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Atelier de Physiologie Respiratoire, Faculté de Médecine Saint-Antoine, 75012 Paris, France
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Because it
has been recently suggested that nitric oxide (NO) may mediate the
effects of hypoxia on body temperature and ventilation, the present
study was designed to assess more completely the effects of a neuronal
NO synthase inhibitor (7-nitroindazole, 25 mg/kg ip), at ambient
temperature of 26 and 15°C, on the ventilatory (
), metabolic
(O2 consumption), and thermal
changes (colonic and tail temperatures) induced by ambient hypoxia
(fractional inspired O2 of 11%)
or CO hypoxia (fractional inspired CO of 0.07%) in intact,
unanesthetized adult rats. At both ambient temperatures, 7-nitroindazole decreased oxygen consumption, colonic temperature, and
in normoxia. The drug reduced ambient or CO
hypoxia-induced hypometabolism and ventilatory response, but the
hypothermia persisted. It is concluded that NO arising from neural NO
synthase plays an important role in the control of metabolism and
in normoxia. As well, it mediates, in part, the
hypometabolic and the ventilatory response to hypoxia. The results are
consistent with the notion that central nervous system hypoxia resets
the thermoregulatory set point by decreasing brain NO.
thermoregulation; control of breathing; carbon monoxide; cold
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ACUTE EXPOSURE TO HYPOXIA reduces metabolic rate, and this may secondarily reduce body temperature and pulmonary ventilation (8). Such hypoxic hypometabolism, hypothermia, and relative hypoventilation likely represent a centrally regulated response rather than a manifestation of a simple limitation in oxygen availability to the peripheral tissues (21). The mechanisms mediating these central effects of hypoxia remain to be clarified.
Nitric oxide (NO) has been shown recently to act as an important neuromodulator in the central nervous system, and recent studies using NO synthase (NOS) blockers in rats suggest that NO may play a role in the development of hypoxic hypothermia and may also affect the ventilatory response to hypoxia. Thus it has been shown that systemic injections of a nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in large doses largely prevent hypoxia-induced hypothermia (3). Furthermore, administration of the same drug increases the early ventilatory response and the late ventilatory reduction in hypoxia (11).
The aim of the present study was to assess more completely the effects of neural NOS (nNOS) inhibition on the ventilatory, metabolic, and thermal changes induced by hypoxia in the adult rat. Hypoxia was produced either by decreasing the inspired oxygen concentration [ambient hypoxia (AHx)] or by inhalation of a low concentration of CO [CO-induced hypoxia (COHx)], which induces hypometabolism but does not stimulate arterial chemoreceptors (8). Experiments were carried out at thermoneutral and at lower ambient temperature, which magnifies the hypometabolic effects of hypoxia (8). Cutaneous temperature was recorded, because heat loss related to peripheral circulation may be affected by both hypoxia and NOS inhibition (25).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
The study was performed in six adult male Wistar rats, which were ~2 mo old at the beginning of the investigation. The animals were housed, three per box, in an animal room kept at ambient temperature of 23-25°C for at least 2 wk before the experiments. During that period, they were handled and weighed three times per week. They were also habituated (three training sessions, 2 h each) to a multiperforated cylindrical restrainer that lightly restricted translocational movements and prevented circular motion. During these training sessions, rectal probe for measurements of rectal temperature was also inserted (see below). They were fed with commercial rat chow and tap water ad libitum. The study was approved by the institutional animal care committee.Measurements
Rats were weighed and randomly injected intraperitoneally with 2 ml of vehicle (1:5 DMSO-saline) or 25 mg/kg of a selective neuronal NOS inhibitor 7-nitroindazole (7-NI; Sigma Chemical) (15) dissolved in the vehicle. Next, the rats were placed in the restrainer, and a thermistor probe (YSI model 402) was inserted 6 cm into the colon and secured in place with adhesive tape at the base of the tail. Another probe (YSI model 427) was similarly fixed 1.5 cm from the anus, on the ventral surface of the tail. The restrainer was transferred to the recording chamber, which, after sealing, was immersed in a water bath, the temperature of which was controlled at the desired value by adding hot water or crushed ice. Metabolic rate [oxygen uptake (O2), in ml
STPD · min
1 · kg
body wt1] was
determined by using a closed-circuit barometric method in terms of the
time taken by the rat to consume 10- or 20-ml aliquots of oxygen.
Ventilation (; in ml
BTPS · min1 · kg
body wt1) was monitored
by using the plethysmographic technique, originally described and
validated in the rat by Bartlett and Tenney (2). Pressure changes
in the closed chamber, associated with the breathing movements, were
recorded on paper for ~10 s at the speed of 50 mm/s. Data analysis
(tidal volume, breathing frequency, and ) was
subsequently performed by digitization using a graphic tablet connected
to a computer. Between each closed-chamber measurement of
O2 and
, the chamber was purged with a preselected gas mixture at a flow of ~1,800 ml/min.
O2, ,
and colonic (Tc), tail
(Ttail), and ambient
(Tam) temperatures,
respectively, were recorded at 5-min intervals. To assess more
precisely the changes in peripheral vasomotor tone induced by hypoxia,
the heat loss index (HLI) was calculated according to the equation HLI = (Ttail 
Tam)/(Tc Tam) (22). This equation
eliminates direct influences of both
Tam and
Tc on
Ttail, and the value of HLI varies
between 0 (maximal heat conservation due to skin vasoconstriction) and 1 (maximal heat loss due to skin vasodilation).
Protocols
Animals were initially exposed to normoxia at a Tam of 26 or 15°C. Twenty minutes after injection of the vehicle or 7-NI, all variables were recorded for 30 min in normoxia at 5-min intervals. The rats were then exposed to either AHx or COHx.AHx was induced by exposure for 15 min to an inspired concentration of 11% oxygen, monitored with a Beckman OM14 oxygen analyzer. Thereafter, animals were exposed to normoxia for 10 min. These experiments were carried out at Tam of 26 and 15°C.
COHx was induced by exposure for 20 min to an inspired concentration of 0.07% CO diluted in room air. The CO concentration was monitored with an infrared CO analyzer (COSMA Diamant 6000). Thereafter, animals were exposed to 100% oxygen for 10 min. These experiments were carried out at Tam of 15°C.
All six animals were exposed at random, at 2-day intervals, to three different protocols: AHx at 26°C, AHx at 15°C, and COHx at 15°C, under two different conditions: injection of vehicle or 7-NI.
Statistics
The significance of the effects of 15 min AHx or 20 min COHx, compared with the preceding normoxic conditions, as well as the effects of 7-NI, compared with the vehicle, on the different variables, was assessed by using a paired t-test with Bonferroni correction for multiple comparisons when the analysis of variance revealed a significant F. Results are presented as means ± SE; P < 0.05 was considered to be of statistical significance.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Vehicle Injection
The results concerning the metabolic and ventilatory effects of AHx and COHx observed after injection of the vehicle confirm previous studies in rats (8) and can be briefly summarized as follows: 1) at 26°C, AHx induced a significant decrease inO2
(~15%) and in Tc (~0.4°C)
and a sustained increase in (~65%) and
/O2
(~90%) (Fig. 1);
2) at 15°C, AHx induced larger decreases in O2
(~40%) and Tc (~1.8°C)
while increased progressively to reach ~15% above
control, and
/O2 was
sustained at ~90% above control (Fig.
2); and
3) COHx resulted in a progressive decrease in O2 and
Tc, reaching ~23% and
~0.8°C, respectively, after 20 min. did not
change consistently, whereas after 20 min of COHx
/O2 was
significantly increased by ~20% (Fig. 3).
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During AHx at 26°C, Ttail
increased slightly (0.35 ± 0.14°C) and decreased thereafter
during the recovery in normoxia (Fig. 4).
After vehicle injection, HLI increased significantly during AHx and was
less than before hypoxia during the recovery in normoxia. At 15°C,
under normoxic conditions, Ttail
and HLI were lower than at 26°C (Table
1), but no significant changes were
observed during AHx or COHx (data not shown).
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Effects of 7-NI Injection in Normoxia
Mean values measured at 26 and 15°C before AHx or COHx (that is, 45-50 min after vehicle or drug injection) are listed in Table 1.O2 was significantly less in
rats receiving 7-NI, compared with vehicle injection at both
Tams. Similarly, 7-NI rats
exhibited lower than control at both
Tams. Nevertheless, /O2 was
significantly increased in 7-NI rats compared with control animals.
With 7-NI, Tc decreased at
26°C and, more markedly, at 15°C while
Ttail did not change significantly.
Effects of 7-NI Injection in Hypoxia
During AHx at 26°C,O2
(Fig. 1), Ttail, and HLI (Fig. 4)
were not significantly affected. However,
Tc decreased progressively and was
0.60°C lower after 15 min of AHx than before AHx. The ventilatory
response to AHx was markedly reduced, since and /O2
increased only by 40 and 47%, respectively (vs. 70 and 95% after
vehicle injection) (Fig. 1). At 15°C, the decreases in
O2 (~21%) and
Tc (~1.65°C) were smaller
than after vehicle injection (~40% and ~1.8°C, respectively).
increased to the same extent, but because the drop
in O2 was smaller than after vehicle injection, the increase in
/O2 was
also smaller (~51 vs. ~90%) (Fig. 2). After 20 min of COHx, the
decrease in O2 was smaller
(~13%) and the drop in Tc
greater (~1.15°C) than after vehicle injection (23% and
~0.8°C, respectively). did not change, and the
increase in
/O2 was
smaller after 7-NI injection (~14 vs. ~20%). The exposure to 100%
oxygen after COHx induced marked increases in
O2 and decreases in
/O2, as
did not change significantly (Fig. 3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Summary of the Results
The present study shows that 1) 7-NI injection induced marked decreases in normoxicO2 and
Tc and an increase in
/O2; and
2) the hypometabolic effects of AHx
and COHx were markedly reduced after 7-NI injection, but hypothermia
persisted, and the ventilatory response to AHx was decreased.
Effects of 7-NI on Metabolism and Thermoregulation
Normoxia. The present study, in which a specific nNOS blocker was used, agree with recent reports in rats showing a decrease inO2 and
Tc after intraperitoneal or
intravenous injection of nonselective NOS blockers such as
L-NAME (3, 6, 23) or
N
-nitrol-arginine
(L-NNA) (1). Most likely, this
is a result of a reduction in nonshivering thermogenesis,
since L-NAME reduces interscapular brown adipose tissue (BAT) temperature and the firing rate of the sympathetic nerves innervating BAT (6).
Hypoxia. The effects of AHx and COHx
on O2 are markedly attenuated
after NOS blocker injection. The values of
O2 attained at the end of AHx
or COHx are lower after 7-NI compared with vehicle injection, probably
because of the marked hypometabolic effects of the drug observed in
normoxia. These results suggest that NO may, at least in part, mediate
hypoxic hypometabolism. One could argue that because
O2 is already reduced to
minimal levels in normoxia as a result of 7-NI on BAT, an additional
hypoxia-induced drop in O2 is
precluded. This is unlikely, because previous studies revealed that
hypoxic hypometabolism can be further reduced by a more severe AHx (7).
Similarly, AHx, when added to COHx, induces an additional drop in
O2 (8).
The present results are the first to show that hypoxic hypometabolism is reduced after treatment with a specific nNOS blocker. It follows that our results are in agreement with those of a recent study in rats, which showed that the hypothermia that resulted from exposure to 7% oxygen could be reduced by pretreatment with L-NAME injected intracerebroventricularly (3). In the present study, Tc decreased progressively during hypoxia after 7-NI injection, even at 26°C, because the hypoxic hypothermia, although slightly reduced, was superimposed on the hypothermia caused by the drug in normoxia, as discussed above.
Of interest in this regard, the increase in Ttail and HLI, observed at 26°C during AHx after vehicle injection, was abolished after 7-NI injection. This indicates that the increases in skin blood flow and temperature induced by AHx, previously reported in humans (5), were probably centrally mediated by NO.
The precise mechanism by which NO affects metabolism and, thereby, body
temperature in normoxia and hypoxia is unknown. Because 7-NI is thought
to inhibit NOS solely in the brain in vivo (15), even though nNOS is
also encountered in spinal cord, kidney, and sympathetic ganglia (24),
it may be speculated that NO influences thermoregulatory centers that
ultimately control such effectors as BAT (heat production) and vascular
smooth muscles of the skin (heat conservation). In support of this
view, NO is required for the elevation of the set point observed during
fever induced by lipopolysaccharide injection in the rat (23).
Conversely, during hypoxia, the thermal set point may be reset to lower
values because brain NO is decreased. This may result from a decrease
in NO synthesis associated with an inhibition of NOS activity by
hypoxia, which has been found in several studies (13, 18, 20). In this respect, our hypothesis agrees with the conclusions of Gozal (9), who
suggested that hyperoxia lead to enhanced nNOS activation and increased
NO release, since this enzyme exhibits oxygen dependency. In contrast,
other researchers (10, 19) have observed an increase in nNOS expression
after exposure to prolonged hypoxia. Another possibility concerns the
fact that, in the present experiments, hypoxia and/or blockade of NO
formation may also affect regional cerebral blood flow (14) and,
secondarily, body temperature regulation. As a unifying speculation, we
believe that O2 and body temperature decreased less after NOS inhibition because body temperature was already lowered toward the hypoxic thermal set point.
Effects of 7-NI on Ventilatory Control
Normoxia. As reviewed by Gozal et al. (11), NO may play a role in respiratory control by enhancing the excitability of the neurons involved in the generation of central respiratory activity. Consequently, a depression in the regulation of breathing would be expected after nNOS inhibition. In the present study, at both Tams, a significant decrease in was indeed observed
after 7-NI, compared with vehicle injection. However, when the
concomitant decrease in O2 is
taken into account, the ventilatory control efficiency, as reflected by
the air convection requirement
/O2, is
slightly increased. This confirms the results of Barros and Branco (1)
showing that L-NNA, a
nonspecific NOS inhibitor, caused no change in , even
though the pattern of breathing was irregular and
O2 was significantly
decreased. Furthermore, in anesthetized rats, was
not altered after 7-NI injection (20-400 mg/kg ip) (17). Finally,
Gozal et al. (9, 11) have reported that with a nonspecific NOS
inhibitor, such as L-NAME,
S-methyl-L-thiocitrulline (SMTC), and more recently with 7-NI (both selective neural NOS inhibitors), the remained unchanged or transiently
increased. The effects on O2
were not assessed in these studies. In conclusion, it appears that, in
normoxia, NOS inhibitors may result in only small changes in
ventilatory activity, particularly when the associated decrease in
O2 is taken into account.
Hypoxia. The present results show that
7-NI depresses the ventilatory response to hypoxia. The same conclusion
is valid when the associated decrease in
O2 is taken into account,
i.e., when the response is assessed in terms of
/O2. These
results confirm those of Ogawa et al. (16), who provided evidence that
NO is an excitatory chemical messenger in the brain stem neurons during hypoxia. They also confirm the observations of Haxhiu et al. (12) showing that in anesthetized, artificially ventilated rats, the electromyographic diaphragmatic response to isocapnic hypoxia was
markedly depressed in animals pretreated with
L-NNA for 7 days. Similarly,
Gozal et al. (11) have shown that the late (30 min) ventilatory
response of unanesthetized rats was depressed with
L-NAME or SMTC.
The depressed ventilatory response to hypoxia after 7-NI injection does
not involve the carotid chemoreceptors because
1) their responses should be
increased by NOS blockers (4); and 2) during COHx, which does not
affect carotid body discharge, a decrease in
/O2 was
also observed. Therefore, the depressed ventilatory response to hypoxia
induced by neural NOS blockers must be of central origin, confirming
that NO is centrally involved in the modulation of the ventilatory
response to hypoxia (16). Two major effects of hypoxia have been dealt
with in the present study: 1) an
increase in ventilatory output; and
2) a decrease in
O2, which is more prominent
at low temperature. The present results show that 7-NI reduces both
effects of hypoxia. Although the present study does not elucidate which
neuronal populations modulate these effects, it indicates that the two
responses elicited by hypoxia, namely, hyperventilation and
hypometabolism, must, to some extent, share NO as a common mediator.
Interestingly, the role of NO is specific to hypoxia, because the
ventilatory response to CO2 is
unaffected by NOS blockers (1, 11, 16).
In conclusion, the present study confirms that NO, arising from nNOS,
is involved in the mediation of both the hypometabolic and ventilatory
responses to hypoxia, particularly at thermoneutral Tam. Moreover, even in normoxia,
NO is involved in metabolic regulations, since a NOS blocker such as
7-NI induces marked decreases in metabolism, body temperature, and, to
a lesser extent, in .
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ACKNOWLEDGEMENTS |
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The authors thank L. Musselin for typing the manuscript and J. Chandellier for making the illustrations.
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: H. Gautier, Atelier de Physiologie Respiratoire, Faculté de Médecine St-Antoine, 27, rue Chaligny, 75012 Paris, France.
Received 28 January 1999; accepted in final form 24 March 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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)
or 7-nitroindazole (7-NI) (
). 
, Values that, after 10 min of
O2 or 15 min of AHx, are
significantly different (P < 0.05)
from preceding Nx values; 
