pressure
deflection associated with injection of the calibration volume (VK),
PB is the barometric pressure, PC is the vapor
pressure of water vapor in the animal chamber, TC is the
air temperature in the animal chamber, and PR is the vapor
pressure of water at Tb. was calculated by multiplying f by VT. and VT are
presented at the ambient barometric pressure, at Tb, and
saturated with water vapor at this temperature (BTPS).
Determination of Tb
Tb was measured by biotelemetry. The animal chamber was placed on the RLA 3000 telemetry receiver (Mini-Mitter). The output of the receiver displayed the pulse frequency of the transmitter capsule and the corresponding Tb in a microcomputer containing appropriate software (Vital View).Determination of Oxygen Consumption
Oxygen consumption (O2) was
measured with a closed-flow system using an oxygen analyzer (type
OA.272, Saylor Servomex). Each time O2
was measured, the flow was interrupted, the chamber was sealed, and six
samples of chamber air (30 ml) were taken at 2-min intervals and passed
through the O2 analyzer. Therefore, the chamber remained
sealed for 10 min, the time needed to collect sufficient data to obtain
accurate slopes. Assuming a respiratory exchange ratio (CO2
production/O2) of 0.8, which is a
general rule for air breathers (9), and considering the
measured O2, at the end of the 10-min
period the CO2 level inside the chamber will be ~0.6%.
Our laboratory has previously shown that hypercapnia, even at high
levels of 5 and 10% CO2, does not alter the
O2 of rats (2). A curve of
%O2 evolution was constructed, and its slope gave the
value of O2. This metabolic variable is
reported at STPD.
Experimental Protocol
Measurements of and Tb were made in the same
set of experiments, whereas O2 was
obtained in a separate experiment. Animals were exposed first to
humidified room air and then to a humidified hypoxic poikilocapnic gas
mixture containing 7% O2 (AGA). Each animal was exposed to
hypoxia only once and received only one injection of haloperidol or
vehicle. Experiments were carried out randomly between 8:00 AM and 1:00 PM.
Determination of the effect of hypoxia on ,
Tb, and O2.
One week after biotelemetry capsule implantation, control group animals
were individually placed in a Plexiglas chamber (5 liters) and allowed
to move about freely while the chamber was flushed with humidified air.
After the animals remained calm (~30 min), control and
Tb were measured, and the test gas mixture (7% inspired
O2) was flushed through the chamber for 30 min. and
Tb were measured after 30 min of hypoxia. The same
procedure was repeated to measure O2
before and after hypoxia exposure.
Determination of the effect of haloperidol on ,
Tb, and O2 before and after
hypoxia.
Each animal in the vehicle and haloperidol groups was placed in the
same chamber, which was flushed with room air. After the animals
remained calm, control was measured, and Tb started to be continuously measured at 5-min intervals. Subsequently, experimental rats were treated with a haloperidol (Sigma Chemical) dose
of 0.5 µg/animal in 2 µl injected into the third ventricle or the
same dose in 0.25 ml injected intravenously, whereas the vehicle groups
received the same volumes of 5% DMSO in saline (150 mM NaCl). 5% DMSO
in saline was the vehicle in which haloperidol was dissolved.
was measured 5, 15, 20, 30, 40, and 50 min after haloperidol or vehicle
administration. Subsequently, the test gas mixture of 7% inspired
O2 was flushed through the chamber for 30 min. was
measured after 5, 15, 20, and 30 min during hypoxia. Finally, rats were
returned to a 30-min period of normoxic exposure, when was
measured again after 5, 15, 20, and 30 min.
O2. The haloperidol dose
and period of time after its injection were chosen on the basis of
previous studies (21, 26), with the objective to use a low
but effective dose, to avoid sedative effects and to obtain a
steady-state response of all variables measured, considering the long
half-life of the drug. Because haloperidol induces catalepsy (a failure
to correct an externally imposed posture), at the end of each
experiment, animals were submitted to a catalepsy test
(12) to ascertain the effectiveness of the drug. Thus
animals were grasped gently, and their front paws were placed over a
horizontal 10-cm-high bar. The time until both forepaws touched the
floor or until the maximum time allowed in the experiment was reached
(5 min) was measured.
Data Analysis
The air convection requirement (ACR or/O2) was calculated from the
and metabolic mean values
(/O2) to determine whether
putative changes in metabolism would reflect in significant changes in
. To remove the effects of Tb alterations, the
values for were corrected for the fall in Tb using
a temperature coefficient called Q10, which is a fraction
of increase or decrease in a rate when temperature is increased or
decreased by 10°C; Q10 = 
, V2 is the
fictive that was being calculated, T1 is the
measured Tb, and T2 is the fixed Tb
(control value). Q10 values of 2 and 3 were assumed,
because they represent the normal range for most chemical and
physiological processes (e.g., Ref. 3).
Values are reported as means ± SE (unless otherwise stated). The
effects of drug treatment and time course of hypoxia on , VT, f, Tb, and
O2 were evaluated by two-way ANOVA. When
statistical differences were found, one way-ANOVA and the Tukey-Kramer
multiple-comparisons test were applied as a post hoc test.
Point-by-point comparisons between mean values were performed by
Student's t-test. Values of P < 0.05 were
considered to be significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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During the experiments, the mean chamber temperature was 24.4 ± 0.8°C (mean ± SD), and room temperature was 23.5 ± 0.7°C (mean ± SD).
Effect of Hypoxia on , Tb, and
O2
and decreases in Tb and
O2 after 30 min of hypoxia exposure compared with basal measurements in normoxia (Table
1).
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Effect of Haloperidol on , Tb, and
O2 Before and After Hypoxia
,
Tb, and O2 of rats in the
vehicle and haloperidol groups (Figs.
1-3
and Table 2) were similar to those of
control rats (Table 1). Under normoxic conditions, ICV or IV vehicle
injection did not elicit any significant changes in VT, f,
, Tb, or O2 (Figs.
1-3 and Table 2), whereas central haloperidol caused a drop in f,
which was significant 15 min after its injection (Fig. 1B).
During hypoxia, no significant difference in VT, ,
or even f was detected between the vehicle and haloperidol groups,
because hypoxia caused a similar sustained increase in VT,
f, and in all groups (Fig. 1 and Table 2). However, the
decreases in Tb and O2
induced by hypoxia observed in the control (Table 1) and vehicle groups
were attenuated in the central haloperidol group (Figs. 2 and 3) but
not in the IV haloperidol injection group. After hypoxia exposure, the
basal VT, , Tb, and
O2 values of all vehicle and haloperidol
groups were recovered within 30 min of normoxia, whereas f returned to the low value induced by ICV haloperidol injection.
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Changes in respiratory variables occurred concurrently with the fall in
Tb and metabolism. Thus calculations of the ratio of
to metabolism (ACR) and correction for Tb
fall provide information about the interaction of the variables. Figure
4 shows that ACR increased more in
animals of the vehicle group than in rats treated with haloperidol,
because of the attenuation in the O2
drop in the latter. Figure 5 shows that
the increase in corrected (Q10 = 2 or 3) due
to hypoxia was modestly higher than raw data and similar in both
groups, confirming that central haloperidol has no effects on .
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Although no difference in animal behavior was observed between the
vehicle and haloperidol groups, only rats treated with haloperidol
exhibited catalepsy at the end of each experiment (Table
3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study provides the first evidence that central DA is a neuromodulator involved in thermoregulation during hypoxia, because the drop in Tb and metabolism elicited by hypoxia was attenuated when central DA transmission was blocked with haloperidol. However, haloperidol did not affect the sustained hypoxic hyperventilation, indicating that DA has no effects on breathing regulation during hypoxia, at least in the unanesthetized rat that did not exhibit the biphasic ventilatory response to hypoxia. Moreover, the data also indicate that more than one neuromodulator is involved in the ventilatory and metabolic responses to hypoxia.
The basal (1, 2), Tb (1,
2), and O2 (2)
values of Wistar rats measured in the present study agree with previous
reports. As also shown in earlier studies with rats, hypoxia caused
hyperventilation (14) and drops in Tb
(5, 36) and O2
(13). In addition, hypoxia did not elicit a biphasic ventilatory response in the awake rats used in the present study, corroborating the data obtained by Gautier and Murariu
(14). Actually, the biphasic ventilatory response to
hypoxia seems to be consciousness state, age, and species dependent
(1, 14, 10, 34, 35). Demonstrating the effectiveness of
the haloperidol dose used in our study, all rats treated with the drug
showed catalepsy at the end of experiments, because 10 s of
immobility in the imposed posture are already considered significant
for Wistar rats (12). However, the dose that we used was
low enough to avoid sedative effects that could interfere with the
behavior of the animals and alter , Tb, or metabolism.
Effects of Central Haloperidol on Before and After
Hypoxia
There are many contradictory results in the available literature about
the role of DA in breathing regulation. Actually, some of several
studies that investigated the central effects of DA using systemic
administration of haloperidol reported that DA stimulates ventilatory
responses to hypoxia (23, 31), whereas other studies found
that DA may attenuate hypoxic hyperventilation (26, 28,
32). Our study, which is the only one with the central injection
of haloperidol addressing this issue, detected none of these facts,
suggesting that any excitatory or inhibitory effect of DA may originate
in the periphery. The main site may be the carotid bodies, where DA is
released from glomus cells during hypoxia exposure (17).
Although most studies reported that DA in the carotid body has an
inhibitory effect, because tonic D2-receptor blockade with
domperidone increases carotid sinus nerve activity (23,
33), excitatory actions may exist. In fact, Hedner et al.
(21) reported that DA injected intravenously stimulates f
in anesthetized rats. Some of these opposing and complex results may be
explained by the fact that DA can activate both pre- and postsynaptic
D2 receptors in the carotid bodies (18), and
its inhibitory effect seems to be a feedback control of DA release
through presynaptic D2 receptors (17). In
addition, DA and its agonists are reported to inhibit carotid sinus
nerve discharges at low doses and to increase them at high doses,
whereas antagonists of DA seem to increase carotid sinus nerve
discharges at low doses and to inhibit them at high doses
(18). The affinity of DA presynaptic receptors is much
higher than that of postsynaptic receptors (18), and,
therefore, when haloperidol is injected peripherally at high doses, it
may have inhibitory effects on carotid bodies. Regarding another
peripheral effect of haloperidol that may influence the ventilatory
response to hypoxia, Tatsumi et al. (33) reported that
systemic blood pressure is decreased after IV haloperidol
administration (0.1 mg/kg), probably through the effects of the drug on
-adrenergic receptors. Several previous studies using systemic
injection of haloperidol to determine the central effects of DA have
used the same (26) or even higher doses (23, 24,
31).
Thus central DA seems to have a tonic excitatory role in resting f but
no significant effect on breathing during hypoxia. Hedner et al.
(21) showed that, when haloperidol or domperidone was
injected into the lateral ventricles of normoxic rats, at continuously
increasing doses, a depression of f was recorded at doses of 30 and 300 µg, whereas VT increased, and thus there was no
significant alteration or even a drop in . These results are
similar to those of the present study. In addition, animals in which
central DA neurons were destroyed at birth with intracisternally administered 6-hydroxydopamine show a decreased basal (e.g., Ref. 21). Actually, if data using central injection of DA
agonists and antagonists indicate that DA has excitatory effects on
in the central nervous system (CNS) during normoxia, it would be unusual if DA accumulation during hypoxia caused depression in
. Our data showing that central haloperidol has no effects on
breathing regulation during hypoxia suggest that the probable DA
released in the NTS does not actually act on breathing control of awake
rats but may be involved in other adjustments that may serve to
attenuate changes in the O2 supply, such as cardiovascular and thermal regulation (3). On the other hand, our data do not disagree with the idea that the DA is a crucial mediator involved in breathing regulation during hypoxia, especially concerning its
peripheral effects. A recent study on D2-receptor-deficient mice has provided strong evidence that DA participates in the hypoxic
ventilatory response, because of these animals was higher than
that of wild mice during acute hypoxia exposure (25).
Effects of Haloperidol on Tb and
O2 Before and After Hypoxia
Hasegawa et al. (20) measured an elevation in the level of DA metabolites in the preoptic area and anterior hypothalamus by microdialysis in rats submitted to treadmill exercise showing a sustained increase in Tb and suggested that DA is involved in the activation of heat loss mechanisms to prevent hyperthermia during exercise. Our data showing that central haloperidol attenuates the hypoxic anapyrexia are in agreement with the notion of a stimulatory effect of DA on heat loss mechanisms.
Because haloperidol blunted but did not abolish the drop in Tb induced by hypoxia, a cooperative action of other modulators may be necessary to trigger a full-blown hypoxic anapyrexia. In fact, recent data indicate that the role of the CNS in thermoregulation during hypoxia is subjected to numerous modifiers, such as adenosine (14), lactate (29), and opioids (14). Among them, nitric oxide seems to be a proximal mediator of several anapyretic stimuli (5, 7), which may suggest a common final pathway.
The attenuation of the Tb drop induced by hypoxia after
haloperidol treatment was accompanied by a reduction in
O2 drop. Because the drop in
Tb during hypoxia influences but is not the cause of the
O2 drop (3), central DA may
also affect regulation of metabolism. Actually, our laboratory reported
in a previous study that squirrels are able to maintain or elevate
their metabolic rates when ambient temperature is reduced during
hypoxia (7% O2), suggesting that O2 is not
limiting and that they can regulate their metabolism (3).
One possible site of central DA action to regulate metabolism during
hypoxia could also involve Tb regulation; i.e., DA may also
inhibit mechanisms of heat production. Thus further studies
are needed to assess the thermal and metabolic roles of DA in the
hypothalamus during hypoxic stress.
Conclusions
The present study shows that central DA affects thermal and metabolic responses to hypoxia without changing hyperventilation. Thus DA is not a common mediator of this interaction. Even the attenuation of hypoxia-induced drops in Tb and metabolism with haloperidol had no effect on breathing, as illustrated by Figs. 4 and 5. Both ACR and corrected were very similar between animals of
the vehicle and control groups. Although some modulators released by
hypoxia in the CNS may have simultaneous effects on respiratory and
thermoregulatory systems, such as adenosine (1) and nitric oxide (11), which attenuate hyperventilation and play a
role in Tb and O2 drops
during hypoxia, the present data indicate that other mediators, like
DA, may regulate each system independently. DA may act by stimulating
central mechanisms of heat loss and inhibiting those of heat
production, leading to a regulated drop in Tb and
metabolism, as a protective response to decreased O2 demand.
The contribution to the understanding of the interaction among ,
Tb, and hypoxia is essential, not only to the understanding of the strategies of animals that live in hypoxic conditions but also
to provide some insights concerning the protective effects of
hypothermia in experimental and clinical settings when the oxygen
supply is reduced.
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ACKNOWLEDGEMENTS |
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We thank Mauro F. Silva for excellent technical assistance.
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FOOTNOTES |
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This work was supported by Fundação de Amparo a Pesquisa do Estado de São Paolo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico, and Programa Nacional de Desenvolvimento de grupos de Excelência. R. C. H. Barros was the recipient of a FAPESP (98/02993-5) postgraduate scholarship.
Address for reprint requests and other correspondence: L. G. S. Branco, Avenida do Café s/no. 14040-904, Departamento de Morfologia, Estomatologia e Fisiologia, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil (E-mail: branco{at}forp.usp.br).
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.
10.1152/japplphysiol.00852.2001
Received 13 August 2001; accepted in final form 5 November 2001.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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) or vehicle (
) on tidal
volume (VT; A), respiratory frequency (f, in
breaths/min; B), and ventilation (
