39.23°C to 38.31°C (—0.92°C) and tranquil
ized animals decreased rectal temperature
from 39,15°C to 38.15°C (—1.00°C) in the
same period (Fig, 1A).

At 37.8°C rectal temperatures of the tran-
quilized animals rose from 39.35°C to 39.61°C
(+0.26°C), while the untranquilized group
dropped rectal temperature from 39.44°C to
38.88°C (—0.56°C) (Fig. 1B).

At 4.4°C the tranquilized dogs dropped in-
ternal temperature from 39.32°C to 38.25°C
(~1.07°C) in two hours with a low tempera-
ture of 38.02°C (—1.30°C) reached at 80 min-
utes, The control animals, with an initial tem-
perature of 39.04°C demonstrated regulation at
a level of 38.60°C (—0.44°C) after 75 minutes
and remained near that level throughout the
remainder of the exposure (Fig. 1C).

Testing without prior exercise indicated that
rectal temperatures similar to those recorded
after exercise were reached within 25 minutes
at 23.9°C, within 45 minutes at 37.8°C and
within one hour at 4.4°C (Figs. 2A, 2B, 2C).
Thus, even though the initial rectal tempera-
tures without exercise were, on the average,
0.74°C lower than with exercise, the final body
temperatures were the sgme at all environ-
mental temperatures. :

Discussion

Although small differences are reported be-
tween tranquilized and control dogs during ex-
posure to an ambient temperature of 23.9°C,
(Fig. 1A) propiopromazine appeared to reduce
thermoregulatory ability during thermal streg$
(4.4°C and 37.8°C) (Figs. 1B, 1€), During
cold exposure, the drop in internal body tem-
perature could be due to peripheral fasodilata-

tion and consequent incurred heat loss
mediated through sympatholytic actions of this

reduction of contractility of skeletal muscles,
decreasing panting. Panting appeared to be
less pronounced in the tranquilized animals.

It would appear that when panting, shivering
or vasomotor activity are not of critical im-
portance, ie., during exposure to 23.9°C, the
tranquilized dog is able to maintain body tem-
perature as well as the non-tranquilized ani-
mal. As indicated in Table I, no significant
difference exists at any time interval at even
the 0.10 level. However, when thermal de-
fense mechanisms become important, i.e., dur-
ing exposure to 4.4°C and 37.8°C, the tran-
quilized dog is not able to maintain body
temperature as well as the control animal, For
the heat exposure, a 0.10 level of significance
appears at 35 minutes and is at the = .001
level for the last 50 minutes of exposure. Dur-
ing cold exposure the level of significance is
= 0.10 at 25 minutes, = 0.01 at 35 to 45 min-
utes and increases until at 105 minutes the dif-
ference is again above the 0.10 level. (Table I.)

These results for propiopromazine are simi-
lar to those reported for another phenothiazine
derivative, chlorpromazine (2), except that
propiopromazine did not show the marked hy-
pothermia produced at nonstressful environ-
mental temperatures. However, both agents
apparently interfere with heat loss and heat
conservation due to a possible direct effect on
the diencephalon (1, 2). A similar response
has been shown for chlorpromazine during cold
exposure of hamsters (11).

The use of propiopromazine and chlorpro-
mazine would, therefore, seem contraindicated
in tests involving thermal stress, However,
this study indicate$ that propiopromazine
shows lessyinterference with temperature regu-
lation than chlorpromazine at a non-stressful

} environmental temperature,

phenothiazine derivative (1, 2)., A further / These tranquilizers teuld be of benefit as an

contributory factor could be the loss of muscle/

tone and ability to shiver, thus reducing heat
production, During heat exposure, the rise in
internal body temperature could be due to the

e
sd

adjunct to the induction of hypo or hyper-
thermia in animals without the artifacts
introduced by emotional excitation or general
anesthesia.

’

ee


REFERENCES

. Grollman, Arthur, Pharmacology and Ther-
apeutics, Lea and Febiger, Philadelphia,
1962, pp. 75 & 247.

. Drill, V. A., Pharmacology in Medicine,
McGraw-Hill Book Co., Inc., New York,
1958, pt, 7, Ch. 24,

. Rickels, K., Snow, L., Baumm, C., Mock,
J., Amer. J. Psychiat., 1963, v119, 1093.

. Symposium, Ann. N. Y. Acad. Sci., 1957,
v66, 417.

. Tuteur, W., Amer. J. Psychiat., 1963,
v119, 776,

tm

10.
11.

12.

Lear, E., Chiron, A. E., Pallin, I, M., New
York J, Med., 1963, v63, 409.

Supek, A., Uroic, B., Gjiris, V., Marjan, N.,
J. Pharm, Pharmacol., 1962, v14, 284.

Wortis J., Jackim, E., Amer, J. Psychiat.,
1962, vil9, 363.

Hoffman, R. A., Amer, J. Physiol., 1958,
v195, 751.

Hoffman, R. A., ibid, 1958, v195, 755.

Hoffman, R. A., Zarrow, M. X., ibid, 1958,
v193, 547,

Laverty, R., J. Neurochem., 1963, v10, 151.

# U.S, GOVERNMENT PRINTING OFFICE : 1964 © - 719-718



THE EFFECTS OF A TRANQUILIZER ON BODY TEMPERATURE

1: E. ARNOLD HIGGINS, P. F. IAMPIETRO, THOMAS ADAMS and D. D. HOLMES

ABSTRACT

Four young adult mongrel dogs were exposed twice untranquilized to each of three
environmental temperatures: 4.4°C, 23.9°C and 37.8°C and exposed twice tranquilized with
2.2 mg/kg propiopromazine hydrochloride. Rectal temperatures were monitored and re-
corded continuously during two hour exposures. Little difference was noted in rectal
temperature response for tranquilized and untranquilized animals at 23.9°C exposure. Tran-
quilized animals showed a greater decline in internal temperature at an environmental
temperature of 4.4°C than control and when tranquilized showed a rise in rectal temperature
during heat exposure (37.8°C) while control animals showed a decline. These results indicate
an impairment in both heat loss and heat conservation mechanisms in the tranquilized
animals during thermal stress, but little, if any alteration of temperaure contro] at a non-

stressful ambient temperature.

Since the mechanisms of body temperature
regulation of homiotherms are characteristic-
ally altered or ablated by the effects of general
anesthetics (1), studies of thermal control are
better performed on unanesthetized animals.
The recent development of a variety of tran-
quilizers [pharmacological agents which re-
duce activity and agitation and make subjects
more docile (2)] makes available a group of
materials offering the hope of obtaining quies-
cent animal preparations retaining-;‘thermo-
regulatory ability, Earlier studies have inves-
tigated some of these materials as they produce
changes in behavior (3, 4, 5), physiology (6,
7, 8), or to a more limited extent temperature
regulation (9, 10; 11, 12) in various species.
The present program was) designed to Aeter-
mine the effects of propiopromazine//hydro-
chloride (Tranvet, Abbott Laboratories) on
thermoregulatory ability in dogs exposed to
three environmental temperatures. ‘

C4
Methods

Forty-eight two hour experiments were con-
ducted using four young, adult mongrel dogs
(115 to 16 kg) each exposed twice to three
environmental temperatures: 4.4°C (40°F),

23.9°C (75°F), and 37.8°C (100°F), at 50%
relative humidity, without the use of a tran-
quilizer and twice to each temperature tran-
quilized with 22 mg/kg propiopromazine
(intravenously.) No animal was given tranquil-
izer within 48 hours of previous injection.
All animals were placed in the environmental
chamber with body temperatures elevated by
moderate exercise to force regulation and to
provide more comparable initial rectal tempera-
tures within the group. The animals were un-
restrained, but were restricted to a small area
by a collar ahd a short rope. Rectal tempera-
ture was continuously monitored by a thermis-
tor probe inserted 10 cm into the lower colon
and recorded on a Grass Polygraph Recorder
(Model 5C) tHxéugh an appropriate bridge.

In addition tp the above experiments, one
animal was exposed to each of the environ-
mental temperatures without prior exercise to
indicate the influence of this single variable on

* internal body temperature.

Results

During a two hour exposure to an ambient
temperature of 23.9°C, untranquilized animals
fell from the average initial temperature of

-l-



be

als.

ing

im-

the

m- TABLE I
ani- ANALYSIS OF VARIANCE

t i . LEVEL OF SIGNIFICANCE FOR DIFFERENCE

ve { BETWEEN CONTROL AND TRANQUILIZED ANIMALS

lur- Time in

n- minutes 23,9°C 37.8°C 44°C
dy 0 0.68 0.79 0.40
For 5 0.90 0.83 0.80
nce 10 0.70 0.97 0.84
001 15 0.44 0.48 0.15
ur 20 0.24 0.26 0.11
_is 25 0.24 0.16 0.09°
in- 30 0.32 0.15 0.06°
dif- 35 0.41 0.08° 0.01"
1) 40 041 0.09° 0.01°
imi. 45 0.68 0.09° 0.01°
ine 50 0.95 0.07° 0,02°°
that 55 0.56 0.09° 0.07°
hy- 60 0.52 0.02°° 0.04°°
on- 65, 0.35 0.04°* 0.07°
nts 70 0.24 0.01" 0.07°
eat 15 0.18 0.001° 0.12
on 80 0.12 0.001" 0.08"
nse 85 0.12 0.001' 0.10°
old 90 0.15 0.001° 0.08°

95 0.15 0.001' 0.08°

10 100 0.12 0.001° 0.08°
ted 105 10.16 0.001' 0.11
ver, 110 0.18 0.001 0.12
ine 115" H 0.18 0.001" + 0.18
gu- 120 i 0.18 , 0.001" 0.35
sful Average ; 0.31 0.03°° 0.10°
an 1 * = = .10 level of significance; = .05 level of significance*s**

er- 4 @ = & .01 level of significance; .001 level of significance. ,



Civil Aeromedical Research Institute, Federal Aviation
Agency Oklahoma City, Oklahoma. CARI 63-23,
THE EFFECTS OF A TRANQUILIZER ON BODY
TEMPERATURE by E. Amold Higgins, P. F. Iampi-
etro, Thomas Adams, and D. D. Holmes.

Four yt adult mongrel were exposed twice untranquil-
ized 2 each of three oe ea temy 3: 4.4°C, 23.9°C
and 37.8°C and exposed twice tranquilized with 22 mg/kg
Propiopromazine hydrochloride. Rectal temperatures were moni-
tored and recorded continuously during two hour exposures.
Little difference was noted in rectal temperature response for
tranquilized and untranquilized animals at the 239°C .
Tranquilized animals showed a greater decline in internal tem-
perature at an environmental temperature of 4.4°C than control
and when tranquilized showed a rise in rectal temperature during
heat exposure (37.8°C) while control animals showed a decline,
These results indicate an impairment in both heat loss and heat
conservation mechanisms in the tranquilized animals duriny

thermal stress, but little, if any alteration of temperature control
at a non-stressful ambient temperature.

1. Drugs

2. Temperature
Regain
3.

, Temperatures

Civil Aeromedical Research Institute, Federal Aviation
Agency Oklahoma City, Oklahoma. CARI Report 63-23.
THE EFFECTS OF A TRANQUILIZER ON BODY
TEMPERATURE by E. Amold Higgins, P. F. Iampi-
etro, Thomas Adams, and D.D. Holmes. "3

Four young adult mongrel dogs were exposed twice untranquil-
ized 3 cach of three cavironmental tem res: 4.4°C, 23.9°C
and 37.8°C and exposed twice tranguilized with 2.2° mg/kg
propiopromazine hydrochloride, Rectal temperatures were moni-
tored and recorded continuously during two-hour exposures.
Little difference was noted in regtal temperature response for
tranquilized and untranquilized animals at the 23.9°C .
Tranquilized animals showed a greater decline in intemal tem-
perature at an environmental temperature of 4.4°C than vontrol
and when tranquilized showed a rise in rectal temperature during
heat exposure ‘{37.8°C) while control animals showed a decline.
These results indicate an impairment in both heat loss and heat
conservation mechanisms in the trangutlized animals durin
thermal stress, but little, if any alteration of t&mperature con!

at a non-stressful ambient femperature.

Civil Aeromedical Research Institute, Federal Aviation
Agency Oklahoma City, Oklahoma. CARI Report 63-23.
THE EFFECTS OF A TRANQUILIZER ON BODY
TEMPERATURE by E. Amold Higgins, P. F. lampi-
etro, Thomas Adams, and D. D. Holmes.

Four adult mongrel dogs were twice untranquil-
ized t0 each of three Srironeenal ‘emote tures: 44°C, 239°C
and 37,8C and twice tranquil with 2.2 mg/kg
propiopromazine Rectal temperatures were moni-
tored and recorded continuously during two hour exposures.
Little difference was noted in rectal temperature response for
tranquilized and untranquilized animals at the 23.9°C .
Tranquilized animals showed a greater decline in internal tem.
perature at an environmental temperature of 4.4°C than control
and when tranguilized showed a rise in rectal temperature during
heat exposure (37.8°C) while control animals showed a decline.
These results indicate an impairment in both heat loss and heat
conservation mechanisms in the tranquilized animals durin
thermal stress, but little, if any alteration of temperature con!

at a non-stressful ambient temperature.

1. Drugs

2. fein
3,

” ‘Temperatures

Civil Aeromedical Research Institute, Federal Aviation
Agency Oklahoma City, Oklahoma: "CARI Report 63-23.
THE EFFECTS OF A TRANQUILIZER ON BODY
TEMPERATURE by E. Amold Higgins, P. F. Iampi-
etro, Thomas Adams, and D. D. Holmes.

Four young adult mongrel dogs were exposed twice untranquil-
ized to each of three environmental t natures: 4.4°C, 23.9°C.
and 37.8°C and exposed twice tranquilized with 2.2 mg/kgh
propiopromazine hydrochloride. Rectal temperatures were moni-
tored and recorded continuously during two hour exposures.
Little difference was noted in rectal temperature response for
tranquilized and untranquilized animals at the 23.9°C exposure.
Tranquilized animals showed a greater decline in intemal tem-
perature at an environmental temperature of 4.4°C than control
and when tranquilized showed a rise in rectal temperature during
heat exposure (37.8°C) while control animals showed a deakipe.
These results indicate an impairment in both heat loss and heat
conservation mechanisms in the tranquilized animals durin;
thermal stress, but little, if any alteration of temperature cont

at a non-stressful ambient temperature.

1. Drugs

2, Temperature
“3. Body

Temperatures



THE EFFECTS OF A. TRANQUILIZER ON
BODY TEMPERATURE

FEDERAL AVIATION AGENCY

CIVIL AEROMEDICAL RESEARCH INSTITUTE

AERONAUTICAL CENTER
OKLAHOMA CITY, OKLAHOMA.

OCTOBER 1963



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THE EFFECTS OF A TRANQUILIZER ON BODY TEMPERATURE
E. ARNOLD HIGGINS, P. F. IAMPIETRO, THOMAS ADAMS AND D. D. HOLMES
Environmental Physiology Branch

63-23

mee

FEDERAL AVIATION AGENCY
CIVIL AEROMEDICAL RESEARCH INSTITUTE
. . AERONAUTICAL CENTER
o OKLAHOMA CITY, OKLAHOMA

OCTOBER 1963