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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. 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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. 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