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Departamentos de Fisiologia, Faculdade de Odontologia de Ribeirão Preto and Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, 14040-904 Ribeirão Preto, São Paulo, Brazil
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Hypercapnia elicits hypothermia in a number
of vertebrates, but the mechanisms involved are not well understood. In
the present study, we assessed the participation of the nitric oxide
(NO) pathway in hypercapnia-induced hypothermia and hyperventilation by
means of NO synthase inhibition by using
N
-nitro-L-arginine
(L-NNA). Measurements of
ventilation, body temperature, and oxygen consumption were performed in
awake unrestrained rats before and after
L-NNA injection
(intraperitoneally) and L-NNA injection followed by hypercapnia (5%
CO2). Control animals received saline injections. L-NNA altered
the breathing pattern during the control situation but not during
hypercapnia. A significant (P < 0.05) drop in body temperature was measured after both
L-NNA (40 mg/kg) and 5%
inspired CO2, with a drop in
oxygen consumption in the first situation but not in the second.
Hypercapnia had no effect on
L-NNA-induced hypothermia. The
ventilatory response to hypercapnia was not changed by
L-NNA, even though
L-NNA caused a drop in body
temperature. The present data indicate that the two responses elicited
by hypercapnia, i.e., hyperventilation and hypothermia, do not share NO
as a common mediator. However, the
L-arginine-NO pathway
participates, although in an unrelated way, in respiratory function and
thermoregulation.
body temperature; ventilation; carbon dioxide
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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A REDUCTION IN BODY TEMPERATURE (Tb) is generally observed when an animal encounters stress such as hypoxia (36) and hypercapnia (5). Although this response is extremely widespread among taxa (5), little is known about the potential mediators of hypothermia and also about the effect of Tb on the hypercapnic drive to breathe.
The endothelium-derived relaxing factor, which has been definitively
identified as nitric oxide (NO) (23), has started a revolution in the
understanding of several mammalian systems since its description in
1980 by Furchgott and Zawadzki (9). NO is an active regulatory molecule
at the periphery (23) and also serves as a neuronal messenger in the
brain (18). It is synthesized from
L-arginine, and the enzyme
responsible for this synthesis is NO synthase (NOS).
L-arginine analogs such as
N-nitro-L-arginine
(L-NNA) have been used as
inhibitors of NO synthesis. Compared with other analogs,
L-NNA crosses the blood-brain
barrier relatively easily and strongly inhibits NOS in the central
nervous system (cf. Ref. 34).
It has become increasingly clear that NO may play a role in ventilatory (12) and Tb (3) control in mammals. NOS is present in medullary and pontine respiratory regions (8), where a central respiratory neural network involving NO may exist. At the periphery, NO acts as an inhibitory transmitter in the carotid bodies (6). As to its temperature effects, NO plays a role in thermoregulation during exercise in horses (22) and acts as an endogenous antipyretic factor in endotoxin-induced fever in rabbits (11). Recently, it has been shown that NO participates in hypoxia-induced hypothermia (3).
No reports are available about the effect of NOS inhibition on hypercapnia-induced hyperventilation and hypothermia. Branco and Wood (5) demonstrated that hypercapnia causes behavioral hypothermia in the toad Bufo marinus and that this response is mediated by central chemoreceptors, i.e., at the same site where hypercapnia elicits hyperventilation not only in amphibians (4) but also in mammals (29). Because both responses to CO2 inhalation may share to some extent the same central sensor, they may also share some mediators, and NO seems to be a strong candidate. The purpose of the present study was to examine the role of the L-arginine-NO pathway in the hyperventilatory and hypothermic responses to CO2 inhalation of conscious rats.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Animals
Experiments were performed in awake adult male Wistar rats (Rattus norvegicus; Rodentia: Muridae), weighing 230- 300 g, housed under conditions of controlled temperature [25 ± 2 (SD) °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 two groups, an experimental group treated with a NOS blocker (L-NNA) and a control group (n = 8 rats) injected with saline. The experimental group was divided into three subgroups (n = 8 rats/subgroup), according to the NOS-blocker dose used.Ventilation (
E) Measurements
E were performed by the
body plethysmograph method (2). The animal was placed in a Plexiglas
chamber (5 liters) and allowed to move about freely while the chamber was flushed with humidified air or a normoxic hypercapnic gas mixture
of 5% CO2. Each time
E was measured, the flow was
interrupted and the chamber was sealed for short periods of time (no
more than 3 min), and the oscillations in air temperature caused by breathing could be measured as pressure oscillations. This procedure was performed once per experimental condition. Calibration for volume
was obtained during each measurement by injecting the chamber with a
known amount of air (0.2 ml) by using a graduated syringe. Signals from
a differential air transducer displayed on a paper recorder
(Hewlett-Packard) allowed the calculation of respiratory frequency (f) and tidal volume
(VT) by appropriate correction factors (20).
Tb Measurements
Tb was determined by inserting a thermocouple probe into the colon of the animals every time a Tb measurement was made. Before the experiments, the rats were habituated to temperature measurements, which were performed quickly to avoid any stress-induced elevations in Tb.O2 Consumption
(O2) Measurements
O2 was measured by using an
O2 analyzer (Saylor Servomex, type
OA. 272) in a closed-flow system. Animals were placed in the same
5-liter Plexiglas chamber ventilated with humidified air or a normoxic
hypercapnic gas mixture of 5%
CO2. At the end of the control or
experimental period, the flow was interrupted to perform the
measurements. The chamber was then totally sealed, and six samples of
chamber air (30 ml) were taken at 3-min intervals and passed through
the O2 analyzer. Therefore,
the chamber remained sealed for 15 min in each condition. This period
was needed to collect sufficient data to ensure good accuracy of
the slopes. A curve of %O2
evolution was constructed, and its slope was given the value of
O2. Because we obtained
resting O2 values agreeing with data in the literature, we concluded that this method was acceptable.
Experimental Protocols
Experiment 1: Measurements of E and
Tb.
Each animal was placed in the chamber flushed with room air. After the
animals remained calm (at least 30 min), control
Tb and then
E were measured.
Subsequently, experimental rats were treated with
L-NNA (Sigma Chemical) by
intraperitoneal bolus injection of 10, 20, or 40 mg/kg body weight, and
control rats were treated with the same volume of saline (150 mM NaCl).
Two hours after L-NNA or saline
administration, measurements of Tb
and E were obtained. Subsequently, a
normoxic hypercapnic gas mixture of 5%
CO2 (AGA) was flushed through the
chamber for 30 min. At the end of the experiment,
E and
Tb were measured again. Saline was
the vehicle in which L-NNA was
dissolved. The volume of each injection was 0.5 ml.
Experiment 2: Measurements of
O2.
Animals were placed in the chamber ventilated with room air for at
least 30 min until they remained quiet, and the basal
O2 was measured. The three
subgroups of rats received an intraperitoneal bolus injection of 10, 20, or 40 mg/kg body weight of
L-NNA, and the control group
received an intraperitonial injection of saline, and
O2 was measured 2 h later.
Subsequently, a normoxic hypercapnic gas mixture of 5%
CO2 was flushed through the
chamber for 30 min, and O2
was measured again.
Statistical Analysis
Values are reported as means ± SE (unless otherwise stated). The effect of saline or L-NNA injection onE,
VT, f,
Tb, and O2 was evaluated by using
one-way ANOVA. The Tukey-Kramer multiple-comparisons test
(E,
VT, f, and
Tb) and the Kruskal-Wallis test
(O2) were applied as post
hoc tests. Point-by-point comparisons of mean values before and after
hypercapnia 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
Materials & Methods
Results
Discussion
References
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During the two sets of experiments, the mean chamber temperature was
25.81 ± 0.69 (SD) °C, and room temperature was 24.62 ± 0.76°C. Individual values of
E,
Tb, and
O2 during air breathing and
before any injection ranged from 601.6 to 965.86 ml
BTPS · min
1 · kg1, from 36.10 to
36.70°C, and from 14.84 to 24.12 ml
STPD · min1 · kg1,
respectively, and no group differed significantly from the saline group
in baseline values.
Experiment 1
Figure 1 shows the pulmonaryE recordings obtained after saline or
L-NNA injections during air or
5% CO2 breathing. Animals treated
with the NOS blocker had a ventilatory response during air breathing
that consisted of episodes of many breaths separated by episodes of few
breaths. This response was dose dependent but not evenly distributed:
25, 50, and 62.5% of the animals treated with 10, 20, and 40 mg/kg,
respectively, showed this changed ventilatory pattern, whereas no rat
injected with saline was affected. No difference in animal behavior was
observed between control and treated groups. The breathing pattern was
recovered during CO2 inhalation,
when both groups, experimental and control, showed similar recordings.
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The NOS blockade tended to elicit a drop in f because of the
episodes of few breaths, but during the periods of many breaths both f
and VT tended to be higher
compared with control animals. As a result, the NOS blockade
tended to increase E in a dose-dependent way, but this elevation was not significant
(P > 0.05; 1-way ANOVA). Hypercapnia
caused similar increases (P < 0.05;
paired t-test) in
E in both the
L-NNA and saline groups (Table
1). Although E increases 226% with 40 mg/kg
L-NNA and 178% with 20 mg/kg L-NNA, this difference is not
significant (P = 0.1166; unpaired t-test).
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Figure 2 illustrates the effect of the NOS blocker on Tb during air or 5% CO2 breathing. When saline was injected intraperitoneally, no change in Tb was observed. Conversely, L-NNA injected at the 40 mg/kg dose elicited a significant reduction in Tb (P < 0.05; 1-way ANOVA) of 0.74 ± 0.05°C, whereas 10 and 20 mg/kg L-NNA caused no significant change. The changes in Tb caused by NOS blockade were not altered by hypercapnia. When inspired CO2 was increased from 0 to 5%, a significant (P < 0.05; paired t-test) decrease in Tb was observed in the saline group.
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Experiment 2
The individual curves of %O2 evolution showed accurate slopes, i.e., maximum changes observed were <5%. Figure 3 shows the effect of L-NNA onO2 during air or 5%
CO2 breathing.
O2 was significantly reduced
(P < 0.05; 1-way ANOVA) 2 h after
injection of 40 mg/kg of the NOS blocker. The lower doses tended to
decrease O2, but
the differences were not significant. Hypercapnia had no effect on
O2 in the animals injected
with saline and 10 and 20 mg/kg of
L-NNA
(P > 0.05; paired
t-test), whereas in the animals injected with 40 mg/kg of L-NNA,
the low O2 was recovered
during exposure to 5% CO2.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Teppema et al. (34) have recently addressed the effects of NOS inhibition on the peripheral and central chemoreflex loops during hypercapnia in anesthetized cats with clamped Tb. The present study provides evidence that the significant drop of 0.74 ± 0.05°C in Tb caused by NOS blockade has no effect on the hypercapnic drive to breathe in awake rats. As to Tb regulation, both hypercapnia and NOS inhibition are known to cause hypothermia, and we now show that the combination of these two stimuli is not additive because hypercapnia caused no further drop in Tb of the animals previously treated with L-NNA, indicating a possible link between the mechanisms of the two stimuli.
The basal values of E (2),
Tb (24), and
O2 (2) measured in the
present study support previously reported data. As in other studies
with rats, hypercapnia caused hyperventilation (1, 10), hypothermia (1,
10), and no change in O2 (1,
31) in the control situation.
Effects of L-NNA and Hypercapnia
on E
E probably by a
baroreceptor-mediated effect (cf. Ref. 34). NO is linked to
glutamatergic neurotransmission in the central nervous system (27, 34),
and activation of glutamate receptors in the nucleus tractus solitarii
and paragigantocellular nucleus is necessary to maintain normal levels
of E and also for a normal ventilatory CO2 response to occur (26). It has
been demonstrated that NO enhances the excitability and spontaneous
discharge rates of neurons in the nucleus tractus solitarii (19) and
that L-NNA produces a disruption
of the pneumotaxic mechanism (18).
In the present study we found an unusual ventilatory pattern during air breathing 2 h after L-NNA injection. Because this response was totally unexpected and was not the purpose of the study, some information cannot be provided with the present protocol and remains to be investigated, such as the duration of the abnormal ventilatory pattern, the time course of the dose-dependent response, and the situation during normoxia after CO2 breathing. Although no difference in animal behavior was observed between control and treated groups, we should not exclude the possibility of a toxic effect of the drug. This seems to be unlikely because the L-NNA doses in this study and even higher ones have been regularly used without problems regarding toxic effects (34, 35). Thus we continue to think that the changes observed in the present study may be caused by a specific effect of the drug on NO. Because we used systemic administration of a NOS inhibitor, the atypical breathing pattern probably resulted from a balance between the peripheral and mainly the central systems where NO synthesis occurs. This affirmation is based on the facts that L-NNA crosses the blood-brain barrier (34) and that the altered ventilatory pattern, with episodes of many breaths separated by episodes of few breaths that we may call short nonventilatory periods, occurred in a dose-dependent way, but not after saline administration (Fig. 1). Episodic breathing is a pattern in many ectothermic vertebrates that can occur in some species of mammals in states normally associated with metabolic depression, such as hibernation and sleep (15). The lack of NO produced a fictive breathing pattern that resembled the episodic one and may support the argument that respiratory control is a system highly conserved in vertebrates. Furthermore, the present study indicates that NO plays a major role in normal respiratory function in rats.
Hypercapnia induced similar E elevations
in control and treated groups, which resulted from the same strategy,
i.e., they were due to both VT
and f increases. It seems that an additional factor
(CO2) that stimulates the
respiratory center can counterbalance the effect of
L-NNA. Gozal et al. (12) also
found that NOS inhibition, by using
NG-nitro-L-arginine methyl ester and
S-methyl-L-thiocitrulline
injected intravenously, did not alter the overall ventilatory response to hypercapnia. However, changes in the ventilatory strategy consisting of VT decreases with parallel f
increases were reported. These contrasting data suggest that different
responses are likely to occur when different NOS blockers and different
pathways of drug administration are compared. Although the mechanisms
underlying these findings are unclear, NO does not seem to be important
for chemosensitivity per se but may play a role in neurons underlying normal functions of respiratory timing and amplitude (19, 18).
Effects of L-NNA and Hypercapnia on Tb
The NO pathway participates in many systems that can interfere with Tb control, including brown adipose tissue (25), vascular smooth muscle (33), and some areas of the central nervous system, especially the hypothalamus (7). An interesting event is that treatment with L-NNA caused a reduction in Tb (Fig. 2) despite the fact that L-NNA should decrease cutaneous heat loss because it causes vasoconstriction in both large and small arteries (33). Most likely, L-NNA elicits hypothermia by reducing brown fat blood flow (25), which may result in a drop in the firing rate of sympathetic nerves innervating interscapular brown adipose tissue (7). Thus the available data indicate that L-NNA, at least when injected systemically, may induce a more pronounced decrease in heat production (25) compared with the reduction in heat loss (33).A decrease in Tb during
hypercapnia has often been observed in several species, ranging from
amphibians (5) to mammals (31). The mechanisms responsible for
hypothermia are not well understood (36). Available data indicate the
existence of a number of modifiers, including NO, that act on the
central nervous system for Tb
control. Recently, the
L-arginine-NO pathway in the
central nervous system was shown to participate in hypoxia-induced hypothermia (3). We now report the involvement of NO in
hypercapnia-induced hypothermia, which has been less studied than the
hypothermia caused by hypoxia and seems to be more complex because it
appears not to be associated with hypometabolism in rats. Lai et al.
(17) showed that even when
O2 increases during
hypercapnia, Tb consistently decreases by 1-1.5°C, a phenomenon that probably reflects the heat loss of hyperpnea and vasodilatation and is therefore likely to be
related to the severity and duration of hypercapnia. However, these two
effects of CO2 alone are not
sufficient to explain a hypothermic response. Some studies indicate
that hypercapnia-induced hypothermia may involve a central control.
Indeed, Kuhnen et al. (16) reported a shift in the set point of
Tb to a lower level during
hypercapnia in the golden hamster, Mesocricetus
auratus. In addition, the activity of neurons in the
preoptic area, which affect Tb
regulation, is higher during hypercapnia than during hypoxia in Wistar
rats (32).
The present study confirms that hypercapnia-induced hypothermia may
involve other mechanisms in addition to hyperventilation or
vasodilatation because the drop caused by the NOS blockade was not
changed by hypercapnia. The effect of
CO2 inhalation on E was maintained after treatment with
L-NNA, but no additional decrease in Tb was observed,
suggesting that hypercapnia-induced hypothermia has a central component
that may involve the NO pathway.
Effects of L-NNA and Hypercapnia
on O2
O2, mainly
if the thermogenic response is blunted (36). In the present study, a
drop in O2 was
observed 2 h after injection of the higher NO-blocker dose.
A review of the literature reveals contradictory effects of hypercapnia
on O2. Numerous factors such
as intrinsic species differences may contribute to the variability in
the metabolic effects of CO2
inhalation. Some investigators have observed an increase in both
O2 and
E, the former being commonly attributed to the energetic cost of hyperventilation, for example in ponies (14).
In the present study hypercania had no effect on
O2 in rats, as also observed
by Saiki and Mortola (31), who detected only a small but not
significant trend for O2 to
increase with 2 and 5% CO2
inhalation. Finally, cats show a large drop in
O2 during 4%
CO2 breathing at room temperature
(30). Different energetic costs of hyperventilation may complicate the
interpretation of such results. With this fact taken into
consideration, hypercapnia might have reduced the metabolic rate, but
this could not be measured because of the hyperventilation response.
Thus CO2 exposure had no effect on
O2 in rats after saline or
L-NNA, at the two lower doses.
However, the drop in
O2 in the subgroup
injected with the higher dose of
L-NNA was recovered during
CO2 exposure, possibly because of
the hyperventilation response.
Effects of L-NNA on the Interaction Between Hypothermia and Hyperventilation During Hypercapnia
The present study indicates that the responses elicited by hypercapnia, hyperventilation, and hypothermia do not share NO as a common mediator because no interaction exists between the effects of L-NNA on hypercapnia-induced hyperventilation and hypothermia simultaneously. NOS inhibition did not change the ventilatory drive to hypercapnia, even though it caused a drop in Tb. However, the L-arginine-NO pathway participates in normal respiratory function and thermoregulation. Several studies have been conducted to determine whether changes in Tb alter the ventilatory response to changes in inspired CO2 levels, but in homeotherms the methodology always seems to be a problem, yielding divergent results. Olievier et al. (28), using a Tb range of 34-40°C in anesthetized cats, concluded that Tb had no important modifying effects on the response to CO2. However, anesthetics impair the homeostatic mechanisms regulating Tb (21), and exposure to cold affects heat production and heat loss mechanisms but does not establish a lower set-point value of Tb. Maskrey (21) reported that the effect of cooling on the response to breathing CO2-enriched air was to raiseE in awake rats. He used an
abdominal heat exchanger to cause hypothermia, which again does not
affect the set point for Tb.
Ectothermic animals seem to be a better model for studying the effect
of Tb on the hypercapnic drive to
breathe, but data in the literature also show divergent results. In the
toad Bufo paracnemis, decreases in
Tb elicit a reduced hypercapnic
drive to breathe (4). In contrast, Jackson et al. (13) demonstrated
that E in
Pseudemys turtles displays a similar
sensitivity to increases in inspired CO2 at 10, 20, and 30°C. The
present study, conducted in conscious rats and at ambient temperature,
shows that a modest but significant drop in
Tb, caused by NOS blockade, which
seems to interfere with the set point for
Tb, had no effect on the
hypercapnic drive to breathe.
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ACKNOWLEDGEMENTS |
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We thank Dr. Augusto S. Abe for use of equipment.
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FOOTNOTES |
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This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico. R. C. H. Barros was the recipient of a FAPESP postgraduate scholarship.
Address for reprint requests: L. G. S. Branco, Departamento de Fisiologia, Faculdade de Odontologia de Ribeirão Preto/USP, 14040-904 Ribeirão Preto, SP, Brazil (E-mail: lgsbranc{at}usp.br).
Received 10 December 1997; accepted in final form 27 April 1998.
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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) or saline (
) on body temperature during hypercapnia.
Values are means ± SE (n = 8 rats/group). * Significantly different mean values before and
after L-NNA injections
(P < 0.05; 1-way ANOVA).
+ Significant difference in
mean values before and after 30 min of 5%
CO2 exposure
(P < 0.05; paired
t-test).
