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Atelier de Physiologie Respiratoire, Faculté de Médecine Saint-Antoine, 75012 Paris, France
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Gautier, Henry, Cristina Murariu, and Monique Bonora.
Ventilatory and metabolic responses to ambient hypoxia or
hypercapnia in rats exposed to CO hypoxia. J. Appl. Physiol.
83(1): 253-261, 1997.
We have investigated at ambient
temperatures (Tam) of 25 and
5°C the effects of ambient hypoxia
(Hxam; fractional inspired O2 = 0.14) and hypercapnia
(fractional inspired
CO2 = 0.04) on ventilation (
),
O2 uptake
(O2), and
colonic temperature (Tc) in 12 conscious rats before and after carotid body denervation (CBD). The
rats were concomitantly exposed to CO hypoxia (HxCO; fractional inspired CO = 0.03-0.05%), which decreases arterial O2 saturation by ~25-40%.
The results demonstrate the following. 1) At
Tam of 5°C, in both intact and
CBD rats,
/O2 is
larger when Hxam or
CO2 is associated with
HxCO than with normoxia. At Tam of 25°C, this is also the
case except for CO2 in CBD rats. 2) At
Tam of 5°C, the changes in
O2 and
Tc seem to result from additive
effects of the separate changes induced by
Hxam,
CO2, and
HxCO. It is concluded that, in
conscious rats, central hypoxia does not depress respiratory activity.
On the contrary, particularly when
O2 is augmented during a
cold stress, both
/O2
during HxCO and the ventilatory
responses to Hxam and
CO2 are increased. The mechanisms
involved in this relative hyperventilation are likely to involve
diencephalic integrative structures.
thermoregulation; chemoreceptors; hypoxic hypometabolism; control
of breathing; shivering; carbon monoxide
INTRODUCTION IN THE ABSENCE of peripheral chemoreceptor stimulation,
hypoxia may affect respiratory activity by a direct effect on the brain. This has been demonstrated in animals with isolated carotid body
perfusion or with carotid body denervation (CBD) exposed to ambient
hypoxia (Hxam; decreased inspiratory
PO2) and in intact animals during inhalation of
low concentrations of CO. The changes in respiratory activity induced
by brain hypoxia seem to vary with the experimental conditions. In
anesthetized animals, a depressant effect has usually been reported (3,
6, 24, 32), whereas, in conscious animals, brain hypoxia consistently
induces an increase in ventilation ( We have observed in a previous study carried out in unanesthetized
intact rats (13) that central hypoxia resulting from the inhalation of
a low concentration of CO induces an increase in METHODS Animals
; see Ref. 29).
However, independent of the effects of brain hypoxia on breathing
(depression or stimulation), the respiratory responses to hypercapnia
and carotid sinus nerve stimulation during brain hypoxia appear to be
unchanged (23, 29, 32). These results suggest that, under these
conditions, the integration of the chemosensory inputs by the brain
stem is unaltered.
relative to O2
consumption
(/O2),
particularly when the animals were studied at low ambient temperatures
(Tam). Following these results
and using the same experimental conditions, the present study was
designed to test the hypothesis that the ventilatory responses to
Hxam and
CO2 are increased when associated
with central hypoxia induced by CO exposure. The experiments were
carried out at Tam of 25 and
5°C. Furthermore, the contribution of the peripheral chemoreceptors
to the changes observed was assessed by studying rats before and after
CBD.
Measurements
After the rats were weighed, they were placed in a calorimeter. Flow rates through the calorimeter of the various gas mixtures used were measured with a rotameter and kept at 1.5 l/min. The concentrations of O2 (Beckman OM 14), CO2 (Beckman LB 2), and CO (Cosma Diamant 6000, Igny, France) in the inflow or outflow gas streams were continuously recorded on a chart recorder and were used to computeO2 with the
open-circuit method. The analyzers were repeatedly calibrated by using
standard gases of known composition. , colonic
temperature (Tc), and
Tam (calorimeter) were monitored as previously described (13). In all studies,
O2,
Tc,
Tam, and were
computed at 10-min intervals. In the experiments carried out at low
Tam, the shivering activity was
continuously monitored and averaged over 10-min periods
(13).
In each of the following protocols, the rats were studied both before (intact) and after CBD. Under a surgical plane of halothane anesthesia (4% for induction, then 1% for maintenance, in O2), the carotid sinus nerves were exposed by using an operating microscope and were subsequently sectioned at their junctions with the glossopharyngeal nerves. Experiments were carried out within 5-15 days after the surgery.
Ten of the CBD rats described above, as well as 10 additional intact animals, were prepared for arterial blood sampling. During a brief period of halothane anesthesia, an indwelling catheter was inserted into the left carotid artery. The rats were then returned to their cages, and blood-gas measurements were made during the experiments carried out 1-3 days later.
Protocols
Four different protocols were used. The first protocol, which involved measurements of arterial blood gases, was carried out at Tam of 25°C. The other three protocols were performed in each animal on different days at Tam of 25°C (normothermia) and 5°C (hypothermia). These experiments were carried out with hypoxia [fractional inspired O2 (FIO2) of 14%], with hypercapnia [fractional inspired CO2 (FICO2) of 4%] and with CO [fractional inspired CO (FICO) of either 0.03 or 0.05% in ambient air] at Tam of 5 and 25°C, respectively. For Tam of 5°C, the FICO of 0.03% was selected because in a previous study we have shown that, under these conditions, there were marked changes inO2,
Tc, and
/O2 (13). Because at Tam of 25°C,
there were no consistent changes in
O2 or
with
FICO of
0.03%, in the present experiments performed at this
Tam, we have selected a higher
concentration of inspired CO (0.05%).
Protocol 1: Arterial blood gases during hypoxia.
Animals were moderately restrained in a small transparent container
maintained at Tam of 25°C. The
container was flushed with gases of the same composition as detailed in
protocol 3, part 2. A sample of 0.2 ml
of arterial blood was collected after 30 min of exposure to normoxia
(Nx), 30 min of CO (0.03 or 0.05% in ambient air), 30 min of CO and
hypoxia, and finally 30 min of CO again. Blood samples were immediately
analyzed with a Radiometer ABL 500 blood-gas analyzer for arterial
PO2
(PaO2), arterial PCO2
(PaCO2), and arterial pH,
and with a Radiometer OSM3 set for rat blood for arterial
O2 content
(CaO2), and arterial saturation of O2 and CO
(SaO2 and
SaCO, respectively).
Protocol 2: Ventilatory and metabolic responses to
HxCO.
Animals were initially studied during a control period of Nx for at
least 30 min. During this period, they settled down, and the different
variables studied became stable. Thereafter, animals were exposed to CO
mixed with ambient air for 90 min followed by 10-15 min of 100%
O2.
Protocol 3: Ventilatory and metabolic responses to hypoxia.
After the control period of Nx, animals were exposed sequentially to
30-min periods of either 1) Nx,
hypoxia, and again Nx or 2) CO, CO
and hypoxia, and again CO, followed by 10-15 min of 100%
O2.
Protocol 4. Ventilatory and metabolic responses to hypercapnia.
After the control period of Nx, animals were exposed sequentially to
30-min periods of either 1) Nx, then
hypercapnia and Nx, or 2) CO, CO and
hypercapnia, and again CO, followed by 10-15 min of 100%
O2.
Statistics
Statistical analyses were carried out by using BioMedical Data Package programs. A two-way analysis of variance was performed to assess the significance of the changes observed in the variables studied. If a significant (P < 0.05) F-ratio was found, then specific statistical comparisons were made. Dunnett's test was used to assess the significance of the sequential changes induced by 10-90 min of HxCO compared with the control data that were obtained after 30 min of Nx. The same test was used to assess the changes induced by 10-30 min of hypoxia or hypercapnia compared with the control data that were obtained after either 60 min of Nx or 30 min of HxCO. Bonferroni's test was used to compare the effects of 30 min of hypoxia or hypercapnia administered after either 60 min of Nx or during CO hypoxia. A paired t-test was also used when appropriate. Statistical significance was accepted at the P < 0.05 level. The data are presented as means ± SE.RESULTS
Blood Gases
As shown in Fig. 1, in both intact and CBD rats, CO inhalation induced a progressive increase of SaCO and, correlatively, a progressive decrease of SaO2, which after 60 min of HxCO and 30 min of Hxam reached minimums of ~70 and 58% with FICO of 0.03 and 0.05%, respectively (Fig. 1, A and B, respectively) and did not change thereafter. During Hxam, PaO2 decreased to reach nadirs of ~60 and 48 Torr in intact and CBD rats, respectively.
HxCO
Normothermia. Compared with control Nx, exposure to HxCO did not induce any significant change in and
O2 in both intact
and CBD rats (Fig. 2). A significant
decrease in Tc was observed only
in the intact rats toward the end of
HxCO exposure.
),
O2 consumption
(O2), and colonic temperature
(Tc) in rats before (closed
symbols) and after CBD (open symbols). At
Tam of 25°C, animals were
exposed first to Nx (circles) and then to 0.05% CO in room air
(HxCO, squares).
* Significantly different from final measurements in Nx,
P < 0.05.
Hypothermia. As shown in Fig. 3, when intact and CBD rats were exposed to HxCO, there was no significant change in
. In contrast,
O2 decreased markedly and by
the same extent during HxCO in
both intact and CBD rats. It follows that after 90 min of CO exposure, /O2
was significantly increased (P < 0.001) from 23 ± 1 to 29 ± 1 ml/ml in intact rats and from 20 ± 1 to 28 ± 1 ml/ml in CBD rats.
Tc decreased markedly in both
intact and CBD rats. Although shivering intensity did not change
significantly in intact animals, it progressively decreased in CBD
rats, the decrease amounting to 20% after 90 min of
HxCO exposure.
, O2,
Tc, and shivering intensity (in
%average values observed in Nx) in rats before (closed symbols) and
after CBD (open symbols). At Tam
of 5°C, animals were exposed first to Nx (circles) and next to
0.03% CO in room air (HxCO,
squares). * Significantly different from final measurement in Nx,
P < 0.05.
Hxam and HxCO
Normothermia. In intact animals, when Hxam was associated with HxCO, the was significantly greater than during
Hxam alone, but the decreases in
O2 were similar in both
situations (Fig.
4A). As
a result, the
/O2
was significantly greater with
Hxam combined with HxCO than with
Hxam alone (57 ± 3 and 42 ± 2 ml/ml, respectively; P < 0.01). In CBD animals, when Hxam
was combined with HxCO, there was
a small but significant increase in , whereas with
Hxam alone the
did not change significantly (Fig.
4B). In both situations, similar
decreases in O2 were
observed. As in intact animals, the
/O2 was
significantly greater with Hxam
combined with CO than during Hxam
alone (38 ± 1 and 31 ± 1 ml/ml, respectively; P < 0.01).
, O2, and
Tc in rats before
(A) and after CBD
(B). At
Tam of 25°C, animals were
exposed first to Nx (
), next to either Nx or 0.05% CO in room air
(HxCO; 
), then to
Hxam
(FIO2 = 0.14), and finally
again to either Nx or HxCO.
* Values in Hxam that are
significantly different from previous measurements in Nx or
HxCO, P < 0.05. 
Values after 30 min
of Hxam that are significantly different during HxCO compared
with Hxam alone,
P < 0.05.
Hypothermia. In intact animals,
did not change significantly
during the Hxam exposure,
regardless of whether or not the rats were concomitantly exposed to
HxCO (Fig.
5A).
However, after 30 min of Hxam
alone, was significantly greater than when it was
associated with HxCO.
O2 decreased markedly during
Hxam and even more significantly when this was associated with
HxCO. As a result,
/O2 was
significantly greater during
Hxam and
HxCO than during
Hxam alone (34 ± 1 and 30 ± 1 ml/ml, respectively; P < 0.05). During Hxam,
Tc decreased progressively but
partially recovered during the subsequent return to Nx. Such recovery,
however, was absent in the HxCO
experiments (Fig. 5A). At the onset
of Hxam, shivering intensity
decreased, but it returned to control values thereafter. Such recovery
was not observed in the HxCO
experiments.
, O2,
Tc, and shivering intensity in
rats before (A) and after
(B) CBD. At
Tam of 5°C, animals were first
exposed to Nx (), next to either Nx or 0.03% CO in room air
(HxCO, ), then to
Hxam, and finally again to either
Nx or HxCO. * Values in
Hxam that are significantly
different from the previous measurement in Nx or
HxCO,
P < 0.05. Values that are
significantly different after 30 min of
HxCO compared with Nx or after 30 min of Hxam with
HxCO compared with
Hxam alone,
P < 0.05.
In CBD animals, an initial drop in
was observed with
both Hxam and
Hxam with
HxCO, with a gradual recovery by
30 min of hypoxia (Fig. 5B).
O2 decreased markedly with
Hxam and even more with
Hxam and
HxCO. As a result,
/O2 was
significantly greater with
Hxam and
HxCO than with
Hxam alone (30 ± 2 and 26 ± 1 ml/ml, respectively; P < 0.05). Tc and shivering activity exhibited the same response as in intact animals. Similarly, shivering was significantly less with Hxam
and HxCO than with
Hxam alone.
Hypercapnia and HxCO
Normothermia. In intact animals, CO2 with or without HxCO induced a marked increase in while
O2 did not change
significantly during hypercapnia (Fig.
6A).
As a result,
/O2 was
significantly increased with CO2
and HxCO compared with normoxic
CO2 (54 ± 2 and 47 ± 2 ml/ml, respectively; P < 0.05). During both normoxic hypercapnia and hypercapnia with
HxCO,
Tc decreased similarly, although
not significantly. In CBD animals, the ventilatory response to
CO2 was the same in Nx as during
HxCO (Fig.
6B). Also
O2, /O2, and
Tc were not significantly
different under both conditions of hypercapnia.
, O2, and
Tc in rats before
(A) and after
(B) CBD. At
Tam of 25°C, animals were
exposed first to Nx, next to either Nx or 0.05% CO in room air
(HxCO), then to hypercapnia
(FICO2 = 0.04), and finally
again to either Nx or HxCO.
* Values in CO2 that are
significantly different from previous measurement in Nx or
HxCO,
P < 0.05.
Hypothermia. In intact animals,
increased progressively during
hypercapnia, and the level reached after 30 min was not significantly different in HxCO than in Nx.
O2 decreased significantly at the onset of hypercapnia and more markedly when
CO2 was associated with
HxCO. Under both conditions,
O2 partially recovered during the last 20 min of hypercapnia (Fig.
7A). As
a consequence,
/O2 was
significantly higher with CO2
during HxCO than during Nx (40 ± 1 and 33 ± 1 ml/ml, respectively;
P < 0.01).
Tc decreased significantly only
during hypercapnia with HxCO. In
contrast, shivering decreased significantly at the onset of
hypercapnia, with a subsequent partial recovery both during normoxic
hypercapnia and hypercapnia combined with
HxCO (Fig.
7A).
, O2,
Tc, and shivering intensity in
rats before (A) and after
(B) CBD. At
Tam of 5°C, animals were
exposed to Nx, next to either Nx or 0.03% CO in room air
(HxCO), then to
CO2, and finally to either Nx or
HxCO. * Values in
CO2 that are significantly different from the previous measurement in Nx or HxCO,
P < 0.05. Values that are significantly
different after 30 min of HxCO compared with Nx or after 30 min of
CO2 with
HxCO compared with Nx,
P < 0.05.
In CBD animals, the ventilatory response to CO2 was about the same in HxCO as in Nx (Fig. 7B). As
O2 decreased substantially more with HxCO,
/O2 was
significantly greater in the former situation (36 ± 2 and 28 ± 1 ml/ml, respectively; P < 0.01).
Tc decreased significantly only
during hypercapnia with HxCO,
while shivering did not change significantly under both experimental conditions.
DISCUSSION
The discussion of the results of the present study must take into
account the fact that in small mammals, such as rats, the ventilatory
responses to hypoxia and hypercapnia may reflect the interaction of two
opposing effects, namely, an increase in chemoreceptor drive and a
decrease in metabolism. As recently pointed out, this is particularly
prominent at low Tam (11, 25). It
follows that the ventilatory response to a given stimulus should be
analyzed not only in terms of changes in absolute
but also in terms of changes in relative to the
O2
(/O2). With
this in mind, the results of the present study may be summarized as
follows. 1) In intact animals, at
Tam of both 25 and 5°C, the
ventilatory responses to CO2 and
Hxam are increased during
HxCO.
2) In CBD animals, even though the
ventilatory response to Hxam is
markedly reduced compared with intact rats, it is nevertheless enhanced when associated with HxCO. The
ventilatory response to CO2 is also increased with HxCO at
Tam of 5°C, whereas it remains
unaffected at Tam of 25°C.
3) The changes in metabolic
responses to cold, and, therefore, in
Tc observed during
HxCO,
Hxam, and hypercapnia in intact
and CBD rats are in general agreement with several previous studies
(13, 15, 26). 4) The latter
responses seem to result from the additive effects of
Hxam and
CO2 with
HxCO.
Ventilatory Response to HxCO
We have reported in a previous study (13) that there are no appreciable changes in in rats exposed to normothermia with FICO of
0.03%, which causes a decrease in CaO2
of 25%. This is confirmed by the present findings obtained at a higher
level of FICO
(0.05%), which induces a 40% decrease in
CaO2. It should be noted, however, that
rats may respond to HxCO
differently from other animal species, such as goats (27) and cats
(13), that characteristically exhibit hyperventilation (hypoxic
tachypnea) with a similar decrease in
CaO2 to that observed in the present study. Recently, a maximal increase in of 275% has
been observed in anesthetized rats exposed to
HxCO which, like the present
study, induced a 40% decrease in CaO2
(10). However, the latter results are at variance with those of
Matsuoka et al. (20). They showed that in conscious rats in which
hemoglobin concentration ([Hb]) was acutely reduced by
~50%, there was a maximal increase in of only
30%.
In hypothermia, the present results confirm those of our previous
study, showing that does not change significantly
during HxCO while
O2 decreases markedly (13).
This absence of coupling of to
O2 led us to postulate the
existence of an additional -stimulating factor that
counteracts the ventilatory effects of
HxCO-induced hypometabolism.
Because the present study shows that identical results are found in CBD
animals, it follows that this -stimulating factor
originates centrally (see Integrated Effects of
HxCO and Hxam or CO2 on
).
Effects of HxCO on the Ventilatory Response to Hxam and CO2
The effects of brain hypoxia on the control of breathing have been the object of many previous studies. According to recent reviews, brain hypoxia is believed to primarily promote ventilatory depression (3, 6). Such depressant effects, which are consistently observed in anesthetized preparations in the absence of peripheral chemoreceptor stimulation, have been advanced to explain the biphasic nature of the ventilatory response to hypoxia observed in intact animals. However, in the past 20 years, several studies have clearly shown that, in unanesthetized animals, isolated brain hypoxia induced by 1) Hxam after peripheral chemodenervation, 2) HxCO in intact animals, or 3) systemic hypoxia and selective carotid perfusion with normoxic blood characteristically results in hyperventilation. Furthermore, when the carotid bodies are concomitantly stimulated by hypoxia, the resulting increase in is about the same whether the brain is hypoxic or
normoxic (4, 29). In contrast to the above results, the present study
shows that the ventilatory responses to
Hxam and
CO2 are enhanced during
HxCO, even though brain hypoxia
per se had no effect on control .
Several studies similar to ours have dealt with the ventilatory
response to Hxam and
CO2 when
CaO2 was decreased by experimental anemia or by HxCO in rats and
cats. With a decrease in [Hb] of ~50%, the ventilatory
responses to both Hxam and
CO2 were found unchanged (1).
However, it should be noted that
O2 was not measured in these
studies. Similarly, in goats in which [Hb] was decreased
>60%, the response to steady-state (6 min)
Hxam or
CO2 was unaffected (28). In both
of the above studies, the ventilatory responses to
Hxam or
CO2 were investigated 3-5
days after the induction of anemia. This delay may be critical, as
recently shown in a study on rats. Three hours after induction of
anemia ([Hb] reduced by 50%), the was
increased while O2 and
Tc were decreased. After 3 days,
however, all of these variables had returned to control values (20).
The effects of HxCO on the ventilatory response to CO2 have been investigated in goats and cats. In unanesthetized goats, the ventilatory response to CO2 studied with the rebreathing method was not consistently changed (27). In anesthetized, curarized, CBD, and vagotomized cats, the phrenic response to CO2 was not blunted as expected and, in fact, may have been accentuated by HxCO (22). In another study using the same experimental approach (23), it was found that the response of the phrenic neurogram to supramaximal carotid sinus nerve stimulation was unaffected even during severe hypoxemic respiratory depression. These studies suggest that the processing by the respiratory centers of the central and peripheral afferent information is unchanged by central hypoxemia. In all of the above studies, CaO2 was reduced by ~50% as a result of the inhalation of 0.5-1.0% CO in 40% oxygen, with PaO2 maintained well above 150 Torr. In contrast, a much lower concentration of CO (0.03-0.05%) in ambient air was used in the present study, resulting in no change in PaO2 (see Fig. 1). Conceivably, for a given reduction in CaO2 by HxCO, the respiratory control mechanisms may be affected differently in the presence of a higher PaO2. Also, the present results are in agreement with those of a previous investigation in cats exposed to CO in room air in which we also found an increase in the ventilatory response to CO2 (14). Similarly, in conscious CBD cats exposed to a moderate level of Hxam (FIO2 = 0.13), the ventilatory response to CO2 was significantly higher than that observed during Nx (12).
Finally, it may be expected that prolonged exposure to
HxCO should have a time-related
effect on gas exchange because of the increase in carboxyhemoglobin
between 30 and 60 min (see Fig. 1). Such time dependency is clearly
seen on O2 under hypothermic conditions during either HxCO
alone or when associated with Hxam or CO2. The increase with time in
the ventilatory response to Hxam
and CO2 may, however, be modulated
by several factors: 1) the
progressive decrease in O2 in
hypothermia that may counteract and mask the relative increase in
ventilatory stimulation; 2) the
partial recovery in O2
between 10 and 30 min, as seen during CO2 in hypothermia; and
3) a possible delayed effect
of HxCO on , even when the level of carboxyhemoglobin is
maintained constant, as observed in ponies by Lowry et al. (18).
Integrated Effects of HxCO and
Hxam or CO2 on
that is observed in goats and cats during
HxCO persists after CBD (16, 27).
The present results, however, cannot exclude a possible role of the aortic or other extracarotid chemoreceptors, which could be stimulated by HxCO.
The nature of the central mechanisms that mediate the increase in
/O2 during
HxCO in hypothermia and the
increased responsiveness to Hxam
or CO2 during
HxCO remains speculative. Whereas
the central depressing effects of hypoxia described in anesthetized
animals are usually assumed to occur at the pontomedullary level (7), the central stimulatory effects of
Hxam and
HxCO, which elicit rapid shallow
breathing in conscious animals, have generally been attributed to
stimulation of structures rostral to the brain stem, particularly at
the level of the diencephalon (16, 31). Furthermore, according to
Gallman and Millhorn (9), in peripherally chemodenervated cats there is
a long-lasting facilitatory effect on respiration after hypoxia, which
probably involves also the diencephalon. Finally, there is recent
evidence that Hxam may stimulate
caudal hypothalamic neurons, whose basal discharge is correlated with respiratory activity and, interestingly, the stimulation elicited by
Hxam does not require any input
from the peripheral chemoreceptors (5). Accordingly, it can be argued
that these mechanisms may also have a role in the present study,
accounting for the observed interactions of
HxCO and the enhanced ventilatory
responses to Hxam and
CO2. However, most of the above
studies, in which the increase in respiratory activity during hypoxia
has been attributed to diencephalic structures, have involved
Hxam and not
HxCO. The effects of
HxCO may be different from those
of Hxam and, in fact, appear to be
multifactorial. In addition to a decrease in
CaO2 and the shift to the left of the
oxyhemoglobin dissociation curve, HxCO may markedly affect cerebral
blood flow. Furthermore, it has been recently suggested that CO acts as
a neural messenger in a manner very similar to nitric oxide (21).
Effects of HxCO on the Metabolic Responses to Hxam and CO2
The present results confirm previous studies showing that in rats, especially during cold exposure, Hxam and HxCO, and to a smaller degree CO2, may affect heat production [shivering and nonshivering thermogenesis (NST)],O2, and hence
Tc (13, 15, 25, 26). In addition,
the present results show that in both intact or CBD rats,
hypometabolism and hypothermia resulting from exposure to either
Hxam or
HxCO are increased in an additive
manner when Hxam and
HxCO are administered
concomitantly. The same additive effects, although of a smaller
magnitude, are observed when HxCO is associated with CO2.
The hypometabolism during hypoxia results from the inhibition of shivering and/or NST, as shown in a previous study (13). Thus, it appears that, in intact animals, shivering is not affected during HxCO. Accordingly, the hypometabolism must result entirely from an inhibition of NST. In contrast, in CBD animals exposed to HxCO, our results show that shivering is significantly depressed. The mechanism of this unexpected finding is not clear. Indeed, the elimination of any carotid body stimulation cannot explain this result as it is generally agreed that, shivering is inhibited rather than stimulated by carotid body (33). Furthermore, CO does not significantly stimulate carotid body. As initially suggested by von Euler (33), shivering may be potentially affected by several factors that are related to both chemoreceptor and baroreceptor functions. The present results suggest that, during HxCO in CBD compared with intact animals, changes in such factors (e.g., hypoxia, hypercapnia, blood pressure) may secondarily affect shivering. The role of these factors, however, cannot explain the fact that, in intact as well as in CBD rats, shivering is more inhibited when Hxam is associated with HxCO compared with Hxam alone. Because no such interaction is observed between CO2 and HxCO, it may be argued that the magnification of the effects of Hxam by HxCO could be related to the interaction between PaO2 and CaO2 under these conditions. Clearly, further studies are needed to fully account for these results.
The present results confirm previous reports (11) showing that the effects of Hxam and CO2 on body temperature regulation are probably mediated centrally, as they persist after CBD. The interactions of HxCO, Hxam, or CO2 with body temperature probably involve the same structures. Even though the mechanisms involved in the reduction of thermogenesis are not completely understood, it is now generally agreed that, particularly during cold exposure, hypoxia and hypercapnia lower the body temperature set point, which is probably controlled at the level of the diencephalon (11). This notion is supported by the fact that the thermosensitivity of the preoptic neurons is affected by Hxam and CO2 (30). In this connection, it should be emphasized that the diencephalon appears to have a pivotal role in the modulation by brain hypoxia (HxCO) of both the ventilatory and the metabolic responses to Hxam and CO2. This is supported by a recent study (19) showing that in anesthetized rats the depressant interaction between hypothermia and hypoxia, which results in inhibition of respiration, was eliminated after lesions in the posterior hypothalamic area.
In conclusion, the present results indicate that brain hypoxia induced
by HxCO in conscious rats does not
elicit ventilatory depression. On the contrary, it potentiates the
ventilatory responses to Hxam and
to CO2 and accentuates their
hypometabolic effects. The observed responses are not qualitatively
affected by CBD and are likely to involve diencephalic structures. The
latter probably integrate the interactions between the control of
and the control of metabolism, and hence body
temperature, in response to changes in oxygenation and/or
CO2.
ACKNOWLEDGEMENTS
We thank M. Gras for typing the manuscript, J. Chandellier for art work, and D. Billet for performing blood-gas analyses.
FOOTNOTES
Address for reprint requests: H. Gautier, Faculté de Médecine Saint-Antoine, 27 rue Chaligny, 75012 Paris, France.
Received 8 May 1996; accepted in final form 14 March 1997.
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