Prostaglandin
El hyperthermia:
on ability to work in the heat
effects
RALPH
FRANCESCONI
AND MILTON
MAGER
US Army Research Institute of Environmental
Medicine,
FRANCESCONI,RALPH,AND
MILTON MAGER. Prostaglandin
effects on ability to work in the heat. J. Appl.
Physiol.: Respirat. Environ.
Exercise Physiol. 51(l) : 62-67,
I981.-To
assess the effects of preinduced hyperthermia
on the
ability to exercise in the heat, prostaglandin
El (PGEI) was
administered
intracerebroventricularly
to male rats weighing
275-350g. Following injection of PGE1, a fever of 2°C developed
within 20-30 min, at which time a l-ml blood sample was taken.
When these animals exercised in the heat (35°C) to hyperthermic exhaustion (42.5-43”C),
their endurance capacity was significantly reduced (P < 0.001) when compared with controls.
Exercise to hyperthermic
exhaustion resulted in significantly
(P < 0.05, minimal) increased plasma levels of lactate, potassium, and urea nitrogen
in both control animals and those
receiving PGE1. However, PGE1 pretreatment
did not exacerbate these increments. Plasma glucose and sodium levels were
significantly
(P < 0.05) increased in PGEI-treated
animals,
whereas glucose levels were reduced significantly
(P < 0.05) in
both groups postrun. We concluded that preinduced hyperthermia severely reduces the ability to work in the heat. Although
the clinical chemical indices of heat injury are unaffected by
PGE, pretreatment,
the effects of PGEI administration
on
circulating levels of glucose and sodium require further study.
E, hyperthermia:
heat-exercise injury;
gain and loss
RECENTLY
endurance
WE HAVE
capacity;
UNDERTAKEN
plasma indices; heat
a series
of studies
designed to quantitate the debilitating effects of a variety
of factors known to predispose individuals to heat-exercise injury. For example, it has been extensively reported
that chronic usage of the phenothiazine drugs might
compromise the ability to withstand heat stress (21, 25).
To investigate this possibility, we chronically administered a representative phenothiazine, chlorpromazine, to
rats and quantitated its effects on endurance capacity,
thermoregulatory responses,and pathochemical manifestations (11). We also completed similar experiments using
various percentages of ethanol as the sole source of
drinking water (12). Other conditions that have been
documented to predispose subjects to heat injury include
obesity, advanced age, recent immunization, fatigue, and
prior heat illness. Several recent publications (1, 3, 4, 19,
26, 27) noted that infectious diseases with fever may
predispose the afflicted individuals to a greater risk of
serious heat injury, because the increased metabolic heat
production is exacerbated by the ambient and/or work
conditions. However, as in the case of many of the
62
Natick,
Massachusetts
01760
aforementioned factors, we are unaware of any reports
describing quantitatively
the physiological cost or the
severity of the heat injury incurred when work in the
heat follows the preinduction of a hyperthermic condition.
To this end, a pharmacologic dose of prostaglandin El
(PGEI) was administered to experimental rats for the
rapid and consistent induction of appropriate hyperthermia. The rats were subsequently exercised in the heat to
hyperthermic exhaustion and the results compared with
those of control animals. We were thus able to quantitate
the pathophysiological and thermoregulatory effects of
preinduced hyperthermia on the ability to exercise in the
heat.
METHODS
Adult male rats (CD, Charles River Breeding Laboratories, Wilmington, MA), weighing 275-350 g at the time
of experimentation, were used in all investigations. The
rats were housed in windowless rooms (one animal/wirebottomed cage) with automatically controlled fluorescent
lighting (on, 0600-1800 h), at an ambient temperature of
22 -* 1°C until they were used. Food (Charles River
laboratory chow) and water were available ad libitum.
The rats were usually maintained under these conditions
for 5-7 days to ensure stabilization of temperature
rhythms and dietary habits. On the day before an experiment each rat, anesthetized with 50 mg/kg pentobarbital
sodium ip, was fitted with a permanent stainless steel
cannula, which was implanted in the lateral cerebral
ventricle by stereotaxic means. The cannula consisted of
a beveled 20-gauge needle, which was affixed to the
cranium with Permabond (methyl a-cyanoacrylate) and
secured with dental cement (zinc oxide and Eugenol).
While the rat was still unconscious, a permanent indwelling catheter (Silastic) was inserted into the external
jugular vein for rapid convenient blood sampling. The
animals were then allowed to recover from surgery for
approximately 24 h.
Immediately before the experiment, a rectal thermistor
(Yellow Springs Instrument,, series 700) was inserted to
a depth of 7 cm, and a skin probe was securely affixed
midlength on the tail for monitoring rectal (T,,) and skin
(T& temperatures. The surgical procedure of the previous day had no effect on initial T,, and Tsk, nor did the
cannula affect endurance capacity or thermoregulation
PGEl
HYPERTHERMIA
AND
WORK
IN
THE
63
HEAT
in control animals. Following a short stabilization
period
(30-60 min), experimental animals received an intracerebroventricular
injection consisting of 40 lug PGEI (Sigma
Chemical) /20 ~1 sterile nonpyrogenic
physiological
saline. The PGEl was originally dissolved in a minimal
volume of 70% ethanol, diluted with the physiological
saline, and deep frozen (-20°C)
until used. Control animals received an equivolumetric
injection of the physiological saline. T,, and T,k were then monitored
closely
until T,, of the experimental
group reached 39.5-4O”C,
which ordinarily required 20-30 min.
When T,, reached this predetermined
level, or 20-30
min after injection of saline in control rats, 1 ml of blood
was removed from the previously implanted intravenous
catheter; a microhematocrit was immediately obtained,
and the remainder of the blood was centrifuged (10,000
g, 4”C), the plasma removed, deepfrozen (-20°C)) and
stored for subsequent assay. After removal of the blood
sample, tim,e 0, T,, and Tsk were recorded and the rats
rapidly removed to a hot (35 t 0.5”C, 25% rh) stainless
steel chamber where the rat was exercised (9.14 m/min,
0” angle of incline) until hyperthermic exhaustion ensued
(T re = 42.5 - 43°C and rats unable to right themselves).
At the time of hyperthermic exhaustion a second blood
sample was drawn and processed exactly as the first.
Plasma samples were assayed for the commonly report!ed indices of heat-exercise exhaustion. Plasma levels
of urea nitrogen (UN), creatine phosphokinase (CPK),
and glucose were quantitated by use of Statzyme test
kits (Worthington Diagnostics) designed for use on the
Gilford Stasar III automated spectrophotometer by procedures detailed in their technical bulletins. Lactic acid
(LA) was assayed using Sigma test kits, and plasma
potassium (K’) and sodium (Na+) levels were determined
by flame photometry (Radiometer, FLM 3) using procedures outlined in their respective technical bulletins.
Data were analyzed by the nonpaired and paired t
tests, where appropriate, and the null hypothesis was
rejected at P < 0.05.
RESULTS
Figure 1 depicts the changes in temperature as a result
of exercise in the heat in the PGEl-hyperthermic
rats
and a group of saline-treated normothermic controls.
Because of small variability (O.l-0.2), the standard errors
of the means were omitted from Figs. 1 and 2. The data
indicate that the PGEI-treated animals had significantly
(P < 0.001) increased Tre before the treadmill exercise
began (-30 min) and throughout the exercise interval.
Figure 2 illustrates the changes in skin temperature
occurring in response to mild exercise in the heat for the
two groups of animals. The appropriate arrow in each of
these two figures clearly demonstrates that the PGEl
hyperthermia significantly (P < 0.001) attenuated the
mean endurance capacity (21.42 vs. 32.33 min) of this
45
Mean Endurance Mean Endurance
Capacity
(control)
44
43
ICV
Injection
42
0
41
0
E
+ 40
39
-
38
PGE,
Control
37
1
- 40
1
L
- 30
- 20
1
-10
//,
‘lo
1
5
L
10
I
15
1
20
1
25
1
30
1
35
1
40
TIME (MIN)
FIG. 1. Effects
of prostaglandin
El ( PGE1)-induced
hyperthermia
on
rectal temperature
(TRE) response of rats to exercise in the heat. Mean
values are depicted
for 12 rats in each group. At time -40 min, 40 pug
PGEJ20
~1 NaCl was injected
intracerebroventricularly
into each
experimental
animal, and at time 0 rats were removed
to a hot environment where they exercised
to hyperthermic
exhaustion.
Control
rats
received
20 ,u10.9% nonpyrogenic
sterile saline.
64
R. FRANCESCONI
group of rats, although maximum T,, and Tsk are unaffected by the pretreatment. Figures 1 and 2 indicate that
while T,, in the PGE1-treated group were significantly
(P c 0.05, minimally) elevated at -30, -20, -10, and 0
min, no apparent differences occurred in Tsk at these
AND
M.
MAGER
intervals. It is also important to note that administration
of physiological saline in control animals had no effects
on either T,, or Tsk.
Figure 3 demonstrates that the initial hyperthermia
induced by central administration of PGEI had no sig-
36
ICV
Injection
Mean Endurance Mean Endurance
32
26
-
PGE,
Control
24
22
1
1
- 40
1
- 30
- 20
1
-10
I
N,
1
1
L
1
I
1
I
L
5
10
15
20
25
30
35
40
TIME (MIN)
FIG.
criteria
2. Effects
of prostaglandin
are as noted under Fig. 1.
PGE1
PRE
CONT
100 _’ POST
CONT
PRE
El (PGE&induced
hyperthermia
on skin
CONT
PRE
PGE,
POST
24
temperature
(TSR)
response
of rats
to exercise
in the heat.
All
PGE,
POST
PGE1
PRE
CONT
POST
FIG. 3. Effects
of prostaglandin
El
(PGEI)
hyperthermia
on plasma levels
of lactate (left) and urea nitrogen
(UN)
(right)
before and after exercise in the
heat. Blood samples
from experimental
and control rats taken immediately
prior
to and subsequent
to exercise in the heat
to hyperthermic
exhaustion.
uPGEl
o-------O
PRE
-
wPGE,
0111110
8
Control
POST
PRE
Control
PGE,
HYPERTHERMIA
AND
WORK
IN
THE
65
HEAT
n&ant
effects on the circulating plasma levels of LA or
UN. In both groups of animals significant
(P c 0.001)
increments were recorded for both indices of heat-exercise stress when prerun levels were compared with postrun levels. This indicated that the hyperthermia
per se,
induced by the intracerebroventricular
administration
of
PGEI, had no effect upon these pathochemical
correlates.
Figure 4 depicts data that demonstrate
that exercise
CONT
PRE
f%E,
POST
to hyperthermic
exhaustion resulted in significant increments in plasma levels of K+ in both control (P < 0.01)
and PGE1-treated
(P < 0.05) animals. Less consistent
data were recorded when the results for Na’ responses
are noted. For example, relatively
low levels of Na’
(mean, 138.7 meq/l) in NaCl-treated
rats, prerun, gave
rise to significant
differences
when pre- and postrun
samples were compared in this group (P < 0.01) and
CONT
PRE
PGE,
POST
PGE1
PRE
CONT
8 . POST
FIG. 4. Effects
of prostaglandin
El
(PGEI)
hyperthermia
on plasma levels
of potassium
(K’)
(left)
and sodium
(Na+) (right)
before and after exercise in
the heat. Blood samples taken as noted
under Fig. 3.
.
.
-PGE,
m
PRE
-PGE,
0---+
Control
CONT
PRE
I
POST
I
PRE
POST
PGE,
POST
Control
CONT
PRE
PGE,
POST
.
160
&60
3
E
t;
ml20
z
3
cs
80
2
2
L'I_.120
zCJ
80
-PGE,
0111110
PRE
FIG. 5. Effects
of prostaglandin
E1
(PGEI)
hyperthermia
on plasma levels
of creatine
phosphokinase
(CPK)
(left)
and glucose (right)
before and after exercise in the heat. Blood samples
taken
as noted under Fig. 3.
-
oIILIp='IQ
Control
POST
PRE
PGE,
Control
POST
66
when PGE&eated
rats, prerun, were compared with
NaCl-treated rats, prerun (P < 0.02).
The relatively brief run times to hyperthermic exhaustion in both groups of animals did not significantly affect
CPK levels (Fig. 5). However, plasma glucose levels were
reduced in both the PGEI-treated group (P < 0.005) and
the NaCl-treated group (P < 0.05). Furthermore control
levels of plasma glucose are reduced significantly (P <
0.05), prerun, when compared with levels recorded for
PGEl-treated rats.
DISCUSSION
Following the discovery of the hyperthermic effects of
the E series of prostaglandins (7, 23), PGEI and PGEZ
have been widely used to induce elevated body temperature in a variety of mammalian species,including rabbits
(28)) sheep (2)) and squirrel monkeys (6). In cats and
rabbits prostaglandin-induced hyperthermia was associated with shivering, vasoconstriction, and piloerection
(23). Crawshaw and Stitt (6) la.ter demonstrated the
effects of ambient temperature on the mechanism of
fever production in squirrel monkeys. In the current
experiments a rather high dosage of PGEI was selected
in order to reduce the latent period before peak temperature was achieved and to ensure a significant hyperthermia during this brief interval. Also, because we were
not injecting directly into the preoptic area of the anterior hypothalamus, we selected this pharmacological dose
of PGE1. Usually we were able to achieve a 1.5-2°C
increment in T,, within 20-30 min after injection and
thus ensure the homogeneity of starting T,, for the
initially hyperthermic rats.
The data depicted in Fig. 2 are consistent with those
of Crawshaw and Stitt (6) who demonstrated in squirrel
monkeys that, at ambient temperatures below thermoneutrality, increases in T,, are due principally to increases
in metabolic rate. In the present experiments there was
no evidence of vasoconstriction as reflected in Tsk or
piloerection involvement in the mechanism of hyperthermia; however, O2 consumption was not measured. Additionally, while the rats were running on the treadmill,
vasodilation was also unaffected by PGEl pretreatment,
as T,k increments during the first lo- or 20-min intervals
were unchanged.
The impetus for the present investigation came primarily from the hypothesis that low-grade fever would
adversely affect the capacity to work in the heat. While
we had previously demonstrated the efficacy of reduced
initial T,, in increasing the time to hyperthermic exhaustion in a hot environment (9, lo), we were unaware of
any report that quantitated the degree of the decrement
which might be expected under hyperthermic conditions.
The data demonstrate that the significant increment in
initial T,, caused a 34% reduction in endurance capacity
under conditions of the present experiment. However,
despite this marked effect upon endurance capacity, examination of the clinical chemical data reveals that PGE1
pretreatment and its accompanying hyperthermia had
virtually no effect on the common clinical chemical indices of heat-exercise injury. Thus plasma levels of LA,
UN, K’, and CPK were not different in prerun samples
R. FRANCESCONI
AND
M.
MAGER
of PGEI-treated rats when compared with data of control
animals. Subsequent to exercise in the heat to hypertherrnic exhaustion, circulating levels of LA, K+, and UN
were all significantly elevated in both PGE1- and salinetreated rats. However, it is important to add that PGEl
hyperthermia did not exacerbate these increments. We
attributed the lack of effect of exercise on CPK levels in
either group both to the mild exercise conditions and the
brevity of this interval.
Effects of PGEl hyperthermia on plasma glucose and
Na’ levels are more difficult to interpret. It can be noted
in Fig. 5 that, in preexercise blood samples, circulating
plasma glucose levels are significantly (P < 0.05) higher
in P@El-treated rats. Examination of the literature reveals evidence that PGEl may have subtle effects on
glucose metabolism. For example, Vaughan (29) has demonstrated that PGEl is approximately one-third as effective as insulin in stimulating fatty acid and glycogen
biosynthesis from glucose. Alternatively,
Hertelendy et
al. (16) demonstrated in rats that intracardiac injection
of PGEI elicited significant increases in plasma growth
hormone levels in 15-20 min, accompanied by elevated
free fatty acid and glucose levels. In their recent reviews
on the physiological effects of prostaglandins, both Hinman (17) and Weeks (30) noted the diversity and inconsistency of the effects of prostaglandins on adenosine
3’,5’-cyclic monophosphate production and sympathetic
nervous system activity. The authors point out that the
effects may be dependent on the tissue studied, the
species selected, the dosage administered, and the route
of administration. Thus it is possible, albeit speculative,
that the large dosage administered centrally in the present experiments may have mediated a glycogenolytic
response causing the higher blood glucose levels in the
PGE1-treated animals. Decrements in these levels postrun are consistent with the data of Costrini et al. (5) who
demonstrated in human heat-stroke patients significantly decreased plasma glucose levels when compared
with levels in heat-exhausted patients. Further studies
are clearly necessary to elucidate the effects of PGEl
administration on glucose and glycogen metabolism.
The moderately increased levels of Na’ in experimental rats (prerun) could be related to the effects of prostaglandin administration on natriuresis and diuresis.
However, effects on Na+ and HZ0 homeostasis are, once
again, inconsistent and dependent on a variety of parameters (20). Both PGAl (8) and PGEl (18) have been
shown to stimulate production of aldosterone by the
adrenals. However, in the present experiments it is
doubtful that PGEl is exerting its effects in this way,
because the relatively brief interval between PGEI administration and blood sampling seems to preclude a
secondary, hormone-mediated role of PGEI. In anesthetized dogs, Mills and Obika (22) had demonstrated that
arterial administration of PGE1 effected increases in Na+,
K’, and HZ0 excretion with no notable effects on plasma
Na+ and K+, whereas Fujimoto and co-workers (13, 14)
demonstrated a biphasic diuretic-antidiuretic response to
PGAZ and PGEB. The significant increment in Na’ levels
in the postrun (control) samples have been reported
many times, particularly in exertion-induced heat injury
PGE,
HYPERTHERMIA
AND
WORK
IN
THE
67
HEAT
cases (15, 24). It is also apparent that additional work is
required to elucidate further the effects of PGEl administration on circulating Na’ levels.
In conclusion, the results clearly demonstrate
a decrement in physical performance
caused by preexisting
hyperthermia.
Critical rectal temperatures
(>42.5” C) are
attained more rapidly, even though thermoregulatory
responses during treadmill
work are unaffected.
The
clinical chemical indices of heat-exercise
injury are apparently not affected by PGEl pyrexia. Additional investigations are necessary to clarify the effects of PGE1
administration
on circulating levels of glucose and Na’.
The authors
gratefully
acknowledge
the skilled technical
assistance
of SP-4 Bruce Ruscio, SP-5 Shawn Wright,
Natalie Maslov,
and Elaine
Tanney. We express our gratitude
to Sandra Beach and Cynthia
Bishop
for typing the manuscript.
The views, opinions,
and/or
findings
contained
in this report
are
those of the authors
and should not be construed
as an official department of the Army position,
policy, or decision,
unless so designated
by
other official
documentation.
In conducting
the research
described
in
this report,
the investigators
adhered
to the “Guide
for Laboratory
Animal
Facilities
and Care,” as promulgated
by the Committee
on the
Guide for Laboratory
Animal
Facilities
and Care of the Institute
of
Laboratory
Animal
Resources,
National
Academy
of Sciences-National
Research
Council.
Received
1 December
1980; accepted
in final
form
24 February
1981.
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