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K. Kato, M. R. Sairam, and K. Ramasharma

The acute effects of pooled porcine follicular fluid (PFF), before and after various methods of processing to eliminate steroids, were studied on the luteinizing hormone releasing hormone (LH-RH)-induced release of FSH and LH by whole pituitary glands, from 34-day-old mice, incubated in vitro for 3–4 h. Charcoal treatment of PFF eliminated the steroids and reduced the inhibitory potency on gonadotrophin secretion. On the other hand, dialysis or ultrafiltration (mol. wt > 10 000) did not reduce the inhibitory activity on gonadotrophin secretion.

Of the three steroids tested, only oestradiol at a concentration of 10−10 mol/l inhibited FSH and LH secretion in vitro. This inhibitory effect was counteracted by the inclusion of the oestrogen antagonist tamoxifen in the incubation medium. The presence of tamoxifen did not decrease the suppression of FSH and LH induced by PFF, suggesting that the inhibition observed under the conditions of incubation was not due to oestrogen. Preincubation of mouse pituitary tissue for 1 h with PFF reduced the subsequent release of bioactive FSH and LH induced by LH-RH. The inhibitory effect of PFF was rapid and sustained. The continuous presence of PFF throughout the incubation period was not necessary for manifestations of the inhibitory effects on gonadotrophin release. The suppression of gonadotrophin secretion was related to the dose of PFF with the curve showing a biphasic pattern. The degree of FSH suppression was uniformly greater than that of LH, showing the preferential nature of the inhibitory effect of PFF. At high doses of PFF, the degree of FSH suppression was decreased significantly. This effect on LH release was less pronounced.

The inhibition caused by PFF in the in-vitro incubation procedure was not due to destruction of LH-RH or the released gonadotrophins.

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H Shimizu, K Ohtani, Y Kato, and M Mori

Interleukin (IL)-6, one of the cytokines released from inflammatory cells, stimulates insulin secretion in a physiological concentration (1-100 pg/ml), but the exact mechanism is still unknown. The present studies were undertaken to investigate the mechanism of IL-6-induced stimulation of insulin secretion in HIT-T 15 cells. The effects of the addition of nifedipine on the IL-6 (100 pg/ml)-induced stimulation of insulin secretion were investigated. We also examined the possibility that IL-6 (1-100 pg/ml) may stimulate insulin messenger ribonucleic acid (mRNA) expression, using the reverse transcription-polymerase chain reaction method. The addition of 100 and 1000 nM nifedipine significantly attenuated the stimulatory effects of 100 pg/ml IL-6 on insulin secretion. The addition of 1-100 pg/ml IL-6 dose-dependently increased preproinsulin mRNA expression relative to beta-actin mRNA. IL-6 increased insulin gene promoter activity of fragments A (-2188 to +337 bp) and B (-1782 to +270 bp) but not fragments C (-1275 to +270 bp), D (-1138 to +270 bp), E (-880 to +236 bp) or F (-356 to +252 bp). The addition of 10 nM nifedipine completely abolished the stimulatory effect of 10-100 pg/ml IL-6 on relative preproinsulin mRNA expression. These data raised the possibility that IL-6 increased preproinsulin mRNA expression via the stimulation of Ca(2+) influx which enhances insulin gene expression.

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ZW Fu, T Kubo, K Sugahara, T Noguchi, and H Kato

We investigated the effects of vitamin A (VA) nutritional status on the levels of expression of retinoic acid (RA) receptor-beta (RARbeta) gene in the various tissues of Japanese quail. VA deficiency caused a significant decrease in the mRNA levels of brain, liver, heart, lung and kidney RARbeta2/beta4, whereas no change was observed in the level of testis RARbeta2 transcript. In contrast, reduction in the RARbeta1 transcript caused by VA depletion was observed only in the lung, remaining unchanged in the other tissues. The administration of RA to the VA-deficient quail rapidly induced the expression of RARbeta2/beta4 mRNAs in all the tissues examined, but RA increased the expression of RARbeta1 transcript in the liver, heart, lung and kidney at a lower magnitude. RA could not change the expression of the brain RARbeta1 transcript, while it induced the expression of the testis RARbeta1 mRNA in a temporal way. These results clearly indicate that VA nutritional status differently regulates the expression of RARbeta1 and RARbeta2/beta4 transcripts in a tissue-specific manner.

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N. Sugino, H. Tamura, Y. Nakamura, K. Ueda, and H. Kato


The present study investigated possible sites through which ACTH or corticosterone inhibit progesterone secretion in pregnant rats, and the role of placental factors in blocking the inhibitory effect. The number of conceptuses was adjusted to one (1C group) or more than ten (FC group) on day 7 of pregnancy by aspirating the desired number. Serum concentrations of progesterone, testosterone and oestradiol were significantly (P<0·01) lower on day 15 in the 1C group than in the FC group. Corpora lutea (CL) obtained on day 15 were incubated for 6 h with corticosterone or ACTH. Corticosterone (1 μmol/l) significantly (P<0·05) inhibited progesterone secretion in the IC group but not in the FC group. The inhibitory effect of corticosterone in the IC group was completely blocked by co-addition of 1 μmol testosterone/l or 1 μmol oestradiol/l but not by 1 μmol dihydrotestosterone/l. ACTH (1 μg/l–1 mg/l) had no direct effect on progesterone secretion in either the IC or the FC groups, although ACTH apparently decreases progesterone secretion in vivo. Placentae obtained from rats of the FC group on day 15 were incubated for 24 h with or without ACTH (1 mg/l). The supernatant after placental incubation without ACTH significantly (P<0·01) increased progesterone secretion by the CL in both the IC and FC groups, and also eliminated the inhibitory effect of corticosterone in the IC group. The supernatant after placental incubation with ACTH also increased progesterone secretion in the FC group as effectively as the supernatant from the control incubation, but it had no effect in the IC group. It is concluded that corticosterone directly inhibits progesterone secretion by the CL, whereas the inhibitory effect of ACTH is mediated through the placenta. The results indicate that these inhibitory effects of corticosterone or ACTH are eliminated if the CL has been exposed to enough placental hormones before day 15 of pregnancy.

Journal of Endocrinology (1991) 129, 405–410

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Y Nakamura, H Tamura, M Ono, K Shimamura, N Sugino, F Numa, K Ueda, and H Kato


The purpose of this study was to examine the possible mechanism through which RU486 induces luteolysis during the late-luteal phase in pseudopregnant (PSP) rats. PSP rats received a subcutaneous injection of RU486 in sesame oil (5 mg/kg body weight) or sesame oil alone once a day between day 9 and day 11 of pseudopregnancy. Serial blood samples were collected on days 5, 9, 10, 11 and 12 and assayed for progesterone content. To examine the possible action of RU486 through a uterine and/or a pituitary (prolactin-dependent) mechanism, PSP rats and chronic hysterectomized PSP rats which had been hysterectomized before PSP induction received a subcutaneous injection of RU486 in sesame oil (5 mg/kg body weight), sesame oil alone, prolactin in 50% polyvinylpyrrolidone (15 IU/day), or RU486 and prolactin once a day between day 9 and day 11 of pseudopregnancy. Serial blood samples were collected on days 5, 9, 10 and 11 and assayed for progesterone content. Blood samples were also collected at 0400 h on day 12 and used for prolactin and progesterone determinations. To examine the direct effect of RU486 on corpus luteum and/or pituitary, hysterectomized rats underwent hypophysectomy and pituitary autotransplantation on dioestrus 1 and received a subcutaneous injection of RU486 in sesame oil or sesame oil alone for 3 days between day 21 and day 23 after surgery. Serial blood samples were collected on days 10, 21, 22, 23 and 24 and assayed for progesterone and prolactin contents.

In ordinary PSP rats, serum progesterone levels were significantly (P<0·01) lower in the RU486-treated group than in the control group (9 ± 1 vs 53 ± 7 ng/ml; mean ± s.e.m.) on day 11. Serum prolactin levels at 0400 h on day 12 of pseudopregnancy were significantly (P<0·05) lower in the RU486-treated group than in the control group (16 ±4 vs 154 ±44 ng/ml; mean ± s.e.m.). The concomitant prolactin treatment reversed the luteolytic effects of RU486 on day 11 of pseudopregnancy. In hysterectomized PSP rats, RU486 also suppressed serum prolactin levels, and the concomitant prolactin treatment again reversed the luteolytic effects of RU486. In hysterectomized rats which were hypophysectomized and pituitary autotransplanted, RU486 treatment did not induce any significant changes in serum progesterone and prolactin levels.

These results indicated that RU486 induced luteolysis during the late-luteal phase in PSP rats by suppressing prolactin secretion via a hypothalamic mechanism.

Journal of Endocrinology (1996) 150, 93–98

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N Hirayama, K Kitamura, T Imamura, J Kato, Y Koiwaya, T Tsuji, K Kangawa, and T Eto

In the biosynthesis of adrenomedullin (AM), an intermediate form, AM(1-52)-glycine-COOH (iAM), is cleaved from proAM and subsequently processed to a biologically active mature form, AM(1-52)-NH2 (mAM), by enzymatic amidation. We recently reported that immunoreactive AM in human plasma consists of mAM and iAM. To clarify the pathophysiological roles of mAM and iAM in heart failure, we established an assay method to specifically detect mAM, and we determined the plasma concentrations of mAM and iAM in 68 patients with congestive heart failure (CHF). The plasma mAM concentrations of the CHF patients classified as being class I or II of New York Heart Association (NYHA) functional classification were significantly greater than those of the 28 healthy controls, and a further increase was noted in the class III or IV patients. Similar increases in plasma iAM were also observed in these patients compared with controls. The increased plasma mAM and iAM in 12 patients with exacerbated CHF were significantly reduced by treatment of their CHF for 7 days. In addition, the plasma concentrations of both mAM and iAM were significantly correlated with pulmonary capillary wedge pressure, pulmonary artery pressure, right atrial pressure, cardiothoracic ratio, heart rate, and the plasma concentrations of atrial and brain natriuretic peptides in the CHF patients. Thus the plasma concentrations of both mAM and iAM were increased progressively in proportion to the severity of CHF. These results suggest that, though the role of iAM remains to be clarified, mAM acts against the further deterioration of heart failure in patients with CHF.

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M. Ohashi, N. Fujio, K. Kato, H. Nawata, H. Ibayashi, and H. Matsuo


To determine the effects of atrial natriuretic polypeptide (ANP) on plasma levels of ACTH, cortisol, aldosterone and dehydroepiandrosterone (DHEA), synthetic human α-ANP (hα-ANP) was infused i.v. into eight normotensive, disease-free volunteers, at a dose and duration previously found to be sufficient to produce apparent cardiovascular and renal effects.

The mean basal concentration of plasma ACTH determined by radioimmunoassay was 18·2 ± 3·1 ng/l. Plasma ACTH concentrations tended to be decreased during the infusion in all subjects. However, the change in plasma ACTH concentrations during infusion of hα-ANP was essentially the same as that during the infusion of saline. The mean plasma cortisol concentration was significantly suppressed from 25 to 40 min after the end of synthetic hα-ANP infusion. At 90 min after infusion, the mean plasma level of cortisol reverted to the pretreatment level. There was a non-significant increase in plasma renin activity following the infusion. The mean plasma aldosterone concentration was reduced by 15% (P < 0·05) during the infusion and returned to preinfusion levels 10 min after termination of the infusion, after which the mean plasma concentration declined to the level seen during infusion. Administration of hα-ANP had no significant influence on plasma DHEA concentrations, but there was a tendency to decrease during the infusion.

Our data suggest that synthetic hα-ANP inhibits adrenocortical steroidogenesis in man.

J. Endocr. (1986) 110, 287–292

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H Tokuda, O Kozawa, M Niwa, H Matsuno, K Kato, and T Uematsu

We investigated the effect of prostaglandin E2 (PGE2) on the induction of heat shock protein 27 (HSP27) and HSP70, and the mechanism behind the induction in osteoblast-like MC3T3-E1 cells. PGE2 time-dependently increased the level of HSP27 without affecting the level of HSP70. PGE2 stimulated the accumulation of HSP27 dose-dependently in the range between 10 nM and 10 microM. PGE2 stimulated the increase in the level of the mRNA for HSP27. Staurosporine and calphostin C, inhibitors of protein kinase C (PKC), suppressed the PGE2-induced HSP27 accumulation. The effect of PGE2 on HSP27 accumulation was reduced in the PKC down-regulated cells. BAPTA/AM, a chelator of intracellular Ca2+, or TMB-8, an inhibitor of intracellular Ca2+ mobilization, reduced the accumulation of HSP27 induced by PGE2. Dibutyryl cAMP had little effect on the basal level of HSP27. PGE2 induced the phosphorylation of both p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase. PD98059 and U-0126, inhibitors of the upstream kinase of p44/p42 MAP kinase, reduced the accumulation of HSP27 induced by PGE2. SB203580, a specific inhibitor of p38 MAP kinase, suppressed the HSP27 accumulation induced by PGE2. U-73122, an inhibitor of phospholipase C, and calphostin C reduced the PGE2-induced phosphorylation of both p44/p42 MAP kinase and p38 MAP kinase. These results indicate that PGE2 stimulates the induction of HSP27 through PKC-dependent activations of both p44/p42 MAP kinase and p38 MAP kinase in osteoblasts.

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F. Miyauchi, H. Kato, H. Yamashita, K. Ueda, H. Tamura, T. Mano, and T. Torigoe


The effects of a conceptus-derived substance on the activity of 3β-hydroxysteroid dehydrogenase (3β-HSD) and 20α-HSD in the ovary were studied in the rat. On day 7 of pregnancy (day 1 = insemination), rats were laparotomized and the desired number of conceptuses was aspirated from the uterus; thus, rats carrying one, two, three, four, five to seven or eight to ten conceptuses were prepared. They were autopsied on day 15 and 3β-HSD and 20α-HSD activity in the corpus luteum (CL) or non-luteal ovarian tissue (NLO) was determined. Conceptus number was directly related to 3β-HSD and inversely related to 20α-HSD activity in the CL. The serum progesterone level and CL weight were also directly related to conceptus number. Neither 3β-HSD nor 20α-HSD activity in the NLO was affected by conceptus number. These results indicated that 3β-HSD and 20α-HSD in the CL are probably regulated by placental hormone secreted in proportion to the number of conceptuses; in the NLO these enzymes may be controlled by a different mechanism.

J. Endocr. (1984) 101, 285–288

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M Makino, N Oda, N Miura, S Imamura, K Yamamoto, T Kato, K Fujiwara, Y Sawai, K Iwase, A Nagasaka, and M Itoh

Thyroid hormones affect reactions in almost all pathways of lipid metabolism. It has been reported that plasma free fatty acid (FFA) concentration in hypothyroidism is generally within the normal range. In this study, however, we show that plasma FFA concentration in some hypothyroid patients is higher than the normal range. Symptoms of thyroid dysfunction in these individuals were less severe than those of patients with lower plasma FFA concentrations. From these findings we hypothesized that the change in FFA concentration must correlate with thyroid function. Using an animal model, we then examined the effect of highly purified eicosapentaenoic acid ethyl ester (EPA-E), a n-3 polyunsaturated fatty acid derived from fish oil, on thyroid function in 1-methyl-2-imidazolethiol (MMI)-induced hypothyroid rats. Oral administration of EPA-E inhibited reduction of thyroid hormone levels and the change of thyroid follicles in MMI-induced hypothyroid rats. These findings suggest that FFA may affect thyroid functions and EPA-E may prevent MMI-induced hypothyroidism.