Download Physiologic and Anatomic Effects of Propylthiouracil on Normal and

Physiologic and Anatomic Effects of Propylthiouracil
on Normal and Hypertensive Rats
By
M. J. FREGI,Y, PH.D., AND C. I. HOOD,
M.D.
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
The antithyroid drug propylthiouracil prevented or removed the hypertension associated
with bilateral kidney encapsulation with latex envelopes. This effect did not appear to
be the result of hypofunction of the adrenal glands. Propylthiouracil reduced growth
rate in young rats and caused weight loss in adult rats. The latter effect appeared to
be true tissue loss because water contents of heart, kidney, testes, liver, psoas, aorta and
adrenal were unaffected. Administration of propylthiouraeil for 7 to 19 weeks tended
to reduce heart weight to body weight ratio as well as the ratio of kidney weight to
body weight in both control and "encapsulated" rats. However, ratios of organ weight
to body weight in the eases of thyroid, testes and eyes were larger than those of untreated
control rats. In addition to its antihypertensive effect, propylthiouracil treatment of
encapsulated rats also prevented the appearance of certain other manifestations of
hypertension usually accompanying1 kidney encapsulation.
P
ROPYLTHIOUBACIL has been used
successfully both to prevent the elevation of blood pressure of rats whose kidneys
were bilaterally encapsulated with latex envelopes and to reduce the elevated blood pressure of rats whose kidneys were encapsulated
9 weeks previously.1 The mechanism of this
antihypertensive action was not ascertained
although the reduction in blood pressure did
not appear to be due solely to the partial inanition caused by this drug. 1 The experiments reported here were performed to
determine whether propylthiouracil administration : (a) prevented the development of
other manifestations of renal hypertension
usually accompanying latex encapsulation of
kidneys, e.g., cardiac hypertrophy and kidney
damage; (b) affected the spontaneous NaCl
aversion and increased water intake of encapsulated rats 2 ' 3 ; (c) produced its typical
weight loss by progressive dehydration or by
tissue loss; and (d) produced adrenal atrophy
as has been reported for thiouracil.4"8
From the Departments of Physiology and Pathology, College of Medicine, Universitj1 of Florida,
Gainesville, Fla.
Supported by grant H-3503 from the National
Heart Institute, Xational Institutes of Health and
by a grant from the American Heart Association.
Eeceived for publication January 12, 1959.
METHODS
Six separate experiments were performed, each
utilizing different groups of male rats of the
Holtzman strain. All rats were kept in individual
cages in a thermoregulated room maintained at
26 ± 1 C. and illuminated from 8 a.m. to 6 p.m.
All were fed finely ground Purina chow and were
given tap water to drink except as indicated. The
type of food and fluid containers used have been
described previously.7 Hypertension was induced
by encapsulation of both kidneys with latex envelopes.8 Blood pressures were measured by the
microphonic manometer technic0 but without anesthesia, as described previously.3 In all, 84 rats
were employed comprising 53 with kidneys encapsulated and 31 non-encapsulated controls. Approximately half of each group received propylthiouracil in their diet.
Administration of Propi/lthiouracil at Kidney
Encapsulation
Experiment 1. Sixteen rats weighing 200 to 230
Gm. were used. Both kidneys of 12 animals were
encapsulated with latex envelopes. Beginning the
day of operation, six of the operated rats received
0.1 per cent propylthiouracil (PTU) mixed thoroughly into the food; the other six received the
same food without the drug. The remaining four
rats neither had their kidneys encapsulated nor
received PTU. Beginning the eighth week of
the experiment, the grade of renal function was
assessed by dehydration for 4S hours (powdered
chow but no fluids available). The specific gravi486
Circulation Research. Volume VII, May 195S
487
PROPYLTHIOURACIL AND HYPERTENSION
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
ties of urines, collected under oil, were measured
by the method of Lowry and Hunter.10 The experiment was carried out over a period of nine
weeks. At the end of this time all rats were killed
by ether inhalation. Organs, including testes, prostate, seminal vesicles (drained of seminal fluid),
kidneys, adrenals, heart (drained completely of
blood), thymus, thyroid and eye balls were weighed
on a Roller-Smith torsion balance. The results are
presented in terms of the organ weight to body
weight ratio. All organs were carefully trimmed
of fat and connective tissue. This is especially important in the case of the kidneys where the thick
connective tissue capsule which customarily grows
between the latex capsule and the kidney surface
may add 10 per cent to the weight. In addition,
water content of each of these organs was measured by drying a tared piece of the organ at 110
C. to constant weight. An analytic balance was
used.
Experiment 2. Ten rats weighing 340 to 390
6m. were used in this experiment which was carried out in essentially the same fashion as experiment 1. Half received 0.1 per cent PTU in their
diet immediately after kidney encapsulation for
14 weeks. Starting the twelfth week, for two weeks,
each rat was allowed to choose freely between
water and 0.15 M NaCl solution as drinking fluids.
Daily measurements of food and fluid intakes and
body weights were made. Intakes were measured
by the weight difference technic and are expressed
as ml./lOO Gm. body weight/day. At the end of the
fourteenth week all rats were sacrificed by decapitation and the organs listed above were weighed.
Experiment 3. Ten rats weighing 215 to 289
6m. were used in this experiment which differed
from the first two in that 0.06 per cent PTU was
used. The kidneys of all rats were bilaterally encapsulated. Beginning the day of operation five
rats received PTU mixed into the food while the
remaining five received food without the drug. The
experiment was carried out for nine weeks. To help
assess the degree of hypothyroidism induced by
PTU, resting body temperatures of all rats were
measured two days prior to sacrifice using a rectal
thermometer inserted 5 cm. into the colon and
held in place for 1 minute. The rat was placed in
a chamber to minimize struggle and facilitate the
measurement. At sacrifice, the organs listed in
experiment 1 were removed, weighed, and water
contents determined.
Experiment 4A. For convenience of description, experiment 4 will be divided into two parts
and described separately, although parts A and B
were performed simultaneously. Nine rats weighing 256 to 323 Gm. were used. All had their kidneys bilaterally encapsulated. Five were given 0.1
per cent PTU in their diet immediately after the
operation; four were used as encapsulated controls. The experiment was carried out for 19 weeks,
at the end of which all rats were sacrificed by ether
inhalation. At sacrifice organs were weighed and
adrenal cholesterol concentration of the left
adrenal of each rat was measured by the method
of Knobil et al.11
Administration of Propylthiouracil to Non-Encapsulated Eats
Experiment 4 B. Ten non-encapsulated rats were
used; six were given 0.1 per cent PTU in their
diet while four were normal controls. The weight
range of the rats and experimental procedure were
the same as that for experiment 4 A.
Experiment 5. Seventeen non-encapsulated adult
rats weighing 386 to 449 Gm. were used. Eight
of the rats were given 0.1 per cent PTU in their
food while nine received food without the drug
over a seven-week period. Prior to sacrifice at the
end of the seventh week, resting colonic temperature was measured. The animals were killed by
ether inhalation, organs were weighed, and organ
water contents determined. Adrenal cholesterol
concentration was measured in the left adrenal
gland of each rat.
Administration of 'Propylthiouracil to Established
Hypertensive Rats
Experiment 6. Twelve rats weighing 485 to 540
Gm. were used. The kidneys of all rats had been
encapsulated nine weeks prior to the beginning of
the experiment. Six of the rats were given 0.1 per
cent PTU mixed into the food while six were given
food without the drug for nine weeks. Beginning
the fifth week of the experiment, and for 1 week
only, water and food intakes of all rats were measured as described in experiment 2. At the end of
the ninth week, all rats were sacrificed and the
same organs were weighed and water content
measured, using the same technic described for experiment 1. In addition, the cholesterol concentration of the left adrenal of each rat was measured. The right adrenal was fixed in formalin,
sectioned and stained with hematoxlyn and eosin
and with oil red 0.
In all experiments statistical analysis of the difference between means was performed by the use
of the t test for the 95 per cent confidence limit.12
RESULTS
Effect of Propylthiouracil on the Ratio of
Organ Weight to Body Weight of Certain
Organs
The effect of propylthiouracil on the body
weight and ratio of organ weight to body
weight of certain organs of the rat is shown
(table 1). Body weight of young, PTU-
488
FKEGLY, HOOD
TABLE ].—Effect
of J'royylthiouracil on the Organ Weight to Body Weight Ratio of Certain
Organs
Initial
mean
No. of w e ight
Expt'l conditionNo.ofweightweightrats(Gm.)
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
PTU administration at time
Experiment 1
Encap.
6
Encap. +
0.1% PTUf
6
Normal
4
Experiment 2
Encap.
5
Eneap. 0.1% PTU'-'fl 5
Experiment 3
Encap.
5
Encap. +
0.06% PTUf 5
Experiment 4A
Encap.
4
Encap. +
0.1% PTU"# 5
. Final
mean
weight
( G m .) H e a r t
Organ weight/body weight ratio (mg./lOO Gm.)
Kidney
Testes
Thyroid
Thymus
Eyeballs
of kidney encapsulation
246
375
325± 9* 768±28
226
278
216
398
308±13
30.1 ±12
676±19t 1174±82§ 31.9±1.6§
7.19±]9
876±35§ 4.2±0.2§
381
478
308±10
625± 9
742±22
5.3±0.3
79.9±9.5
07.5±].4
351
397
283±20
566±23J
832±21
33.4±1.9§
48.1±3.3t
99.7±2.0t
304
395
381 ±12
955±54
582±84
6.2±0.6
88.3±1.7
279
266
32(i± 4§ 886±42
835±50§
28.9±4.8§
137.7±1.6§
278
488
307± 8
664±]7
750±23
6.4±0.6
64.9±4.4
68.0±3.1
284
316
285± 9
075±17
975±45§
48.4±3.8§
43.6±2 J §
95.5±2.8§
265± 7
709± l l
790±20
4.5±0.7
69.1±2.1
70.7±2.1
256± 6
610±17§
959±52§
32.8±2.5§
54.4±6.0
86.1±3.6§
268± 4
686±11
701±15
4.5±0.2
76.7±9.8
66.5±1.0
252± 5J
582±19§
962±3.1§ 24.6±1.5§
65.7±4.0
8.r).2±2.7§
PTU administration to established hypertensive rats
Experiment 6
Encap.
6
452
501
305± 7
Encap. -f
0.1% PTUf
6
467
440
297± 8
781 ±24
705±21
70.1±3.3
66.0±2.1
720±53
862±.19§ 19.8±3.9§
74.2±6.3
7S.4±1.2§
PTU administration to non-encapsul;:ited rats
Experiment 4B
Normal
4
242
461
Normal -+0.1% PTV*# 6
254
358
Experiment 5
Normal
9
449
500
Normal +
0.1% PTU-f 8
464
388
852±49
4.4±0.2
5.4±0.8
•
•
*± 1 standard error of mean,
f 9 weeks of treatment.
{Significant difference (p < .05).
§Signiflcant difference (p < .01).
1114 weeks of treatment.
#19 weeks of treatment.
•f 7 weeks of treatment.
treated rats generally remained at the weight
level at which administration began, although
this was not always the ease. For example,
the treated rats in experiments 2, 4A and 4B
gained weight, though at a rate much less than
controls. Older, treated rats generally lost
weight although the extent of weight loss was
not consistent (compare, for example, weight
Joss of treated rats in experiment 5 with that
of treated rats in experiment 6).
Heart weight to body weight ratio of encapsulated rats tended to be greater than that
of normal rats in both experiments 1 and 4,
but only in experiment 4 was this difference
PROPYLTHIOURACIL AND HYPERTENSION
TABLE 2.—Effect
Expt'l condition
No. of
rats
of Propylthiouracil on the Water Content of Certain Organs
Heart
Kidney
PTU administration at time of kidney encapsulation
Experiment 1
78.7S±0.56* 78.34±0.21
6
Encap.
Encap. -f6
79.27±0.31
78.78±0.40
0.1% PTU
78.78±0.88
76.37±1.21
4
Normal
Experiment 3
Encap.
Encap. +
0.06% PTU
5
5
489
Water (%)
Liver
Testes
Psoas
Adrenal
69.97±1.54
72.63±0.33
86.18±0.41
77.54±0.61
72.39±0.52
72.38±0.07
86.37±0.30
86.69±0.69
76.71±1.56 69.55±1.20
77.77±0.20 71.93±1.44
78.81±0.37
79.82±0.6S
72.92±0.29
S5.S0±0.37
77.14±0.51
80.14±0.62
79.36±0.30
73.54±0.65
85.07±0.76
79.68±1.14
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
PTU administration to non-encapsulated rats
Experiment 5
Normal
Normal 0.1% PTU
9
80.54±0.63
77.54±0.52
73.73±0.52
87.08±0.21
77.54±0 .20
8
79.75±0.34
78.45±0.7C
71.88±0.60
87.30±0.48
78.36±1 31
PTU administration to established hypertensive rats
Experiment 6
Encap.
Encap. +
0.1% PTU
Aorta
79.09±2.33
6
80.79±1.21
84.00±1.40
77.97±2.22
89.08±1.33
78.34±1 .79
6
84.19±1.00
80.12±4.76
77.48±2.1G
88.32±1.28
81.00±l 73 73.12±3.4G
*±1 standard error of mean.
statistically significant (p < .01). Experiment 4 lasted 10 weeks longer than experiment 1, -which may account for the difference
observed. In 2 of 6 cases (experiments 3 and
5) propylthiouracil treatment decreased significantly heart weight to body weight ratio.
Of these experiment 3 dealt with encapsulated
animals while experiment 5 was made on
normals. In all other cases PTU tended to
reduce the ratio of heart weight to body
weight, but the differences were not statistically significant.
With respect to kidney weight to hotly
weight ratio, PTU treatment significantly
(p < .05) lowered the ratio of normal rats in
experiment 5, of normal rats in experiment
4B, and of encapsulated rats in experiments 1
and 2. Though the kidney weight to body
weight ratios of the other groups listed in
table 1 were not decreased significantly below
those of comparable controls, a definite trend
also appeared. PTU treatment decreased kidney weight to body weight ratio in all treated
groups with the single exception of the encapsulated rats in experiment 4A.
One of the most striking features about
PTU treatment was the relative increase in
testes tueight to hotly weight ratio in all
treated groups, both normal and encapsulated.
PTU treatment (0.1 per cent or 0.06 per cent
mixed into the food) always significantly increased this organ weight ratio.
Propylthiouracil treatment always produced
an enlarged thyroid gland. The increase in
weight varied from four to eight times that
of corresponding controls. The thyroid weight
to hody weight ratio of untreated, encapsulated rats appeared to be the same as that of
untreated normal rats.
The effect of propylthiouracil treatment on
the thymus weight to hody tveight ratio appeared to vary with the duration of treat-
FREGLY, HOOD
490
TABLE 3.—Effect of Propylthiouracil on Adrenal Weight to Body Weight Ratio, Adrenal
Cholesterol Concentration and Resting Colonic Temperature of the Sat
Expt'l condition
No. of rats
Adrenal wt./
body wt.
(mg./lOO Gm.)
p
PTU administration at time of kidney encapsulation
Experiment 1
6
12.8 ± 0.6»
Encap.
Encap. +
6
15.0 ± 0.4
0.1% PTU
4
12.0 ± 0.8
Normal
Experiment 2
5
9.7 ± 0.5
Encap.
Encap. +
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
5
10.0 ±
0.1% PTU
Experiment 3
5
11.8 ±
Encap.
Encap. -|5
12.2 ±
0.06% PTU
Experiment 4A
9.3 ±
Encap.
4
Encap. 5
12.7 ±
0.1% PTU
PTU administration to non-encapsulated rats
Experiment 4B
4
10.5 ±
Normal
Normal -f10.4 ±
0.1% PTU
6
Experiment 5
9
9.2 ±
Normal
Normal -f0.1% PTU
8
9.7 ±
Adrenal
cholesterol cone.
(mg./lOO msr.)
p
Resting colonic
temp (C.)
5.92 ± 0.43
.72
0.6
.68
5.68 ± 0.36
0.6
37.6 ± 0.1
.02
.57
37.0 ± 0.2
0.4
0.2
4.92 it 0.51
0.8
4.71 ± 0.50
.75
4.55 ± 0.34
0.5
.99
.54
4.83 ± 0.28
0.2
37.1 ± 0.1
5.40 ± 0.18
0.4
0.2
.12
.35
PTU administration to established hypertensive rats
Experiment 6
Encap.
6
10.6 ± 0.7
Encap. +
0.1% PTU
6
10.4 ± 0.3
37.8 ±
4.87 ± 0.26
0.2
5.75 ± 0.20
.79
.03
4.32 ± 0.52
*±1 standard error of mean.
ment. Administration of PTU for seven to
nine weeks had no significant effect, but rats
treated with PTU for 14 to 19 weeks showed
significant reduction in thymus weight to
body weight ratio. In all cases the thymus
weight to body weight ratio of treated rats
tended to be less than that of comparable
controls.
A third consistent finding among all treated
groups was a significant (p < .01) increase in
the eye ball weight to body weight ratio above
that of corresponding controls. In this respect,
0.06 per cent PTU appeared to be as effective
as 0.1 per cent.
Effect of Propylthiouracil on the Water Content of Certain Organs
Propylthiouracil treatment did not influence
the water contents of heart, kidney, liver,
testes, psoas, aorta or adrenals of normal or
encapsulated rats (table 2). The adrenal gland
showed the lowest water content while the
testes showed the highest of the organs tested.
Effect of Propylthiouracil on Adrenal Weight
to Body Weight Batio and Adrenal Cholesterol Concentration
Table 3 summarizes the effect of propylthiouracil on the adrenal weight to body weight
PROPYLTHIOURACIL AND HYPERTENSION
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
ratio, adrenal cholesterol concentration and
resting eolonic temperature. Propylthiouracil
treatment generally had no effect on adrenal
weight to body weight ratio. Two exceptions
to this statement can be seen in the data of
experiments 1 and 4, in which treated rats
had a greater adrenal weight to body weight
ratio than did controls. It niay also be observed that the adrenal weight to body weight
ratios of untreated, encapsulated rats in experiments 1 and 4 were the same as those of
corresponding, untreated controls. It would
appear that the hypertensive syndrome accompanying kidney encapsulation had no effect on adrenal weight to body weight ratio.
Adrenal cholesterol concentration of treated,
normal rats was similar to that of untreated,
normal rats (experiments 4B and 5, table 3).
The adrenal cholesterol concentration of
treated, encapsulated rats in two separate experiments (experiments 2 and 4A, table 3)
were similar to those of untreated, encapsulated rats. One group of treated, encapsulated
rats (experiment 6, table 3) showed significant lower (p < .05) adrenal cholesterol concentration than untreated, encapsulated rats.
It was observed in experiment 4 (A and B)
that the adrenal cholesterol concentration of
untreated, encapsulated rats was not different
from that of untreated normal rats.
Resting eolonic temperature was significantly reduced by PTU administration in two
separate experiments. Both normal and encapsulated rats were affected in the same
fashion (experiments 3 and 5, table 3).
Physiologic Effects of Propylthiouracil
Table 4 lists some of the physiologic effects
of propylthiouracil. The rise in systolic blood
pressure of encapsulated rats was prevented
if the drug was administered immediately
after kidney encapsulation (experiments 1, 2,
3 and 4A). The blood pressure of rats whose
kidneys were encapsulated nine weeks previously also manifested a decrease in systolic
blood pressure (experiment 6). The systolic
blood pressure of normotensive, non-encapsulated rats was also decreased by PTU-treatment (experiments 4B and 5).
When treated and untreated encapsulated
491
rats were allowed to choose freely between
water and 0.15 M NaCl solution, it was observed that PTU-treated, encapsulated rats
ingested significantly less water and more
NaCl solution than untreated, encapsulated
rats (table 4, experiment 2). The untreated,
encapsulated rats manifested a typical NaCl
aversion; the treated, encapsulated rats actually manifested an appetite for NaCl solution
in that they ingested significantly more salt
solution than water. When water was the sole
drinking solution, PTU-treated, encapsulated
rats ingested significantly less water than untreated, encapsulated controls (experiment
6). PTU-treated rats ingested less food than
untreated rats (experiments 2 and 6).
When the three groups of rats in experiment
1 were subjected to dehydration for 48 hours,
it was observed that the urinary specific gravity of the encapsulated group failed to reach
the same high level as that of either normal
or PTU-treated, encapsulated rats. The concentrating ability of the kidneys of the encapsulated rats treated with PTU was similar to that of normal rats but different from
that of untreated-encapsulated rats. Urinary
flows of the three groups during the second
day of dehydration were similar. The results
suggest, but do not prove, that PTU-treatment prevented the kidney dysfunction observed in untreated-encapsulated rats.
DISCUSSION
Of the parameters studied in these experiments, it would appear that PTU: (a) prevented the elevation of blood pressure accompanying kidney encapsulation; (b) prevented
the polydipsia accompanying kidney encapsulation; (c) permitted normal concentration
of urine ofter 48 hours of dehydration; (d)
prevented the development of the NaCl aversion, and (e) reduced, though not always significantly, the hypertrophy of the heart. On
the other hand, PTU appeared to manifest
certain less desirable effects. It prevented
growth of young rats or caused weight loss
in older rats, produced an apparent exophthalmos and goiter, decreased metabolic rate
and food intake, reduced resting body temperature, and increased testieular size.
ownloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
Blood pressure (mm. Hg)
Initial
Final
204. ± ot
.132 ± 4
4
134 ± 6
122 ± 7
125 ± 9
5
134 ± 4
176 ±11 %
131 ± 4
5
5
153 ± 2
144 ± 2
it
133 rt 5
9
.138 ± 4
116 zt 2
6
6
173 ± 3
164 ± 4
130 ± 4
180 ± i)f
S
134 ± 4
110 ± 8f
to established hypertensive rats
134 ± 4
(i
*±1 standard error of mean,
tAfter 48 hours of dcliydratiou.
JSiguificaat, difforenee (/><.01).
0.1% PTU
ElH'iip. +
0.1'/n PTU
Experiment; 5
Normal
Normnl +
0.1% PTU
PTU administration
Experiment (i
Kneap.
11.32 ± 0.60
14.85 ± 0.72t
4.74 ± 0.83
11.17 ± 1.37
4.80 ± 0.13
5.43 ± O.OSt
3.78 ± 0.27
174 ± ?4
132 ± 3
5
4.37 ± 0.84J
.06S ± 0.003
.074 ± 0.002
1.046 ± 0.003
J.039 ± 0.008
.136 ± 5
147 ± 5
127 ± 7
138 ± 5
6
4
4.69 ± 0.84t
1.040 ± 0.004tt
2.0
3.2
3.4
18.5J
0.9
.13.0
Urinary vol. (ml./day)
Control
Tlehyclratlon
1.017 ± 0.001J
Urinary s.gr.
Dehydration
171 ± 7J
Control
125 ± 0*
9.86 ± 0.9.11
Food
0
at time of kidney encapsulation
No. of
rats
PTU Mdniini.stTsition to iion-eticnpsulatc<l rats
ExporiiiRMit 4B
Normal
4
132 ± 4
145 ± \%
Normal -j-
/f PTU
r
.ElK'ap.
0.1'/ PTU
Experiment 3
Eneap.
lEnenp. +
0.06'/ PTU
Experiment 4A
ElK'ap.
PTU administration
Experiment 1
Eaeap.
Eneap. -f
0.1'/( PTU
Normal
Experiment 2
Expt'l condition
Intake (Gm./lOO Gm. b.w./day)
.15 M NaCl
Water
solution
.E 4.—Some Physiologic Effects of PropylthionraoU
a
O
C
INS
PROPYLTHIOURACIL AND HYPERTENSION
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
A possibility existed that the hypotensive
effect of PTU might be due to hypoadrenalisni
for thiouracil is known to produce adrenal
atrophy4"" and adreualectomy is known to reduce the blood pressure of established, hypertensive rats.13 In contrast to the studies of
others with thiouracil, propylthiouracil did
not appear to alter significantly the adrenal
weight to body weight ratio or the adrenal
cholesterol concentration (table 3). These
facts are supported by histologic examination
of the adrenal glands. Histologic appearance
of the adrenal glands of PTU-treated rats
staiued with hematoxylin and eosin or oil
red 0 was not different from that of untreated
rats, normal or encapsulated. These findings
agree with those of Gabrilove and Soffer14 and
Perry15 who observed normal responses to injections of either ACTH or epinephrine in
rats treated with PTU. Gabrilove and Soffer14
administered PTU for 6 weeks at a dose
level comparable to that used here; Perry 15
used "massive" doses of PTU. In addition,
it was observed in the present studies that
the thymus weight to body weight ratio of
PTU-treated rats was always less than that
of untreated rats. If adrenal hypofunction
were present, one would expect an increase
in thymus weight to body weight ratio. These
facts support the thesis that the hypotensive
effect of PTU is not due to hypoadrenalisni.
Although the effects on the adrenal glands of
thiouracil and propylthiouracil were not compared simultaneously and at the same dose
levels, comparison of these results with those
of others5 using a similar dose level of thiouraeil makes it seem likely that the two
drugs differ with respect to their effects on
the adrenal gland.
It may be noted that PTU generally reduced heart weight to body weight ratio
(table 1) although not always significantly.
Methimazole (Tapazole), another antithyroid
drug, has been shown to reduce significantly
the heart weight to body weight ratio when
administered to rats for 45 days.18 The effect
on heart weight to body weight ratio of longterm administration of either PTU or methimazole has not been reported. It is possible
that treatment with PTU for longer periods
493
of time may produce the cardiac hypertrophy
and decreased cardiac output observed clinically in hypothyroid disease.17 The hypotensive effect of PTU could conceivably be due
to the latter. In only one group of encapsulated rats was the characteristic hypertrophy
of encapsulation significantly prevented (table
1, experiment 3), although heart weight
to body weight ratio of treated rats was consistently lower than that of untreated rats. It
seems likely that larger groups of rats will
be needed to show this effect on a firm statistical basis.
A consistent finding in all PTU-treated
rats was the significant increase in eye ball
weight to body weight ratio (table 1). This
has been observed previously by Sellers and
Ferguson.18 The absolute weights of the eye
balls of PTU-treated rats were not different
from those of normal rats. The smaller body
weight of treated rats made the ratio significantly larger. This is in contrast to many of
the other organs weighed. In other experiments, not reported here, interpupillary distance was measured with micrometer calipers.
The inter-pupillary distance of treated rats
at autopsy Avas similar to that of untreated
rats. Hence it would seem unlikely that
the apparent exophthalmos is due to accumulation of retrobulbar fat or to edema of
the ocular muscles. This interesting fact implies that the eyes continue to grow at a normal rate despite a decrease in somatic growth
and general metabolic rate. Similar results
have been observed by Essex19 in hypophysectomized rats.
PTU-treated rats failed to grow normally
and showed marked thyroid hypertrophy and
hyperplasia (table 1). Further evidence that
PTU effectively decreased metabolic rate was
obtained from decreased food intake (table
4), decreased resting body temperature (table
3) and failure to grow in young rats or loss
of weight in older rats. The weight loss observed in the PTU-treated rats appeared to
be a true tissue loss rather than the result
of progressive dehydration (table 2).
Another consistent finding was the increased
testieular weight to body weight ratio of rats
treated with either 0.1 per cent or 0.06 per
494
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
cent PTU (table 1). The significance of this
change is unknown. The increase in weight
was not due to accumulation of water (table
2). It is possible that PTU increases output
by the pituitary of gonadotrophic hormone or
that the sensitivity of the testes is increased
to normal gonadotrophic titer. Similar results have been reported in surgically thyroidectomized rats.20 These data, taken together, indicate an interaction between thyroid and testes. In the absence of thyroid
hormones, testicular size increases. The increase in size brought about by PTU-treatment varied from 12 to 44 per cent in the
six experiments described here. In contrast
to propylthiouracil, thiouracil is reported to
have no effect on testis weight to body weight
ratio.21
In all treated groups except one (experiment 4A), kidney weight to body weight ratio
of treated rats was reduced under the conditions of these experiments. In four of six experiments, the ratio was reduced significantly.
This finding suggests that the increased testicular size observed in all the treated rats was
not accompanied by increased secretion of
testosterone. A usual finding accompanying
administration of testosterone is an increase
in kidney size. In these experiments a decrease
in kidney weight to body weight ratio of
treated rats was usual finding. Similar results have been observed in surgically thyroidectomized rats.22
A NaCl aversion has been observed characteristically when hypertensive, kidney encapsulated rats are given choice between water
and 0.15 M NaCl solution as drinking
fluids.2-3> 7 The encapsulated, hypertensive
rats choose water in preference to NaCl solution. One of the aims of the experiment was
to determine the effect of PTU administration
on the spontaneous NaCl intake of encapsulated rats. It was observed that treated, encapsulated (but normotensive) rats ingested
more salt solution and less water than untreated, encapsulated (but hypertensive) rats
(experiment 2, table 4). When water was the
only drinking fluid given, treated, encapsulated
rats ingested significantly less water than un-
FREGLY, HOOD
treated, encapsulated rats (experiment 6,
tabel 4). The polydipsia characteristic of encapsulated, hypertensive rats was not present
in encapsulated, PTU-treated rats. These
findings point to the desirability of sodium
balance study of PTU-treated rats to determine if the NaCl appetite of the treated rats
is accompanied by excessive salt loss. A natriuretie action of this drug, if it exists, could
explain its hypotensive effect at least in part.
It was shown previously1 that PTU did not
"cure" the hypertension when given to established hypertensive rats since removal of
the drug was followed by a return of blood
pressure to previous high levels within three
weeks. It is possible that PTU exerts its hypotensive effect in some fashion other than by
way of the thyroid gland. Other investigators
have shown that surgical thyroidectomy or
treatment with large doses of radioactive
iodine both failed either to prevent the development of, or to lower, the blood pressure
of dogs with Goldblatt-type hypertension.23'24
Surgical thyroidectomy has also been unsuccessful in the treatment of human hypertension.25 These results contrast with those reported here and with those of Braun-Menendez28 and Salgado27 who reported respectively
that surgical thyroidectomy lowered the blood
pressure of hypertensive rats and prevented
the development of hypertension, nephrosclerosis and cardiac lesions produced by injections of desoxycorticosterone acetate. It is
possible that a species difference may exist. It
seems clear that further study is needed to
compare within a single species the effects of
surgical thyroidectomy with those of PTUtreatment on the development and maintenance of renal hypertension.
SUMMARY
The antithyroid drug propylthiouracil, prevented the hypertension which usually accompanies bilateral kidney encapsulation with
latex envelopes, and reduced the elevated
blood pressure to normal levels in rats whose
kidneys had been encapsulated nine weeks
before. Administration of this drug also
tended to reduce ratio of heart weight to
PROPYLTHIOURACIL AND HYPERTENSION
body weight as well as ratio of kidney weight
to body weight in both control and ' ' encapsulated" rats. However, ratios of organ weight
to body weight in the eases of thyroid, testes
and eyes were larger than those of untreated
rats. In addition to its hypotensive effect,
propylthiouracil treatment also prevented the
appearance of other manifestations of hypertension usually accompanying kidney encapsulation, viz., polydipsia, NaCl aversion and
decreased urinary concentrating ability during dehydration.
495
3. FREGLY, M. J.: Effects of extremes of temperature on hypertensive rats. Am. J.
Physiol. 176: 275, 1954.
4. BAUMAN, E. J., AND MARINE, D.: Involution
of the adrenal cortex in rats fed with thiouraeil. Endocrinology 36: 400, 1945.
5. DEANE, H. W., AND GREEP,, R. 0.: A eytoehem-
6.
7.
ACKNOWLEDGMENT
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
It is a pleasure to acknowledge the technical
assistance of Mrs. G. Hindman and Mr. 0. Galindo.
8.
SUMMARIO IN INTERLINGUA
Le droga antithyroide propylthiouracil
preveniva le hypertension que accompania
usualmente le incapsulation bilateral del
renes in enveloppes de latex e reduceva le
elevate tension sanguinee a nivellos normal
in rattos con renes incapsulate 9 septimanas
previemente. Le administration de propylthiouracil tendeva etiani a reducer le proprotion de peso cardiac a peso corporee si ben
como le proportion de peso renal a paso corporee, tanto in rattos normal omo etiam in
rattos a incapsulation renal. Tamen, in le
caso del glandulas thyroide, del testes, e del
oculos, le proportion de peso del organo a
peso del corpore esseva plus basse in rattos
intacte. A parte su effecto hypotensive, propylthiouracil etiam preveniva le apparition
de altere manifestationes de hypertension
que usualmente accompania le incapsulation
renal, i.e. polydipsia, aversion contra NaCl, e
reduction del capacitate de concentrar le
urina durante dishydratation.
REFERENCES
1. FREGLY, M. J.: Effects of propylthiouraeil
on the development and maintenance of
renal hypertension in rats. Am. J. Physiol.
194: 149, 1958.
2. ABRAMS, M., DEFRIEZ, A. I. C, TOSTESON,
D. C, AND LANDIS, E. M.: Self-selection of
salt solutions and water by normal and hypertensive rats. Am. J. Physiol. 156: 233,
1949.
9.
10.
ical study of the adrenal cortex in hypoand hyperthyroidism. Endocrinology 41:
243, 1947.
FREEDMAN, H. H., AND GORDON, A. S.: Effects
of thyroidectomy and of thiouraeil on adrenal weight and ascorbic acid. Proc. Soc.
Exper. Biol. & Med. 75: 729, 1950.
FREGLY, M. J.: Hypertension, NaCl aversion
and polydipsia in rats: Time course and
relation to age. Am. J. Physiol. 182: 139,
1955.
ABRAMS, M., AND SOBIN, S.: Latex rubber
capsule for producing hypertension in rats
by perinephritis. Proc. Soc Exper. Biol. &
Med. 64: 412, 1947.
FRIEDMAN, M., AND FREED, S. C.: Microphonic
manometer for indirect determination of
systolic blood pressure in the rat. Proc. Soc.
Exper. Biol. & Med. 70: 670, 1949.
LOWRY, O. H., AND HUNTER, T. H.: Determination of serum protein concentration
with a gradient tube. J. Biol. Chem. 159:
465, 1945.
11. KNOBIL, E., HAGNEY, M. G., WILDER, E. J.,
AND BRIGGS, F. N.: A simplified method for
the determination of total adrenal cholesterol. Proc Soc Exper. Biol. & Med. 87:
48, 1954.
12. FISHER, R. A.: Statistical Methods for Research Workers. Ed. 10. New York: Hafner,
1948, p. 114.
13. TOSTESON, D. C, DEFRIEZ, A. I. C, ABRAMS,
M., GOTTSCHALK, C. W., AND LANDIS, E. M.:
Effects of adrenalectomy, desoxyeortieosterone acetate and increased fluid intake on
intake of sodium chloride and bicarbonate
by hypertensive and normal rats. Am. J.
Physiol. 164: 369, 1951.
14. GABRILOVE, J. L., AND SOFFER, L. J.: Adrenal
cortical response of propylthiouracil treated
rats to the administration of epinephrine
an adrenoeortieotropin. Endocrinology 47:
461, 1950.
15. PERRY, W. F.: The effect of propylthiouracil
on the weight and concentrations of cholesterol and ascorbic acid of the adrenal gland.
Canad. J. M. Se. 30: 36, 1952.
16. VAN LIERE, E. J., AND NORTHRUP, D. W.:
Ef-
fect of methimazole on size of the heart in
the rat. J. Appl. Physiol. 10: 459, 1957.
FltEGLY, HOOD
496
17.
athyroid state on vascular reactivity and arterial pressure in neurogenic and renal hyj>ertensive • dogs. Circulation 5: 397, 1952.
LER.MAX, J., CLARK, R. J., AXI> MEANS, J. H. :
Further observations on the heart in niyxedenia. Ann. Int. Med. 8: S2, 1934.
\V.:
24. GLE.V.V, F., AND LASHER, E. P . : Effect of total
Exophthalmos in rats after prolonged administration of propylthiouracil. Endocrinology 45: 345, 1949.
19. ESSEX, H. E.: Exophthalmos in hypophysectomized and cortisone-treated albino rats.
Am. J. Physiol. 181: 375, 1955.
20. HESS, M.: Effect of thyroidectomy on adrenal
weight in adult male rats. Proe. Soe. Exper.
Biol. & Med. 84: 127, 1953.
thyroidectomy upon the production and
maintenance of experimental hypertension.
Proc. Soe. Exper. Biol. & Med. 38: 15S,
1938.
18.
21.
SELLERS, E.
A.,
AND FERGUSON, J.
K.
WILLIAMS, R. H., WEIXGLASS, A. R., BISSELL,
G. W., AND PETERS, J. B . : Anatomical efDownloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
fects of thiouracil. Endocrinology 34: 317,
1944.
22. BRATJX-MEXEXDEZ, E.: Mecanismo de la re-
gresion renal en las ratas hipon'soprivas.
Rev. Soe. Argent. Biol. 26: 65, 1950.
23.
MCCUBBI.V, J. W., AXD PAGE, I. H . : Effect of
25.
KOUXTZ, W. B., AXD HE.MPELMAXX, L.
H.:
Chronuitropic degeneration and rupture of
the aorta following thyroidectomy in cases
of hypertension. Am. Heart J. 20: 599,
1940.'
26. BRAUX-MEXEXBEZ, E.: Tiroides e hipertension
nefrogena experimental. Rev. Soe. Argent.
Biol. 30: 138, 1954.
27. SALGADO, E. :• Effect of thyroidectomy on hypertension, nephrosclerosis and cardiac
lesions produced by desoxycortocosterone
acetate (DCA) treatment in rat. Endocrinology 55: 377, 1954.
Physiologic and Anatomic Effects of Propylthiouracil on Normal and Hypertensive Rats
M. J. FREGLY and C. I. HOOD
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
Circ Res. 1959;7:486-496
doi: 10.1161/01.RES.7.3.486
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1959 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7330. Online ISSN: 1524-4571
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circres.ahajournals.org/content/7/3/486
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the
Editorial Office. Once the online version of the published article for which permission is being requested is
located, click Request Permissions in the middle column of the Web page under Services. Further information
about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation Research is online at:
http://circres.ahajournals.org//subscriptions/