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Department of Physiology, McGill University, Montreal, Quebec, Canada H3G 1Y6
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Saiki, Chikako, and Jacopo P. Mortola. Effect of
2,4-dinitrophenol on the hypometabolic response to hypoxia of conscious adult rats. J. Appl. Physiol. 83(2):
537-542, 1997.
During acute hypoxia, a hypometabolic response is
commonly observed in many newborn and adult mammalian species. We
hypothesized that, if hypoxic hypometabolism were entirely a regulated
response with no limitation in O2
availability, pharmacological uncoupling of the oxidative
phosphorylation should raise O2
consumption
(
O2) by
similar amounts in hypoxia and normoxia. Metabolic, ventilatory, and
cardiovascular measurements were collected from conscious rats in air
and in hypoxia, both before and after intravenous injection of the
mitochondrial uncoupler 2,4-dinitrophenol (DNP). In hypoxia (10%
O2 breathing, 60% arterial
O2 saturation),
O2, as measured by an
open-flow technique, was less than in normoxia (~80%). Successive
DNP injections (6 mg/kg, 4 times) progressively increased
O2 in both normoxia and
hypoxia by similar amounts. Body temperature slightly increased in
normoxia, whereas it did not change in hypoxia. The DNP-stimulated
O2 during hypoxia could
even exceed the control normoxic value. A single DNP injection (17 mg/kg iv) had a similar metabolic effect; it also resulted in
hypotension and a drop in systemic vascular resistance. We conclude
that pharmacological stimulation of
O2 counteracts the
O2 drop determined by
hypoxia and stimulates O2
not dissimilarly from normoxia. Hypoxic hypometabolism is likely to
reflect a regulated process of depression of thermogenesis, with no
limitation in cellular O2
availability.
cellular hypoxia; hypoxic ventilatory response; oxidative
phosphorylation; oxygen consumption; uncoupling agents
INTRODUCTION IN MANY MAMMALS, acute hypoxia, in addition to
increasing pulmonary ventilation, decreases
O2 consumption
( If the hypoxic hypometabolic condition were a manifestation of a
regulated thermogenic inhibition, one would expect that in hypoxia
METHODS The study was performed on adult male Sprague-Dawley rats and was
approved by the Animal Ethics Committee of this institution. The body
weight of the rats ranged between 193 and 227 g [mean 204 ± 3 (SE) g]. One group of animals was used for the metabolic response
to successive administration of DNP in normoxia or hypoxia (hypoxic
hypoxia). A second group was the object of respiratory and
cardiovascular measurements in normoxia, followed by hypoxia before and
after a single injection of DNP.
All measurements were performed on conscious animals, in the afternoon
after the morning preparation, and at an ambient temperature of
15°C, i.e., in moderately cold conditions.
O2). The latter is
particularly apparent in newborn and small adult species (6, 24) and
becomes of paramount importance in cold conditions (12, 21, 31). The
mechanisms of hypoxic hypometabolism are not fully understood, but it
is known that it results mostly from the inhibition of both shivering
and nonshivering thermogenesis (see Ref. 22 for review).
This is likely to be a regulated phenomenon, although the possibility
that it reflects a limitation in
O2 availability has not been
entirely ruled out. The fact that in rats modest hypoxemia lowers
O2, and that this hypoxic
O2 level can be increased by
exposure to cold (7), could be taken as an indication that hypoxic
O2 does not result from
O2 limitation. However, one could
also argue that exposure to cold, by redistributing perfusion from the
peripheral regions to the central organs, improves O2 delivery to tissues which, in
effect, were O2 limited, raising their O2. The
affinity for O2 of many cytosolic
O2-dependent enzymatic pathways is
very low (i.e., high Michaelis constant) compared with the
notoriously high O2 affinity of
the cytochrome oxidase. Hence, a portion of
O2 could already be limited
by O2 supply at a relatively high
level of oxygenation and before any decline in oxidative
phosphorylation (14, 22).
O2 could be increased
pharmacologically by hypermetabolic agents and that this increase would
be approximately similar to that observed in normoxia. On the other
hand, if limitation in O2
availability to some tissues were a contributing factor to hypoxic hypometabolism, we would then expect hypermetabolic agents to
be less effective in raising
O2 in hypoxia than in
normoxia. In the present study, we tested this hypothesis by using
2,4-dinitrophenol (DNP). This drug increases cellular
O2 by uncoupling oxidative phosphorylation, i.e., by freeing the oxidative processes of the mitochondrial respiratory chain from the constraint of high-energy phosphorylation (1). This property of DNP has been often exploited to
study ventilatory and cardiovascular responses to increased metabolic
demands (13, 16-20, 29, 33). We have measured the effect of DNP
administration on O2 of
conscious rats during air breathing or hypoxia. The results supported
the hypothesis and are in agreement with the concept that hypoxic
hypometabolism is a regulated response and not necessarily a reflection
of limited O2 availability at the
mitochondrial level.
O2,
CO2 production (CO2)],
as well as minute expiratory ventilation
(E). The venous and arterial catheters emerged outside the chamber. Both were
connected to syringes via a three-way stopcock for blood sampling, and
the arterial catheter was connected to a pressure transducer (model
1290C, Hewlett-Packard) for MAP and heart rate measurements. The
sampling procedure and MAP recording were as previously described in
detail (31).
The chamber temperature was preset at 15°C by adjusting the
temperature of a water jacket surrounding the chamber. At this temperature, normoxic thermogenesis was expected to be increased, thus
magnifying the hypometabolic response to hypoxia.
Gaseous metabolism was measured by an open flow system, following the
same procedure described previously (6, 31). Briefly, a polarographic
O2 analyzer (Beckman OM-11) and an
infrared CO2 analyzer (Beckman
LB-2) monitored the O2 and
CO2 concentrations of a gas
delivered through the chamber at a constant flow rate (900-1,050
ml/min) maintained by a calibrated flowmeter. Data were acquired and
displayed on a computer monitor every 5 s.
O2 and
CO2 were computed from the
average inflow-outflow difference in gas concentration over a time
interval, multiplied by the flow. The error introduced by a respiratory
quotient (RQ) <1, for the O2 and
CO2 concentrations used in the
present study, was small, ranging from almost zero for
CO2 to 6% for
O2 in the worst case of RQ = 0.7 in normoxia (5). Therefore, no RQ correction was considered
necessary. O2 and
CO2 are presented,
normalized by the weight of the animal in kilograms at
STPD conditions.
The breathing pattern was monitored by the barometric technique, after
complete sealing of the chamber for the period of ~100 breaths (<1
min), and the oscillations of chamber pressure were recorded on paper
at a speed of 10 mm/s. From the record and the appropriate correction
factors, breathing frequency (f) and tidal volume
(VT) were determined with the
help of a graphics tablet connected to a minicomputer, from which
pulmonary ventilation (E = f · VT) was
calculated (23).
Blood samples were collected anaerobically (~0.25 ml/sample) and
immediately analyzed for blood gases
(PO2,
PCO2, and pH at the rat's
Tb) with a blood-gas analyzer
(Instrumentation Laboratory System 1302, with repeated calibration
before the measurements), and for hemoglobin (Hb) concentration (g/100
ml) and arterial O2 saturation
(SaO2 in %) with
a hemoximeter (OSM2b, Radiometer). Additional venous blood (~0.2 ml)
was sampled in normoxia and hypoxia + DNP for the purpose of measuring
lactate concentration. The deproteinized sample (1:2 vol/vol in 8%
perchloric acid) was centrifuged (2,700 revolutions/min for 20 min at
4°C). The supernatant was assayed spectrophotometrically following
standard enzymatic procedures (lactate kit 826, Sigma Chemical, St.
Louis, MO).
From the above data, arterial and venous
O2 contents
(CaO2,
CvO2,
respectively, in ml O2/100 ml
blood) were calculated from the corresponding
O2 saturation, as
(SO2/100) · Hb · 1.34. Cardiac output (CO; in
ml · kg
1 · min1)
was calculated from the Fick principle as
|
1 · kg · min)
were also computed. Pulmonary volumes
(VT,
E) are presented at BTPS condition.
The hypoxic gas (10% O2) was
prepared by blending air and pure
N2 with flowmeters. DNP (Sigma
Chemical) was prepared fresh as a 0.6 or 1.2% solution in
phosphate-buffered saline (PBS) at pH 7.4.
Protocols.
Experiments were conducted in the afternoon, once the animal was
resting quietly, usually ~30 min after its placement in the metabolic
chamber.
A first set of measurements in six rats was obtained for the purpose of
establishing the effect of progressive dosages of DNP in either
normoxia (n = 3) or hypoxia
(n = 3). The normoxic group was
exposed to air followed by injection of 6 mg/kg DNP every 20 min, for a
total of four injections (i.e., a total of 24 mg DNP/kg). In the
hypoxic group, data were first collected in air, followed by hypoxia
(10% O2). DNP was then injected
four times, as for the normoxic group, while hypoxia was maintained. Metabolic data were collected on each condition.
A second set of rats (n = 6) was
studied in normoxia (30-60 min) followed by hypoxia (30 min). As
hypoxia was maintained, PBS was then injected iv, and, after an
additional 20-30 min, DNP was injected in a single dose (17 mg/kg). Injection of PBS was done to test for possible effects of the
DNP vehicle. The DNP dosage was chosen on the basis of on the results
of the first set of experiments. The volumes injected (0.25-0.3
ml) were then flushed with 0.4-0.5 ml of saline. Each period (air,
hypoxia, hypoxia + PBS, and hypoxia + DNP) lasted
~20-30 min, and data were collected toward the end of each
condition. To test the possibility of a further increase in
O2, a second DNP injection
of the same dosage was administered at the end of the measurements in
four rats of this group.
Statistical analysis.
All values are presented as means ± SE. Comparison of the
dose-O2 curves between
normoxia and hypoxia (protocol 1)
was done by unpaired t-test of the
mean values at the corresponding dosages as well as of the intercepts
and slopes of the two linear regression equations. For
protocol 2, significant differences
between mean data were assessed by repeated-measurements analysis of
variance, followed by three post hoc contrasts with Bonferroni's
limitation (air-hypoxia, hypoxia-PBS, PBS-DNP). In all cases, a
significant difference was considered at a level of
P < 0.05.
RESULTS
O2, from 34 to 51 ml · kg1 · min1
(Fig. 1), the slope of the
DNP-O2 curve being
significantly greater than zero (P < 0.01). Tb also increased, from
37.9 ± 0.3 to 39.0 ± 0.2°C.
O2) before and after
successive administration of 6 mg/kg of 2,4-dinitrophenol (DNP) while
breathing air (21% O2, 
) or
hypoxia (10% O2, 
). Hypoxia
decreased O2 from normoxic
value (
). Successive administration of DNP increased
O2 in both normoxic and
hypoxic conditions, by approximately the same amount. Symbols are mean values; bars represent SE; n = 3 rats
per group.
Hypoxia decreased
O2 by ~7
ml · kg1 · min1,
and Tb decreased by almost
2°C. During hypoxia, as in air, DNP administration increased
O2 and by similar amounts. At
the largest dosages, DNP-stimulated
O2 during hypoxia exceeded
the control normoxic value. The hypoxic
DNP-O2 relationship had a
similar slope (P > 0.05) and
significantly lower intercept (P < 0.01) than the corresponding curve in air (Fig. 1). During hypoxia,
unlike normoxia, DNP administration did not significantly change
Tb (from 35.8 ± 0.5°C
before DNP to 35.5 ± 0.5°C after the last DNP injection).
Single injection.
A second set of experiments was performed on six rats, during air
breathing followed by hypoxia, the latter before and after injection of
PBS and DNP. The DNP dosage (17 mg/kg iv) was chosen on the basis of
the results of the first set of measurements. Hypoxia resulted in the
expected drop in O2 to
~75% of normoxia (Fig. 2), a value that
was not affected by injection of the DNP-vehicle PBS. DNP injection, on
the other hand, significantly raised hypoxic O2, on average by 7 ml · kg1 · min1
(Fig. 2). Tb decreased with
hypoxia and continued to decrease after PBS and DNP injections.
O2 during air breathing,
hypoxia (10% O2), hypoxia + phosphate-buffered saline (PBS), and hypoxia + bolus injection of DNP
(17 mg/kg), each lasting ~20 min. Symbols are mean values; bars
represent SE; n = 6 rats. * Significant difference from immediately preceding condition, P < 0.05. On termination,
an additional DNP injection during hypoxia further increased
O2 to 43 ± 1 ml · kg1 · min1
(n = 4 rats), data not
shown.
The corresponding data concerning metabolic, ventilatory, and cardiovascular variables, including blood gases and derived parameters, are summarized in Tables 1 and 2. Hypoxia resulted in hyperventilation, with a doubling of
E/O2
and a drop in arterial PCO2
(PaCO2) of ~10 Torr, mild
hypotension, and no changes in CO. PBS injection had no significant
effect on most parameters, the only exception being
PaCO2, which further decreased by 2 Torr.
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E,
in parallel with the increase in
O2, i.e., with no significant
change in
E/O2.
However, the stimulatory effect on
VT exceeded that on f, resulting
in a further decrease in PaCO2 (
3
Torr). MAP dropped to 62 mmHg. Because this was not compensated by a
major increase in CO, peripheral vascular resistance after DNP
decreased further, to ~55% of the normoxic value. Venous lactate in
hypoxia after DNP injection was increased to approximately four times
the normoxic value.
At the end of the measurements, a second injection of DNP was
administered in four rats. It resulted in a further increase in
O2 to ~43 ± 1 ml · kg1 · min1.
DISCUSSION
The main finding of this study was that in conscious rats DNP increased
O2 during hypoxic
hypometabolism, and the increase was similar to that observed in
normoxia. The observations that hypoxic
O2 could be pharmacologically
stimulated to levels even exceeding the normoxic value and that the
sensitivity of O2 for DNP
during hypoxia was similar to that during normoxia (same slope of
DNP-O2 curve, Fig. 1) would
seem to conclusively exclude the possibility that in hypoxia cellular
metabolism is limited by O2
availability. Thus the results are compatible with the hypothesis and
support the notion that the hypometabolic response to hypoxia reflects
a regulated inhibition of some of the processes requiring O2. These processes,
in both newborn and adult mammals, are mostly represented by various
forms of thermogenic mechanisms (22). The validity of this
interpretation will be considered within the discussion of other
results.
O2, we
observed only a 1°C increase in
Tb during air breathing, and
no increase during hypoxia. A species difference could be a factor,
because Tb in the conscious rat
increased only ~1.5°C even when "treated with the maximum
nonfatal dose of DNP" (3). Rats, compared with the more commonly
used dogs, have a greater body surface-to-volume ratio, which, in
combination with the low ambient temperature, the hyperpnea, and the
important decrease in vascular resistance, must have favored heat
dissipation. In some studies in dogs, the use of anesthesia could have
compromised their thermoregulatory mechanisms. Indeed, Williams et al.
(33) mentioned that if the dog was not anesthetized, DNP injection did
not result in hyperthermia.
A number of indirect considerations (22), including experiments of
artificial rewarming of hypoxic newborns (28, 30), have indicated that
the drop in Tb during hypoxia is
the effect, not the cause, of the hypoxic hypometabolism. The fact that
O2 had a similar response to
DNP in normoxia and hypoxia, despite Tb being ~2°C lower in
hypoxia, extends this notion, indicating that the hypoxic change
in Tb does not have any sizable
effect on O2 sensitivity.
Ventilatory responses.
Increases in normoxic O2, of
which the most studied are cold-induced thermogenesis and muscle
exercise, are accompanied by parallel changes in
E (4, 22).
Pharmacological increases in
O2 by use of mitochondrial
uncouplers are also accompanied by corresponding increases in
E, with
perfect or nearly perfect isocapnic conditions (13, 16, 18, 20, 29).
When DNP was administered to the hypoxic rats, we also found a parallel increase in E
and O2, i.e., constancy of
E/O2,
indicating that hypoxic hypometabolism does not hinder this remarkable
association. However, we did observe a small drop in
PaCO2 (~3 Torr), suggesting a slightly disproportionate increase in alveolar ventilation
compared with
E. The
hypotension may have provided an additional ventilatory drive (27). In
addition, the DNP-vehicle PBS was reported to stimulate
E in dogs
(33), and we did observe a small drop in
PaCO2 with injection of PBS alone.
Finally, it is known that DNP, in addition to its generalized
hypermetabolic effect, directly stimulates the activity of the carotid
body (26). One effect of the modest hyperventilation after DNP was the
increase in PO2 from 32 to 36 Torr
(Table 2). This lessening of the hypoxemia with DNP was, however, too
minuscule for an appreciable contribution to the reversal of the
hypoxic hypometabolism.
Cardiovascular responses.
A modest drop in MAP is known to occur in conscious rats when they are
exposed to acute hypoxia (25, 31). A much more important hypotension
developed after injection of DNP and was accompanied by a major
decrease in SVR. The causative link between these events is not clear.
Because Tb was not increased, it
seems unlikely that the drop in vascular resistance was the effect of hyperthermia, although in hypoxia the thermoregulatory set point shifts
to a lower value, and a Tb lower
than in normoxia could still be perceived as an hyperthermic condition
(22). DNP could have decreased the energetic efficiency of the heart,
already challenged by the hypoxia. Indeed, DNP has been frequently used in the past as a model of myocardial failure (See Ref. 13 for review).
In anesthetized dogs, administration of DNP decreased vascular
resistance without a drop in MAP (13, 19), and the same was reported to
occur in the isolated hindlimb preparation, both in normoxia and
hypoxia (2). However, while the dogs were breathing 11%
O2, DNP injection was often
lethal, and death was attributed to a precipitous fall in MAP, even
after artificial cooling to control the hyperthermic problems mentioned
earlier (13).
The drop in vascular resistance after DNP may suggest increased
perfusion to peripheral tissues, e.g., hindlimb skeletal muscles, intestines, fat, and skin, possibly underperfused during hypoxia (15).
In such a case, the increase in
O2 after DNP injection during
hypoxia could also be interpreted as the result of reestablishing full
aerobic metabolism to hypoxic tissues that were, in effect, O2 limited before
DNP. At first glance, the finding that blood lactate was
increased after DNP in hypoxia, with respiratory compensation of the
metabolic acidosis (drop in PaCO2 with
constant pH; Table 2), may be taken in support of this view. However,
an increase in blood lactate after DNP injection should be expected,
because the stimulation of mitochondrial respiration far exceeds the
available O2 (e.g., Refs. 10, 19).
Therefore, the increase in blood lactate is much more likely to be the
direct effect of DNP on tissue metabolism, rather than the systemic
result of reperfusion of anaerobic tissues. In the isolated hindlimb of
anesthetized lambs, DNP administration increased skeletal muscle
O2 even during stagnant
hypoxia, when O2 extraction seemed
limited by O2 availability (11).
Finally, if the increase in
O2 after DNP
injection in hypoxia was mostly the result of reoxygenation of
O2-deprived tissues, the
similarity in O2 sensitivity
to DNP between normoxia and hypoxia (Fig. 1) would be a curious
coincidence difficult to explain.
Other interventions.
A few scattered data from previous studies are pertinent to the
issue of metabolic stimulation during hypoxic hypometabolism. In
conscious dogs made severely hypoxic by breathing 7%
O2, the endorphin-inhibitor
naloxone stimulated
E without
changes in blood gases (32). The simplest interpretation is that
naloxone raised hypoxic O2.
Indeed, in two dogs in which
O2 was measured, Schaeffer
and Haddad (32) mentioned that hypoxia dropped metabolism by
50-70% and naloxone more than doubled hypoxic
O2, with no changes in
arterial gases. A comparison of data collected by Gonzalez and
collaborators (8, 9) in conscious rats shows that, during acute
hypoxia, resting O2 decreased
~15%, whereas it doubled during hypoxic exercise. Despite their
paucity and anecdotal appearance, these data are in complete agreement
with the information in the present study. Indeed, if hypoxic
hypometabolism is the expression of selective inhibition of
thermogenesis, without cellular O2 limitation, it would seem likely that not only DNP but also other pharmacological or physiological interventions should result in an
increase of hypoxic O2. It
also follows that in hypoxia the hypometabolic state should not be
assumed to remain constant, and interventions altering ventilatory or
cardiovascular parameters may be mediated by its changes.
In conclusion, DNP stimulated
O2 in conscious rats, not
only during normoxia but also in hypoxia, and by similar amounts, despite the hypometabolic state of the hypoxic condition. The most
likely interpretation is that during hypoxic hypometabolism cellular
O2 availability is not limited.
Rather, hypoxic hypometabolism could indicate a selective, regulated
inhibition of some processes requiring
O2. Among these processes, those
pertinent to thermogenesis are probably the most important.
ACKNOWLEDGEMENTS
We thank Lina Naso for technical assistance, and M. Maskrey for critical reading of the manuscript.
FOOTNOTES
Address for reprint requests: J. P. Mortola, Dept. of Physiology, Rm. 1121, McGill Univ., 3655 Drummond St., Montreal, Quebec, Canada H3G 1Y6 (E-mail: jacopo{at}physio.mcgill.ca).
Received 14 January 1997; accepted in final form 21 April 1997.
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