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  • Author: Kazuo Shizume x
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Kazue Takano, Naomi Hizuka and Kazuo Shizume

Abstract. Twenty patients with Turner's syndrome were treated with methionyl human growth hormone (met-hGH) produced by recombinant DNA technology. Plasma non-esterified fatty acid (NEFA) (mean ± sem) increased significantly from 0.52 ± 0.06 to 1.30 ± 0.09 mEq/l at 4 h after the first administration of 4 IU of met-hGH (P <0.001). Basal plasma somatomedin C (SM) levels were within the normal range; however, they increased significantly at 24 h after the first three daily injections of 4 IU of met-hGH (basal, 0.92 ± 0.14; 24 h, 1.39 ± 0.16; 48 h, 1.68 ± 0.19; 72 h, 1.91 ± 0.22 U/ml; P < 0.001). For long-term treatment, the patients were given 16 IU of met-hGH per week for 6 months. The height increase during treatment was greater in 16 patients, but smaller in 4 than before treatment. The heights increased between 1.4 and 3.7 cm during 6 months of treatment, which corresponds to between 2.8 and 7.4 cm/year. The mean increase of 5.7 ± 0.4 cm/year was greater than the pretreatment value of 3.7 ± 0.2 cm/year (P <0.001). There was a positive correlation between growth rate and maximum increase in SM (r = 0.51, P < 0.05). Antibody against hGH appeared in 3 patients after 2 months; 10 of the 20 patients had antibody after 6 months of treatment. However, the antibody did not suppress the growth effect of met-hGH. Otherwise there were no significant changes in physical, blood, or urine examinations.

These results indicate that hGH treatment is useful for the acceleration of growth velocity in patients with Turner's syndrome.

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Mitsuhide Naruse, Kazuo Shizume and Tadashi Inagami

Abstract. Mouse adrenal tissue has been reported to contain high renin activity. However, it is not clear whether the renin is produced inside the tissue or is derived from a blood-borne component. We have investigated a cloned cell line of mouse adrenocortical tumour (Y-1) which has a steroidogenic activity. Sizable quantities of renin were demonstrated, predominantly in the cell lysate. This renin activity was distinguished from cathepsin D in view of its specific affinity to anti-renin antibody, optimal pH was determined, and the substrate specificity was checked with haemoglobin. Immunoreactive angiotensins were also detectable, but were demonstrated both in the cell and in the culture medium. This study provides further evidence for the existence of renin intrinsic to the adrenal gland. This study also suggests an intracellular role for renin and possible secretion of generated angiotensins.

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Kumiko Asakawa, Jose A. Hedo, Phillip Gorden and Kazuo Shizume

Abstract. IM-9 cultured human lymphocytes were treated with N-linked glycosylation inhibitors, N-linked oligosaccharide processing inhibitors, or neuraminidase to study the effect of glycosylation modification on human growth hormone binding and molecular weight of surface hGH receptor. One mg/l tunicamycin and 20 mmol/l glucosamine decreased 125I-hGH binding to the cells to 46.3 ± 2.4% (mean ± sem) and 21.9 ± 0.2% of the controls, respectively. The hGH binding was 33.0 ± 18.4% of the control value in the cells treated with monensin. The inhibition of binding was due to a decrease in the hGH receptor number without any affinity changes in these cells. Neither 1 mg/l swainsonine nor 100 mg/l castanospermine had any effect on the hGH binding. On the other hand, 125I-hGH binding to neuraminidase-treated cells was significantly enhanced with accompanying affinity changes. When 125I-hGH was cross-linked to IM-9 cells, there were no differences in the molecular weight of hGH receptor complexes (140K) between untreated cells and cells treated with tunicamycin, glucosamine, monensin, or castanospermine. However, the 128K hGH-receptor complex appeared in swainsonine-treated cells; this complex was sensitive to endoglycosidase H. These data show that the altered carbohydrate moiety changed hGH binding and the size of surface hGH receptor and suggest that glycosylation of receptor is important for the binding of hGH and for its physiological action.

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Naomi Hizuka, Kazue Takano, Kazuo Shizume and Koichi Kawai

ABSTRACT

The levels of serum somatomedin A were determined in 59 growth retarded Japanese children by a radioreceptor assay. Low levels were found in 10 children with growth hormone (GH) deficiency and 7 children with relative GH deficiency with means of 0.26 ± 0.03 and 0.48 ± 0.04 U/ml, respectively.

Serum somatomedin A levels in 42 growth retarded children with normal growth hormone levels were within the range of normal adults, and did not correlate with degree of short stature.

Significant increases of somatomedin A after hGH administration were found in children with growth hormone deficiency but not in children with normal growth hormone.

These results show that determination of somatomedin A in serum correlates well with the state of growth hormone secretion, and is of great importance in the selection of patients for treatment with human growth hormone.

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Kazue Takano, Naomi Hizuka, Kazuo Shizume and Yoko Hasumi

ABSTRACT

Eighteen patients with pituitary dwarfism were treated for 1 7/12 to 6 years with human growth hormone (hGH) at a dose of 0.19–0.62 unit (U) per kg of body weight per week. The mean increment in height was 2.0 ± 0.4 and 8.8 ± 0.5 cm/year before and the first year after treatment of hGH, respectively.

A significant positive correlation was observed between serum levels of somatomedin A and growth rate, especially in children with bone age below 10 and a duration of treatment of less than one year (r = 0.66, P < 0.005). Long-term treatment with hGH was accompanied by a decreasing response. However, the serum levels of somatomedin A did not decrease significantly. Therefore, decreased growth increment in these situations was not due to decreased serum levels of somatomedin A.

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Kumiko Asakawa, Kazue Takano, Megumi Kogawa, Yoko Hasumi and Kazuo Shizume

Abstract.

Serum levels of somatomedin A, as measured by radioreceptor assay, and body weight gain were 86.5 ± 9.2% and 166.9 ± 7.8% (N = 5) of the initial values, respectively, after 18 days administration of 2.5 mg cortisone acetate (CA). These values were significantly lower than those for saline treated rats (P < 0.005). Reduced serum somatomedin A and body growth rate were partially restored after halting the injection of CA.

Combined administration of daily doses of 100 μg hGH with CA did not prevent the decrease in somatomedin activity in treated rats. This observation suggests that GH plays a minor (or no) role in the fall of serum somatomedin A in CA-treated rats.

From these data we conclude that glucocorticoids reduce serum somatomedin by inhibiting the effect of GH on the generation of somatomedin.

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Naomi Hizuka, Kazue Takano, Kazuo Shizume and Yoko Hasumi

Abstract.

Changes in serum somatomedin A levels and [125I]somatomedin A binding to membrane fractions from kidney were studied in rats 1–80 days of age. The mean level of serum somatomedin A was 0.80 U/ml at birth and increased with age; at 80 days the mean level was 7.41 ± 0.67 U/ml. There was a close correlation between serum levels of somatomedin A and body weight. Labelled somatomedin A binding to membrane fractions from kidney was highest at birth and decreased with age up to 50 days. In Scatchard analysis of the data the affinity constant did not show a clear change with age, but the binding capacity decreased with age up to 30 days. An inverse correlation was observed between serum somatomedin A levels and labelled somatomedin A binding to membrane fractions from kidney. Compared to changes in circulating somatomedin A, the change in tissue binding was modest. This observation suggests that other circulating growth factors not measured by this radioreceptor assay or altered post-receptor sensitivity to somatomedins may be involved in growth.

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Kaoru Nomura, Hiroshi Demura, Nobuo Horiba and Kazuo Shizume

Abstract. Three patients with idiopathic hyperaldosteronism were continuously treated with trilostane, a competitive inhibitor of adrenal 3β-hydroxysteroid dehydrogenase (3β-HSDH) (3 to 4⅔ years). Trilostane, in conjunction with antihypertensive drugs, effectively decreased plasma aldosterone levels and improved hyperaldosteronism symptoms without undesirable side effects. Trilostane continued to be effective even when treatment was continuous. Rapid ACTH testing (iv bolus of 0.25 mg α1–24 ACTH) was done on the day without trilostane after long-term treatment, and plasma levels of aldosterone and cortisol were compared to those obtained during a pre-treatment period. Results suggest that the inhibitory effect of trilostane on steroid biosynthesis rapidly disappears following discontinuance of trilostane administration even after long-term treatment, and that continuous treatment causes no significant or irreversible change in steroid biosynthesis. These results suggest that trilostane is a safe, feasible therapeutic agent for long-term treatment of idiopathic hyperaldosteronism.

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Kazue Takano, Naomi Hizuka, Koichi Kawai and Kazuo Shizume

ABSTRACT

Somatomedin A was determined by radioreceptor assay of serum from rats with various conditions. The mean value of somatomedin A in 28 day old male rats was 6.2 ± 0.44 U/ml. Following hypophysectomy, serum somatomedin A decreased with a half-life of approximately 6 h. After a single ip injection of human growth hormone into hypophysectomized rats, the levels of somatomedin A increased within 4 h and reached the maximal level between 8 and 24 h. There was a dose-dependent increase of somatomedin A at 24 h after injection of hGH when the injected dose was between 3.2 and 80 μg.

Serum somatomedin A was significantly decreased after 24 h of fasting to the same levels as after hypophysectomy. However the changes in serum rGH between fasting rats and fed rats did not show any significant differences. After different intakes of diets with different composition for 32 days, the mean levels of serum somatomedin A were 14.5 ± 2.2, 6.22 ± 0.4, 2.5 ± 0.3 and 13.0 ± 1.1 U/ml when control-, high protein-, high carbohydrate-low protein- and high fat diets were given respectively. There was a positive correlation between the per cent increase in weight and the serum level of somatomedin A.

These results indicate that not only growth hormone but also adequate food intake is required for the generation of somatomedin.

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Ichiji Wakabayashi, Megumi Kanda, Nobuyasu Miki, Reiko Demura and Kazuo Shizume

ABSTRACT

Effects of chlorpromazine (CPZ) on plasma GH and prolactin levels were observed in conscious rats provided with chronic indwelling right atrial cannulae. The administration of CPZ (200 μg/100 g b.w. iv) suppressed episodic plasma GH burst and resulted in significant elevations of plasma prolactin levels.

These were also observed in rats in which two types of hypothalamic deafferentation, i.e. anterior and complete, had been carried out. The data suggest that CPZ acts within the medial basal hypothalamus and inhibits episodic plasma GH secretion. In addition, it is inferred that catecholamines are involved in the generation of episodic plasma GH burst.