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T. HIROSE, I. MATSUMOTO and T. AIKAWA

SUMMARY

The steroidogenic effect of histamine in isolated adrenocortical cells of the dog was investigated in the presence of prostaglandin E2 (PGE2) and/or dibutyryl cyclic AMP (dbcAMP) in the medium. The effect of histamine, in combination with PGE2, was less than their total individual effects in the production of cortisol, but not of corticosterone. With dbcAMP the effect was just equal to them. However, the combination of histamine, PGE2 and dbcAMP showed an increase twice that of their total individual effects in the production of both steroids. These results indicate that, in the dog, histamine, PGE2 and dbcAMP may act synergistically in the adrenocortical cells.

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T. HIROSE, I. MATSUMOTO and T. AIKAWA

Department of Physiology, Nagasaki University School of Medicine, Nagasaki, Japan

(Received 2 September 1977)

In the dog, intravenous injection of histamine produces a marked increase in adrenocortical secretion (Suzuki, Hirai, Yoshio, Kurouji & Yamashita, 1963; Papp, Stark, Ács & Varga, 1964; Asano, 1966; Katsuki, Ito, Watanabe, lino, Yuji & Kondo, 1967; Tanigawa, 1967; Narita, 1971; Yamashita, Shimizu, Mieno & Kawao, 1973; Hirose, Matsumoto & Suzuki, 1976; Hirose, Matsumoto, Aikawa & Suzuki, 1977). The adrenocortical response of the dog to histamine was found to be markedly reduced, although not completely eliminated, by hypophysectomy (Hirose et al. 1976, 1977). This indicates that the response, although dependent for the main part on the pituitary gland, may involve a direct effect of histamine on the adrenal cortex or some other extrapituitary factor. In the present study, a direct stimulatory effect of histamine on the adrenal cortex was examined by evaluating the production of cortisol

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T. HIROSE, I. MATSUMOTO, T. AIKAWA and T. SUZUKI

Department of Physiology, Nagasaki University School of Medicine, Nagasaki, Japan

(Received 5 January 1977)

A systemic administration of histamine to intact dogs markedly increases the adrenocortical secretion (Suzuki, Hirai, Yoshio, Kurouji & Yamashita, 1963; Papp, Stark, Acs & Varga, 1964; Asano, 1966; Katsuki, Ito, Watanabe, Iino, Yuji & Kondo, 1967; Tanigawa, 1967; Yamashita, Shimizu, Mieno & Kawao, 1973). This effect was found to be completely abolished by hypophysectomy (Asano, 1966). In the experiments by Tanigawa (1967), however, a slight increase in adrenocortical secretion in response to histamine was observed in some hypophysectomized dogs. In the present work a direct adrenocortical stimulatory effect of histamine was examined by evaluating the adrenal secretion of cortisol and corticosterone in response to histamine in hypophysectomized dogs.

Thirteen mongrel male dogs weighing 10·0–16·8 kg were used; four of them were intact, and the others were hypophysectomized. Under sodium pentobarbitone (25 mg/kg, i.v.) anaesthesia, hypophysectomy was

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T Matsumoto, T Tsurumoto, MB Goldring and H Shindo

Insulin-like growth factor-I (IGF-I) is an important anabolic factor for cartilage tissue and its action is, in part, regulated by IGF-binding proteins (IGFBPs). The object of this study was to investigate the effects of IGFBPs on IGF-I action and on binding of IGF-I to cells using a reproducible immortalized human chondrocyte culture model. Treatment of the C-28/I2 cells with IGF-I or des(1-3)IGF-I in serum-free medium stimulated cell proliferation in a dose-dependent manner. However, the effect of des(1-3)IGF-I was more potent, thereby suggesting that endogenously produced IGFBPs inhibited IGF action. The stimulatory effect of IGF-I was inhibited significantly by addition of IGFBP-3 but enhanced slightly by IGFBP-5. However, neither IGFBP-3 nor IGFBP-5 had an effect on basal cell growth. Binding of (125)I-labeled IGF-I to the cells was displaced by both IGFBP-3 and IGFBP-5, although higher concentrations of unlabeled IGFBP-5 were required to displace IGF-I to the same extent as IGFBP-3. Treatment of the cells with IGF-I increased the levels of IGFBP-5 protein measured by Western ligand blotting, and stimulated a corresponding increase in IGFBP-5 mRNA while increasing type II collagen mRNA. Our findings indicate that the balance between IGFBP-3 and IGFBP-5 influences IGF receptor binding and its action on chondrocyte proliferation, and may thereby modulate cartilage metabolism.

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S. MIZUTANI, T. SONODA, K. MATSUMOTO and K. IWASA

Over 50% of men having paraplegia due to traumatic lesions of the spinal cord or cauda equina show decreased spermatogenesis in varying degrees (Paulsen, 1968). The commonest pathology is arrested spermatogenesis with generalized hypoplasia of the germinal epithelium. Leydig cells usually appear normal, but the presence of nodular hyperplasia has been reported (Horne, Paull & Munro, 1948; Keye, 1956). Androgen production has been considered essentially normal judging from clinical symptoms, though most testes become smaller. Although urinary gonadotrophin excretion is reported to be low or absent in the majority of paraplegic men (Paulsen, 1968) and women (Durkan, 1968), there are no reports of plasma androgen concentrations. The concentration of testosterone in peripheral plasma from 51 paraplegic men after spinal cord injuries was therefore measured and compared with that of normal men.

The patients studied (aged 18–66 yr, average 37 yr) had been admitted to Osaka Labour Injury Hospital and the

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T Matsumoto, S E Gargosky, Y Oh and R G Rosenfeld

Abstract

The aim of this study was to assess the regulation of insulin-like growth factor-binding proteins (IGFBPs) by IGFs in primary cultures of rat articular chondrocytes (RAC). Employing Western ligand blotting, immunoprecipitation and Northern blot analysis, RAC were found to secrete IGFBP-5 (29 kDa) and IGFBP-4 (24 kDa) as the predominant IGFBPs, as well as IGFBP-2 (32–30 kDa) and IGFBP-3 (43–39 kDa) as the minor species. Treatment of cells with IGF-I and IGF-II resulted in a dose-dependent increase of IGFBP-5 and a small increase in IGFBP-4 in conditioned media (CM). Des(1–3) IGF-I and [Gln6, Ala7,Tyr18, Leu19] IGF-II ([QAYL] IGF-II), which bind to the type 1 IGF receptor but not to IGFBPs, also induced IGFBP-5 peptide, although the increase was less than with IGF-I or IGF-II treatment of RAC. [Leu27] IGF-II, which does not bind to the type 1 IGF receptor but binds to IGFBPs, resulted in little induction of IGFBP-5, while [QAYL-Leu27] IGF-II, which has reduced affinity for both the type 1 IGF receptor and IGFBPs, did not increase IGFBP-5. These data suggest that the increase in IGFBP-5 in CM is modulated by both the type 1 IGF receptor and the interaction between IGFs and IGFBPs. Northern blotting analysis showed that IGF-I, IGF-II and des(1–3) IGF-I treatment of RAC increased steady state levels of IGFBP-5 mRNA, suggesting that the IGF-mediated increase in IGFBP-5 is transcriptionally modulated. Interestingly, the increase in IGFBP-5 peptide levels and mRNA were not parallel, suggesting the possibility of post-translational modifications of IGFBP-5, such as those seen with IGFBP-5 protease. IGFBP-5 protease activity was detectable in untreated CM, whereas treatment with IGF-I and IGF-II partially protected IGFBP-5 from proteolysis. In summary, treatment of RAC with IGF-I and IGF-II results in dose-dependent increases in both IGFBP-5 peptide in the CM and mRNA levels. These changes are mediated by interactions via the type 1 IGF receptor as well as IGFBPs, both transcriptionally and post-translationally.

Journal of Endocrinology (1996) 148, 355–369

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K Matsumoto, R Morishita, N Tomita, A Moriguchi, K Yamasaki, M Aoki, K Matsumoto, T Nakamura, J Higaki and T Ogihara

We have previously reported that a decrease in hepatocyte growth factor (HGF), which has many protective functions against endothelial damage by high d-glucose, might be a trigger of endothelial injury. However, the regulation of vascular HGF in diabetes mellitus (DM) has not been clarified in vivo, although vascular disease is frequently observed in DM patients. In addition, our previous report revealed that a prostaglandin I(2) (PGI(2)) analogue prevented endothelial cell death through the induction of vascular HGF production in cultured human epithelial cells. Thus, in this study, we examined the effects of a PGI(2) analogue in the regulation of the local HGF system using DM rats. A PGI(2) analogue (beraprost sodium; 300 and 600 micro g/kg per day) or vehicle was administered to 16-week-old DM rats induced by administration of streptozotocin for 28 days. Endothelial function was evaluated by the vasodilator response to acetylcholine, and the expression of vascular HGF mRNA was measured by Northern blotting. Of importance, expression of HGF mRNA was significantly decreased in the blood vessels of DM rats as compared with non-DM (P<0.01). In addition, the in vitro vasodilator response of the abdominal aorta to acetylcholine was markedly impaired in DM rats. Importantly, the vasodilator response was restored by PGI(2) treatment in a dose-dependent manner (P<0.01), whereas N(omega)-nitro-l-arginine methyl ester inhibited the restoration of endothelial function. Of particular interest, vascular HGF mRNA and protein were significantly increased in the blood vessels of DM rats treated with PGI(2) as compared with vehicle. Similarly, an increase in HGF protein was also confirmed by immunohistochemical analysis. In addition, the specific HGF receptor, c-met, was also increased by PGI(2) treatment. Overall, this study demonstrated that treatment with a PGI(2) analogue restored endothelial dysfunction in DM rats, accompanied by the induction of vascular HGF and c-met expression. Increased local vascular HGF production by a PGI(2) analogue may prevent endothelial injury, potentially resulting in the improvement of endothelial dysfunction.

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H Otsubo, S Hyodo, H Hashimoto, M Kawasaki, H Suzuki, T Saito, T Ohbuchi, T Yokoyama, H Fujihara, T Matsumoto, Y Takei and Y Ueta

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T Yoshimoto, M Naruse, Z Zeng, T Nishikawa, T Kasajima, H Toma, S Yamamori, H Matsumoto, A Tanabe, K Naruse and H Demura

To explore the clinical significance of p53 in the pathogenesis of adrenal neoplasms, we investigated the incidence of p53 gene mutations in functioning human adrenal tumours using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique to screen p53 exons 4 to 9. We examined 29 adrenocortical adenomas (primary aldosteronism, n=17; Cushing's syndrome, n=12, all benign), and 33 phaeochromocytomas (benign solitary, n=18; benign multiple, n=5; malignant, n=10) in Japanese and Chinese patients. PCR-SSCP did not show any abnormal band-shifts in any of the adrenocortical adenoma and benign solitary phaeochromocytoma tissues. In contrast, six phaeochromocytoma tissues (two cases benign multiple, four cases malignant) showed PCR-SSCP band-shifts. Subsequent DNA sequencing analysis of the shifted bands revealed six cases with nine mutations or intronic sequence alterations: three cases contained sequence alterations within intronic regions, three cases with silent mutation (sequence alteration in codon without amino acid alteration), and three cases contained missense mutations (one case each in exons 5, 6 and 9). Immunohistochemical staining demonstrated that two of three cases with missense mutations and one case with an intronic sequence alteration over-expressed p53 protein in tumour cell nuclei. We observed no association between p53 gene mutation and p21/WAF1/Cip-1 expression. The relatively high incidence of p53 gene mutations or intronic sequence alteration in multiple and malignant phaeochromocytomas, but not in benign solitary cases, suggests that p53 mutation could play some role in the pathogenesis of multiple and/or malignant phaeochromocytomas.

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A Shirakami, T Toyonaga, K Tsuruzoe, T Shirotani, K Matsumoto, K Yoshizato, J Kawashima, Y Hirashima, N Miyamura, CR Kahn and E Araki

Insulin receptor substrate 1 (IRS-1) gene polymorphisms have been identified in type 2 diabetic patients; however, it is unclear how such polymorphisms contribute to the development of diabetes. Here we introduced obesity in heterozygous IRS-1 knockout (IRS-1(+/-)) mice by gold-thioglucose (GTG) injection and studied the impact of reduced IRS-1 expression on obesity-linked insulin resistance. GTG injection resulted in approximately 30% weight gain in IRS-1(+/-) and wild type (WT) mice, compared with saline-injected controls. There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. Elevated fasting insulin levels but no change in fasting glucose were noted in obese IRS-1(+/-) and WT compared with the respective lean controls. Importantly, fasting insulin in obese IRS-1(+/-) was 1.5-fold higher (P<0.05) than in obese WT, and an insulin tolerance test showed a profound insulin resistance in obese IRS-1(+/-) compared with obese WT. The islets of obese IRS-1(+/-) were 1.4-fold larger than those of obese WT. The expression of insulin receptor and IRS-1 and IRS-2 was decreased in obese IRS-1(+/-), which could in part explain the profound insulin resistance in these mice. Our results suggest that IRS-1 is the suspected gene for type 2 diabetes and its polymorphisms could worsen insulin resistance in the presence of other additional factors, such as obesity.