Abnormal Thyroid Function in Spontaneously Hypertensive Rats AKIRA KOJIMA, TETSUHIRO KUBOTA, AKIRA SATO, TAKASHI YAMADA, AKIRA HARADA, MASAFUMI UTSUMI, MASAHIRO SAKODA, SHIGEAKI BABA, YUKIO YAMORI, AND KOZO OKAMOTO Department of Medicine, Institute of Adaptation Medicine, School of Medicine, Shinshu University, Matsumoto; Second Department of Internal Medicine, Kobe University, School of Medicine, Kobe; and Department of Pathology, School of Medicine, Kyoto University, Kyoto, japan these abnormalities, plasma T4 was significantly lower than normal, but triiodothyronine (T3) was normal, as a result of compensatory processes occurring in T3 synthesis and hydrolysis of thyroglobulin. T4 and T3 were less effective in depressing pituitary TSH synthesis and secretion in SHR than in controls, possibly because of an abnormal setting of the "hormostat." Although the hypothalamic content of TRH was normal in SHR, the exact site of the abnormality in the "hormostat" is not delineated in the present study. (Endocrinology 98: 1109, 1976)
ABSTRACT. Thyroid weight, thyroidal radioiodide uptake, and cyclic AMP-dependent protein kinase activity of a thyroid supernatant fraction were increased significantly in spontaneously hypertensive rats (SHR), apparently because of increased secretion of pituitary TSH. However, the thyroids of SHR did not make supernormal amounts of thyroxine (TJ, and thyroidal radioiodine release was apparently impaired. In the SHR, proteolytic enzyme activity was less than normal and the thyroglobulin was more resistant to normal proteolytic enzyme than was control thyroglobulin. Presumably because of
0
iKAMOTO and Aoki isolated a strain of Wistar rats with spontaneously developed hypertension (1), which has been widely used as an animal model of human essential hypertension. Despite much research on the pathogenesis of hypertension in spontaneously hypertensive rats (SHR) (2), the etiology remains obscure. Okamoto and his associates noticed that this strain of rats had bigger thyroids and pituitaries than those of weight-matched controls (2), and that thyroidal radioiodide uptake was significantly increased in SHR (3). On the basis of these findings, Okamoto postulated that endocrine abnormalities are somehow linked with the development of hypertension in SHR (2). Although the coincidence of the increase of these parameters can best be explained by assuming an increased secretion of TSH, an extensive analysis of these events has not been made previously. In the present study, an attempt was made to clarify whether the altered thyroid paramReceived June 20, 1975. Supported by a grant from the Japan Science and Technology Agency.
eters are actually due to an increased secretion of pituitary TSH. Materials and Methods Seventy-seven SHR and 76 control male rats, weighing 201 to 420 g, were obtained from Kyoto University and NN Laboratory. The animals were fed a pellet diet and water ad lib. in Experiments 1, 5, and 7, whereas in Experiments 2, 3, 4, and 6 the animals were fed a low-iodine diet1 beginning 7 days before the experiment. In the first part of Experiment 1, 0.1 /xCi of 131 I~ was injected ip. Four h later, blood was obtained by cardiac puncture using heparinized syringes. The plasma was separated and kept at —20 C for TSH, T4, and T3 radioimmunoassays. The thyroid was removed and weighed on a torsion balance; thyroidal radioiodide uptake was then measured. The anterior pituitary was homogenized with 1 ml of buffer (0.15M NaCl, 0.01M PO4) and the homogenates were centrifuged at 2,000 rpm for 15 min. The supernatants were separated and kept at -20 C until used. In the second part of Experiment 1, thyroidsoluble protein kinase was partially purified from the supernatant fraction (100,000 x g) by am1
Composition of this diet was indicated in Endocrinology 79: 138, 1966.
1109
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KOJIMA ETAL.
1110
TABLE 1. Blood pressure, thyroid activity, pituitary, and plasma TSH concentration in normal and spontaneously hypertensive rats (SHR) Parameters No. of animals Body weight (g) Blood pressure (mm Hg) Thyroid weight (mg/100 g body weight) Thyroidal I 3 I 1" uptake (%/4 h) Plasma T 4 (/xg/100 ml) Plasma T 3 (ng/100 ml) Plasma TSH (/nU/ml) Pituitary TSH (mU/ pituitary)
Control 15
15
402 ± 6* 121 ± 2 6.7 ± 0.3 12.5 ± 4.8 ± 89.5 ± 35.1 +
p value
SHR
0.6 0.3 2.1 2.6
207 ± 10
380 ± 6 208 ± 6 9.1 ± 0.2 38.1 ± 2.6 ± 85.8 ± 62.3 ±
3.0 0.2 5.1 6.1
412 ± 11
ABSTRACT. Thyroid weight, thyroidal radioiodide uptake, and cyclic AMP-dependent protein kinase activity of a thyroid supernatant fraction were increased significantly in spontaneously hypertensive rats (SHR), apparently because of increased secretion of pituitary TSH. However, the thyroids of SHR did not make supernormal amounts of thyroxine (TJ, and thyroidal radioiodine release was apparently impaired. In the SHR, proteolytic enzyme activity was less than normal and the thyroglobulin was more resistant to normal proteolytic enzyme than was control thyroglobulin. Presumably because of
0
iKAMOTO and Aoki isolated a strain of Wistar rats with spontaneously developed hypertension (1), which has been widely used as an animal model of human essential hypertension. Despite much research on the pathogenesis of hypertension in spontaneously hypertensive rats (SHR) (2), the etiology remains obscure. Okamoto and his associates noticed that this strain of rats had bigger thyroids and pituitaries than those of weight-matched controls (2), and that thyroidal radioiodide uptake was significantly increased in SHR (3). On the basis of these findings, Okamoto postulated that endocrine abnormalities are somehow linked with the development of hypertension in SHR (2). Although the coincidence of the increase of these parameters can best be explained by assuming an increased secretion of TSH, an extensive analysis of these events has not been made previously. In the present study, an attempt was made to clarify whether the altered thyroid paramReceived June 20, 1975. Supported by a grant from the Japan Science and Technology Agency.
eters are actually due to an increased secretion of pituitary TSH. Materials and Methods Seventy-seven SHR and 76 control male rats, weighing 201 to 420 g, were obtained from Kyoto University and NN Laboratory. The animals were fed a pellet diet and water ad lib. in Experiments 1, 5, and 7, whereas in Experiments 2, 3, 4, and 6 the animals were fed a low-iodine diet1 beginning 7 days before the experiment. In the first part of Experiment 1, 0.1 /xCi of 131 I~ was injected ip. Four h later, blood was obtained by cardiac puncture using heparinized syringes. The plasma was separated and kept at —20 C for TSH, T4, and T3 radioimmunoassays. The thyroid was removed and weighed on a torsion balance; thyroidal radioiodide uptake was then measured. The anterior pituitary was homogenized with 1 ml of buffer (0.15M NaCl, 0.01M PO4) and the homogenates were centrifuged at 2,000 rpm for 15 min. The supernatants were separated and kept at -20 C until used. In the second part of Experiment 1, thyroidsoluble protein kinase was partially purified from the supernatant fraction (100,000 x g) by am1
Composition of this diet was indicated in Endocrinology 79: 138, 1966.
1109
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 19 November 2015. at 05:27 For personal use only. No other uses without permission. . All rights reserved.
KOJIMA ETAL.
1110
TABLE 1. Blood pressure, thyroid activity, pituitary, and plasma TSH concentration in normal and spontaneously hypertensive rats (SHR) Parameters No. of animals Body weight (g) Blood pressure (mm Hg) Thyroid weight (mg/100 g body weight) Thyroidal I 3 I 1" uptake (%/4 h) Plasma T 4 (/xg/100 ml) Plasma T 3 (ng/100 ml) Plasma TSH (/nU/ml) Pituitary TSH (mU/ pituitary)
Control 15
15
402 ± 6* 121 ± 2 6.7 ± 0.3 12.5 ± 4.8 ± 89.5 ± 35.1 +
p value
SHR
0.6 0.3 2.1 2.6
207 ± 10
380 ± 6 208 ± 6 9.1 ± 0.2 38.1 ± 2.6 ± 85.8 ± 62.3 ±
3.0 0.2 5.1 6.1
412 ± 11
