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  • Author: Toshikazu Saito x
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Yukiko Yajima and Toshikazu Saito

Abstract. Hypothalamic factors were tested for their effects on the production of hormones and the growth of GH3 cells, cloned rat pituitary cells producing prolactin (Prl) and growth hormone (GH). Hypothalamic extracts (HE) (0.05 mg/ml) and TRH (0.3 μm) stimulated the synthesis of Prl to levels of 306% and 360%, respectively, of the control culture in a medium containing 0.5% foetal bovine serum (FBS) during a 24 h incubation. They did not affect the rate of GH production. The thymidine uptake was suppressed to 57% and 46% of the control by the addition of HE and TRH, respectively. They also inhibited the growth of GH3 to 70% and 74% of the control culture during an 8-day incubation period. On the other hand, LRH affected neither the rate of hormone production nor the thymidine uptake. Somatostatin suppressed the synthesis of Prl and GH, but it did not affect the incorporation of thymidine into the cells.

The gel filtration studies of HE revealed that the inhibitory effects of HE on the thymidine uptake were dependent on two substances, TRH and an unknown factor(s) of high molecular nature. The relationship between hormone synthesis and DNA synthesis will be discussed on the basis of the TRH-induced effects on Prl production and DNA synthesis in GH3 cells.

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San-e Ishikawa and Toshikazu Saito

Ishikawa S, Saito T. Biphasic effect of interleukin-1β on arginine vasopressin-induced cellular cyclic adenosine monophosphate production in cultured rat renal papillary collecting tubule cells. Eur J Endocrinol 1995;132:472–8. ISSN 0804–4643

The present study was undertaken to determine whether interleukin (IL)-1β affects the response of cellular cyclic adenosine monophosphate production to arginine vasopressin (AVP) in cultured rat renal papillary collecting tubule cells. Arginine vasopressin increased cellular cAMP production in a dose-dependent manner. A 10-min exposure of cells to IL-1β at a concentration of 1 × 10−12 mol/l or higher significantly reduced the AVP-induced increases in cellular cAMP production but did not affect the 2 × 10−8 mol/l forskolin-induced increases in cellular cAMP production. The IL-1β inhibition disappeared totally when cells were pretreated with 100 μg/1 pertussis toxin for 2 h. In contrast, more than a 30-min exposure of cells to IL-1β increased basal cAMP levels and enhanced both the AVP- and forskolin-induced increases in cellular cAMP production. These results indicate that IL-1β produces biphasic regulation of AVP-induced cellular cAMP production in renal papillary collecting tubule cells. The inhibition by IL-1β is dependent on the activation of pertussis toxin-sensitive G protein. However, the mechanism whereby the longer exposure to IL-1β enhances cAMP production remains to be determined.

San-e Ishikawa, Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical School, 3311-1 Yakushiji Minamikawachi-machi, Tochigi 329-04. Japan

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Nobuko Sakuma, San-e Ishikawa, Koji Okada, Jun-ichi Miyazaki and Toshikazu Saito

Sakuma N, Ishikawa S, Okada K, Miyazaki J, Saito T, Glucose induces calcium-dependent and calcium-independent insulin secretion from the pancreatic beta cell line MIN6. Eur J Endocrinol 1995;133:227–34. ISSN 0804–4643

The present study was undertaken to determine whether there are Ca2+-dependent and -independent pathways of glucose-induced insulin secretion from the pancreatic beta cell line MIN6. Glucose at a concentration of 16.7 mmol/l caused marked increases in cellular free calcium [Ca2+]1) and insulin secretion, which depended on glucose metabolism. When cells were pretreated with 20 mmol/l mannoheptulose, an inhibitor of glucokinase, the 16.7 mmol/l glucose induced a rise in [Ca2+]1 and insulin secretion disappeared. Also, l-leucine and l-arginine increased [Ca2+]1 and induced insulin secretion. Under Ca2+-free conditions, insulin release was still induced, without any change in [Ca2+]1, by these three different stimulants. The cumulative values of insulin secretion were 13.7–29.3% of the control, which were significantly less than that in the presence of Ca2+. Cellular alkalinization occurred in response to all these stimulants, irrespective of the presence or absence of Ca2+. Forskolin, a diterpene activator of adenylate cyclase, produced insulin secretion independently of [Ca2+]1, which accompanied cellular alkalinization. Also, a high glucose level increased cellular cyclic AMP (cAMP) production in the presence and absence of Ca2+, and the effect was diminished by approximately 73% in Ca2+-free conditions. These results indicate that a high glucose level stimulates both Ca2+-dependent and -independent insulin secretion from pancreatic beta cells. We suggest that the cAMP production and the cellular alkalinization participate in the Ca2+-independent mechanism.

Nobuko Sakuma, Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical School, 3311-1 Yakushiji Minamikawachi-machi, Tochigi 329-04, Japan

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San-e Ishikawa, Toshikazu Saito, Koji Okada, Shoichiro Nagasaka and Takeshi Kuzuya


We studied the changes in plasma arginine vasopressin in 5 patients with diabetic ketoacidosis and one patient with non-ketotic hyperosmolar coma who had marked hyperglycemia (36.6 ± 4.6 mmol/l, mean ± sem) and dehydration. Plasma osmolality (Posm) was 342.2 ± 11.4 mOsm/kg H2O, and hematocrit, serum protein, and blood urea nitrogen were also elevated at hospitalization. Circulating blood volume was decreased by approximately 21% as compared with that on day 7. Plasma AVP level was increased to 8.5 ± 1.6 pmol/l at hospitalization. When hyperglycemia was improved by iv infusion of a small dose of insulin plus fluid administration, plasma AVP level promptly decreased to 2.4 ± 0.4 pmol/l within six hours. When plasma AVP level had normalized, Posm was still as high as 305 mOsm/kg H2O, but the loss of circulating blood volume was only 4.2% of the control state. Plasma AVP level was positively correlated with change in hematocrit (plasma AVP = 3.58 + 0.45 · hematocrit, r = 0.468, p < 0.01), serum protein (r = 0.487, p < 0.01), Posm (r = 0.388, p < 0.01), and blood glucose (r = 0.582, p < 0.01). Plasma AVP level was negatively correlated with the change in circulating blood volume (plasma AVP = 3.6 – 0.14 · change in circulating blood volume, r = −0.469, p <0.01). These results indicate that both non-osmotic and osmotic stimuli are involved in the mechanism for AVP release in patients with diabetic coma, and that the non-osmotic control of AVP may contribute to circulating homeostasis, protecting against severe blood volume depletion in diabetic patients suffering from hyperglycemia and dehydration.

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Toshikazu Saito, Yoshiko Akita, Hiroko Fujita, Yohtaro Furukawa, Yutaka Tsuchiya, Toshiyuki Yasuda, Michiko Yamamoto, Teruo Kitagawa, Yuichi Nakagawa, Akira Takehiro, Takuo Fujita, Soichi Kodama and Takeshi Kuzuya

Abstract. The activity of stimulatory guanine nucleotide regulatory protein (Ns) in the erythrocyte membrane was assayed by the reconstitution method using plasma membrane of cyc S49 mouse lymphoma cells in 18 patients with type I pseudohypoparathyroidism (PHP-I), 2 with pseudopseudohypoparathyroidism (PPHP) and 30 normal subjects, in parallel with other clinical parameters. The Ns activity as expressed by per cent of pooled standard (mean ± se) was 78.9 ±6.1 in PHP-I patients, which was significantly lower (P < 0.01) than the value in normal subjects, 99.5 ± 2.4. In PHP-I patients, the Ns activities (Y) were in significant correlation with three clinical parameters examined (X), i.e., with body height in standard deviation score from the mean of the normal population at the corresponding age, Y = 89.4 + 10.4X (r = 0.616, P < 0.01); with urinary cAMP excretion in relation to creatinine [cAMP(nmol)/Cr(mg)], Y = 56.3 + 7.2X (r = 0.501, P < 0.05); and with TSH levels in plasma (μU/ml), Y = 129–3X (r = 0.639, P < 0.01). The Ns activities of PPHP were as low as 53.8 and 60.0. The decrease of Ns activity in the cell membrane may be implicated in the development of the clinical symptoms such as short stature, decrease in urinary excretion of cAMP and latent or manifest primary hypothyroidism in PHP-I and possibly in skeletal abnormality in PPHP.