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Exercise Physiology Laboratory, Department of Physiology, University of Arizona, Tucson, Arizona 85721-0093
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
FOOTNOTES
REFERENCES
ABSTRACT 
Tipton, Charles M., and Lisa A. Sebastian. Dobutamine
as a countermeasure for reduced exercise performance of rats exposed to
simulated microgravity. J. Appl.
Physiol. 82(5): 1607-1615, 1997.
Post-spaceflight
results and findings from humans and rodents after conditions of bed
rest or simulated microgravity indicate maximum exercise performance is
significantly compromised. However, the chronic administration of
dobutamine (a synthetic adrenomimetic) to humans in relevant
experiments improves exercise performance by mechanisms that prevent
the decline in peak O2 consumption (
O2 peak) and reduce
the concentration of lactic acid measured in the blood. Although
dobutamine restores maximum
O2
values in animals participating in simulated microgravity
studies, it is unknown whether injections of this
1-,
1-, and
2-adrenoceptor agonist in rats
will enhance exercise performance. To investigate this, adult male rats
were assigned to three experimental groups: caged control receiving
saline; head-down, tail-suspended (HDS) receiving saline (HDS-S); and
an HDS group receiving dobutamine hydrochloride injections (1.8 mg/kg
twice daily per rat). Treadmill tests were performed before suspension,
at 14 days, and after 21 days.
O2 peak, run time,
and the rate of rise in colonic temperature (heating index) were
evaluated after 14 days, whereas at 21 days, hemodynamic responses
(heart rate, systolic blood pressure, and double product) were
determined during submaximal exercise with blood pH, blood gases, and
lactic acid concentration values obtained during maximal exercise. In
contrast to the results for the HDS-S rats, dobutamine administration
did restore O2 peak and "normalized" lactic acid concentrations during maximal
exercise. However, daily injections were unable to enhance exercise
performance aspects associated with treadmill run time, the mechanical
efficiency of running, the heating index, or the retention of muscle
and body mass. These simulated microgravity findings suggest that dobutamine's potential value as a countermeasure for postflight maximal performance or for egress emergencies is limited and that other
countermeasures must be considered.
tail suspension and dobutamine; aerobic capacity and suspension; temperature regulation; suspension and lactic acid
INTRODUCTION RESULTS OBTAINED FROM ASTRONAUTS after spaceflight (19)
or from subjects participating in simulated microgravity experiments (horizontal bed rest or head-down tilt; see Refs. 5, 28, 32) have
demonstrated that exercise performance is significantly compromised.
Because return from microgravity carries the risk for unsafe and
unscheduled egress circumstances, inflight countermeasures to ensure
postflight exercise performance are necessary for future space missions
(23, 24).
When dobutamine, a synthetic adrenomimetic drug capable of stimulating
METHODS
1-,
1-, and
2-adrenoceptors (18, 27, 29), has been administered to subjects participating in bed-rest
experiments, their exercise tolerance and aerobic capacity were
significantly improved compared with results from controls receiving
saline (32, 33). Moreover, chronic infusions of dobutamine to animals were associated with improved myocardial
O2 consumption
(O2) during submaximal
exercise, significantly lower resting and exercise blood concentrations
of lactic acid and catecholamines, as well as increased exercise
tolerance (6, 14, 20). Although Desplanches and co-workers (9)
demonstrated in rats that dobutamine would prevent the decrease in
maximum O2
(O2 max)
characteristic of simulated microgravity conditions (25), their
experimental design did not effectively address other performance
aspects related to reduced run time (25, 34, 38), decreased mechanical
efficiency (25, 34, 38), elevated concentrations of blood lactic acid and hydrogen ions (34), or the increased rate of rise in colonic temperature regulation (34). Consequently, to determine whether these
aspects of exercise performance were improved and whether this
adrenomimetic agonist deserved serious consideration as a potential
countermeasure for future space missions, we conducted a
simulated-microgravity study with rats receiving dobutamine.
O2 max results of
cage control animals; however, this dosage would restore the aerobic
capacity of suspended rats. All testing was completed on
day 21; 20 h later, the rats were
anesthetized with pentobarbital sodium (50 mg/kg). Then select muscles
of the hindlimbs were excised before the heart, lungs, kidney, spleen,
and adrenal gland were removed, weighed, and heated in an oven at
100°C before determining their dry weight and water content.
O2
(O2 peak) and the change in the heating index, then randomly assigned to an experimental group. One animal assigned to a suspension group died before the experiment began.
Exercise testing.
All animals performed a progressive treadmill test that has been
described previously (25). Specifically, before the start of the study
and on days 14 and
21, the rat rested for ~30 min in an
airtight Plexiglas chamber that enclosed a motorized treadmill. The
chamber had a constant airflow created by a vacuum pump and was
connected to calibrated O2 and
CO2 analyzers (Applied
Electrochemistry, Ametek, Pittsburgh, PA) that were used to measure the
content of expired air. Once resting values had been obtained, the
animal performed a standardized exercise test that consisted of various 3-min stages. Stage 1 consisted of
running at 13.4 m/min on 0° grade; stages
2-5 were 16.1 m/min at 5°, 21.4 m/min at
10°, 26.8 m/min at 10°, and 32.2 m/min at 12.5°,
respectively. The testing continued until the animal was unwilling or
unable to maintain a position in the middle of the treadmill. Expired
values were recorded after 2 min of the exercise stage had been
completed. For purposes of this study,
O2 and
CO2 results are listed as peak
values for STPD conditions, expressed
on a mass basis, and were calculated by using computer programs that
contained the gas-exchange equations published by Consolazio et al.
(4). On day 14, one rat in the HDS-S
group was injured when he dove under the belt. Subsequently, he was
killed, and his data were removed from the group for data analysis
purposes.
When changes in colonic temperatures were obtained before and after a
treadmill test (34), a commercial thermistor (model 402, Yellow Springs
Instruments, Yellow Springs, OH) was inserted 8 cm into the colon. Once
equilibration was achieved, the temperature was recorded by using a
Thermistemp recorder (model 42, Yellow Springs Instruments). These
values, obtained when the animal was unrestrained on a table near the
treadmill, were used to determine the heating index (rate of rise in
colonic temperature in degrees Celsius per minute of run time). The
animals were tested for
O2 peak and
the heating index before the study began and again 14 days later. On
day 21, the rats performed a
stage 2 treadmill test to determine
changes in heart rate (HR), systolic blood pressures (SBP), and the
double product (HR × SBP) (16). These results were obtained at
rest (while animals were suspended) and during exercise by connecting a
precalibrated Statham pressure transducer (P23 DB, Gould-Statham, Hato
Rey, PR) connected to the catheter in the carotid artery and to a
precalibrated Gilson recorder. After the stage
2 test was completed, the catheter connection to the
transducer was removed and used to obtain arterial blood during maximal
exercise. The testing conditions for maximal exercise were determined
from day 14 O2 peak results.
To calculate the mechanical efficiency of running and its changes,
stage 2 exercise testing results
before the experiment and after 14 days of suspension were used for
each rat. Specifically, the mass of the animal, the distance covered in
1 min, and the sine of the 5° treadmill angle were employed to
calculate the kilogram-meters of work performed (3). The
amount of O2 consumed per minute
during rest and exercise, and the respective respiratory exchange
ratio values were used to determine the calories of energy expended. Gross and net mechanical efficiency were
calculated by using the formulas listed by Brooks et al. (3) with the constant of 1 kg · m being equal to
2.343 calories (3).
Resting colonic temperature and arterial constituents.
Each day, starting at 8:00 AM, colonic temperatures were recorded from
each rat in a standardized manner by using the same equipment and
procedures described in the exercise-testing procedures to evaluate
changes in the heating index. On day
21, when measurements of colonic temperature had been
obtained and the animal had rested for 30 min (weightbearing or while
suspended), two arterial blood samples (0.8 ml) were obtained and
placed in an ice bath. Then donor blood was infused via the venous
canula to replace the withdrawn volume before the animal was placed in
an open treadmill. The findings from day
14 testing were then used to define the maximal testing
conditions before the rat performed a stage
2 test for HR and BP measurements. Once the
measurements were completed, the rat ran at its maximal capacity. After
hematocrits were obtained, 0.8 ml of arterial blood was obtained under
anaerobic conditions for determination of hemoglobin, pH, bicarbonate,
and blood gases, and another 0.8 ml was secured for lactic acid
concentration. The samples were then stored in ice until analyzed.
Immediately after exercise, the colonic temperature of the rat was
measured, and an equivalent amount of blood from a donor animal was
infused into the rat before it was returned to its cage.
One blood sample was analyzed for hemoglobin, pH, arterial
PO2
(PaO2), arterial
PCO2
(PaCO2), and bicarbonate by using a
previously calibrated automated blood-gas analyzer (model 1640, Instrumentation Laboratory) operated by certified research technicians
in the Pulmonary Testing Laboratory of the University of Arizona Health
Sciences Center. The colonic temperature of the rat was used to correct
PaO2 and
PaCO2 values by using an unpublished
computer program developed by Dr. J. Dempsey of the University of
Wisconsin at Madison. The second arterial sample was analyzed for
lactic acid concentration by using procedures from Davies et al. (7).
In brief, the blood was instantly deproteinized with 1 ml of ice-cold
perchloric acid (8% wt/vol), shaken on a Vortex, and then
centrifuged before the supernatant was neutralized with KOH. Lactic
acid concentration (in mM) was measured with calibrated solutions and a
model 2700 biochemistry analyzer (Yellow Springs
Instruments).
Data analyses.
Results were subjected to statistical analyses to determine means ± SE. Analysis of variance for repeated measures was followed to
determine intergroup and intragroup differences. When a significant F value was obtained, post hoc
analyses were performed by using computer programs for Duncan's
multiple-range test. The 0.05 probability level was selected to denote
statistical significance of the findings.
RESULTS
7.5%; HDS-D, 8.0%) and did not return to their
presuspension values before being killed (Table 1). Suspension, either
with saline or dobutamine injections, was associated with significant
atrophy of ankle flexor muscles (soleus and plantaris; Table 2).
Moreover, dobutamine was unable to prevent the atrophy of an ankle
flexor muscle (extensor digitorum longus, Table 2). Suspension was
associated with an increase in mass of the adrenal gland, whereas
dobutamine and suspension were identified with an increase in the
relative mass of the heart compared with the control animals (Table 2).
On the other hand, the experiment did not cause significant intergroup
differences in the mass or the tissue-body mass ratio of
the lungs, kidney, or spleen. In addition, calculations of percent
water for these various structures revealed no intergroup differences
that had statistical significance (Table 2).
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O2 peak findings that
showed the HDS-S rats had significant decreases (13.5%) in
contrast to the nonsignificant changes exhibited by the CC-S
(3.1%) or by the HDS-D rats (0.6%). However, this
restoration of aerobic performance by dobutamine was not evident in the
run-time results of Fig. 2. The HDS-S rats exhibited a significant decrease of 34.4%, whereas the HDS-D group had
a significant reduction of 27.8%. Coupled with decreases in run times
for the two HDS groups were significant increases in their rate of
heating (Fig. 3). Whereas the CC-S group
had a nonsignificant elevation of 14.3%, both HDS groups had
significant increases (87.5 and 58.3% for HDS-S and HDS-D animals,
respectively). However, these differences had no statistical importance
(F = 0.64). The intergroup
F value of 5.00 was statistically
significant at the 0.05 level.
Table 5 demonstrates no significant intergroup differences in mechanical efficiency of running at a submaximal-intensity level (stage 2). Although the HDS-S animals exhibited a 30.6% reduction in this measure, this change was not statistically significant at the 0.05 level (F = 3.79). On the other hand, the HDS-D rats demonstrated a reduction of 28.9%, which was statistically significant (F = 13.28), whereas the CC-S had values that were similar to their baseline results (F = 0.01).
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DISCUSSION
Before evaluating the significance of these results from an animal
model for simulated conditions of microgravity, it is important to
realize that, despite the numerous physiological changes that are
associated with spaceflight (24), maximal exercise in space, as
evaluated by
O2 max tests with
astronauts, is not significantly changed (19). Consequently, a major
issue facing National Aeronautics and Space Administration is whether
returning astronauts have the physiological ability to perform
sustained maximal exercise after scheduled or unscheduled landings.
Data collected after actual (19) or simulated conditions for
microgravity (5, 28, 32, 34, 38, 39) suggest they would experience
marked difficulty.
Sufficient evidence from animal and human investigations has
demonstrated that maximal exercise requires the activation and participation of the sympathetic nervous system (26). However, the
inflight changes in this component of the autonomic nervous system are
unclear. To date, no direct recordings of sympathetic nerve activity
(microneurography) have been done, and inflight measurements of
catecholamines have shown both increases and decreases with brief
duration missions and increases with much longer ones (34). But urinary
data collected on the day of landing of Mir cosmonauts who had been in
space for 1 yr showed decreases in norepinephrine (NE) and increases in
epinephrine (Epi; Ref. 15). One day later, the plasma concentrations of
both NE and Epi were elevated above preflight values. In a 9-day
head-down-tilt experiment, plasma concentrations of both catecholamines
were reduced (12), whereas in a 120-day study, plasma Epi was elevated
whereas NE was decreased compared with baseline values (8). Of
relevance are the reports that animals flown in space for 6.5 days had
a reduction in the number of myocardial -receptors compared with their controls (17), and that suspended rats had significantly higher
resting plasma concentrations of catecholamines (NE for 14 days, Epi
for 7 days) than their caged controls (39). Our results with exercising
rats after suspension (75%
O2 max), compared with
their caged controls, not only exhibited significant decreases in
cardiac output, stroke volume, and blood flow to leg muscles (37) but
showed that the estimated sympathetic nerve traffic (rate of NE
depletion) to the myocardium was 82% lower and to the soleus muscle
was 47% higher (36). Hence, we concluded that simulated microgravity
reduced exercise performance by an inability to augment cardiac output
or to effectively redistribute blood flow because of an altered
sympathetic nervous system.
It is known that dobutamine acts directly on
1-adrenoceptors in the heart
and enhances myocardial contractility (6, 18). Thus the normalization
of the
O2 peak
results in Fig. 1 was likely a result of an elevated
cardiac output caused by an improved stroke volume. Similar findings
were noted for post-bed-rest subjects performing an exercise test after
receiving injections of dobutamine (33). Besides improving stroke
volume and O2 delivery, dobutamine has been associated with increased arteriovenous O2
differences (33) and retention of plasma volume (33). Therefore, the
normalization of the pH and lactic acid data summarized in Figs. 5 and
6 could be explained, in part, by these effects. Limited human data
from cosmonauts (21), postflight animal results (1, 34, 35), and
findings from bed-rest studies (5, 28) suggest that microgravity favors
the utilization of carbohydrates by skeletal muscles and decreases the
utilization of free fatty acids. Thus, value of dobutamine as a
potential countermeasure is enhanced by these collective results.
On the other hand, suspension caused significant reductions in
treadmill run time, and the repeated injections of dobutamine demonstrated no significant group effect (Fig. 2). In fact, mature or
old (34), chemically sympathectomized (36, 38), or hypophysectomized rats (34) that have been previously suspended also exhibit significant reductions in this measure. Many years ago, Donovan and Brooks (10)
concluded from their rat metabolic studies that tests for O2 max and endurance
running were evaluating different physiological mechanisms. Although
the results support their statement and indicate that exogenous
stimulation of adrenoceptors had no apparent benefit, our findings
do not delineate the reasons why.
Dobutamine administration was also unable to prevent the decrease in the mechanical efficiency of running that is associated with suspension (Table 5). Similar trends have been reported in normal, sham-operated, hypophysectomized, or chemically sympathectomized rats, although with these animals (34, 39), an apparent mechanical efficiency value was calculated (2). We decided not to present the mechanical efficiency data in this manner, because this regression method requires more data points and because we were interested in comparing the absolute changes that occurred during stage 2 exercise (16.1 m/min at 5° grade). Why mechanical efficiency decreases with conditions of simulated microgravity is not clear. We repeatedly observe that rats after suspension will run with an altered gait which suggests that a change in central command has occurred because of different sensory stimuli. This situation could result in a recruitment of different muscle groups, which could explain both the gait changes and the decrease in mechanical efficiency.
The decreases in body and muscle mass (Tables 1 and 2) could also
contribute to the decrease in treadmill run time (Fig. 2) and to the
decline in mechanical efficiency (Table 5). However, it was apparent
that dobutamine administration was unable to prevent the decline in
mass that is characteristic of male animals exposed to conditions of
simulated microgravity (34). Moreover, inspection of Table 2 for
antigravity muscle differences showed the HDS-D rats had values for the
soleus and plantaris muscles that were similar to those of the HDS-S
rats. The soleus results confirmed the findings of Desplanches et al.
(9), who demonstrated that significant decreases (~60%) had occurred
after 35 days of suspension. On the other hand, the decrease in body
mass reported by Desplanches et al. was not statistically significant
for their younger female rats. Because clembuterol injections in rats
(an adrenomimetic 2-receptor
agonist) can increase body and hindlimb muscle mass, as well as muscle
functional characteristics (11), differences in
2-receptor
properties may explain our negative results and those reported by
Desplanches et al. (9). Although Sullivan et al. (33) attributed an
increase in aerobic enzyme activity to the actions of dobutamine, this
trend was not present in the muscle data published by Desplanches and
associates (9).
Numerous reports from space suggest that astronauts and cosmonauts
experience problems in their ability to regulate body temperature (13,
34). When temperature regulation experiments have been conducted with
subjects confined to bed for 14 days, the submaximal exercise data
indicated the bed-rested subjects had significantly higher rectal
temperatures than their controls (13). Because the
temperature-regulating system is intimately associated with the
functions of the sympathetic nervous system, we speculated that
dobutamine would help maintain resting colonic temperatures and enhance
vasodilation mechanisms during exercise. The resting-temperature data
in Table 3 indicated that this postulate was not confirmed, as the
HDS-D animals exhibited a decline in colonic temperature that was
statistically significant at the 0.05 level. Unexpectedly, the data in
Table 4 indicated the HDS-S rats did not demonstrate a reduction in
colonic temperature, as reported by Shellock et al. (30) and by our
laboratory (34). Although we cannot state why these specific rats did
not exhibit a significant decline in their mean colonic temperature, we
can state that daily injections of dobutamine were unable to prevent a
reduction. Because dobutamine increases cardiac output and stroke
volume, prevents a fall in plasma volume (32), and acts on
2-adrenoceptors (29), we expected that it would influence the rate of heating index (change in
colonic temperature/min) for the HDS-D rats after exercise. As shown in
Fig. 3, both groups of HDS animals had significant increases in this
index, suggesting that their ability to dissipate a rapidly increasing
heat load had been impaired.
This is an interesting and unexpected finding and may be related, in part, to both groups having significantly shorter run times. The pre- and postexercise colonic temperatures in Table 4 indicate that the treadmill test was sufficiently strenuous to significantly elevate these measures. However, colonic temperatures from the various groups were not sufficiently different to explain their heating index values. As in previous experiments (34), HDS-S rats exhibited trends for higher postexercise values than did their saline-injected controls. However, these differences had no statistical significance. Animals receiving dobutamine had pre- and postexercise values that were similar to the other two groups.
A study of head-down humans in Russia (31) showed that PaO2 values had become significantly decreased with time, presumably because of an increase in pulmonary edema. Because our short-term studies with rats had suggested that lungs had become heavier with suspension (34), we secured blood-gas measurements before (while tilted) and during exercise. However, there were no PaO2 values (Table 6) or lung wet and dry weight results (Table 2) that indicated 14 to 21 days of suspension had a significant influence on these parameters. The other blood data in Table 6 demonstrated that the exercise performed produced significant changes, but none of the intergroup differences, except hematocrit, had statistical importance or dramatized the value of dobutamine as a countermeasure. Frankly, it is unclear why the hematocrit measure with the HDS-S animals was significantly different after exercise (Table 6). We do know that suspension is associated with significant reductions in plasma and red blood cell volumes (25, 34), and this relationship could explain the resting value. However, because exercise is associated with hemoconcentration rather than hemodilution, we must refrain from placing biological significance on the intergroup F value shown in Table 6.
Dobutamine is known to increase myocardial function and
O2 (14, 20); hence, we
collected submaximal exercise data and calculated the double product to
indirectly assess the changes in myocardial
O2 and cardiac contractility
(16). The intergroup exercise data in Table 7 for
stage 2 submaximal exercise shows, compared with control animals, that the HDS-D rats had higher values
for HR (11%) and a lower (4%) SBP. The net effect for estimated myocardial O2 consumption was an increase. It is possible
that the HDS-D rats had a slightly higher stroke volume that enabled them to achieve a higher O2
in a shorter period of time than the CC-S rats. If correct, the
kinetics of O2 with
dobutamine should be investigated in greater detail.
In summary, we used an animal model for simulated microgravity to
investigate the value of dobutamine as a potential countermeasure for
post-spaceflight decrease in exercise performance. We confirmed that
O2 peak was
retained and demonstrated that lactic acid concentrations during
maximal exercise exhibited a trend toward normalization by the
dobutamine treatment. However, this adrenomimetic agonist was
ineffective in restoring treadmill run time, reducing the rate of rise
of colonic temperature after exercise, or preventing the decrease in
the mechanical efficiency of running. In addition, dobutamine was
unable to prevent the decline in the mass of the body or of select
ankle flexors. Finally, resting colonic temperature was significantly
decreased with 14 days of suspension. The impression from these
collective results is that the value of dobutamine as a countermeasure
for post-spaceflight exercise performance is limited to select aerobic
mechanisms and that other approaches and compounds will be needed for
future spaceflights.
FOOTNOTES
Address for reprint requests: C. M. Tipton, Exercise Physiology Laboratory, Dept. of Physiology, Univ. of Arizona, Ina Gittings Bldg., Tucson, AZ 85721-0093.
Received 12 July 1996; accepted in final form 23 December 1996.
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