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Amplification of desensitization of TSH response to thyrotrophin-releasing hormone (TRH) may be important mechanisms in the regulation of its secretion. We have investigated this possibility in vitro, using monolayer culture of rat anterior pituitary cells. Cells (1-1.5 X 10(5)/250 microliters per well) were cultured for 72 h, exposed to TRH or dibutyryl cyclic AMP (dbcAMP) for 6 or 8 h, washed, and then treated for 4 h with various doses of TRH, or with K+ (55 mmol/l) as a non-specific secretagogue. Pretreatment with TRH (20 nmol/l) for 8 h reduced subsequent TSH release: basal release fell to 64% of the control value (1.01 +/- 0.10 micrograms/l pretreated, 1.58 +/- 0.16 control) and release in response to TRH (100 nmol/l) to 69% of the control (2.7 +/- 0.19 micrograms/l vs 3.98 +/- 0.22); K+ response was reduced to 86% of the control (3.77 +/- 0.21 micrograms/l vs 4.39 +/- 0.20), significantly less than the other reductions. The extent of the parallel downward shift of the TRH dose-response curve was proportional to dose and duration of prior TRH exposure. There was no significant change in the dose of TRH required to cause half-maximal TSH release (ED50: pretreated 4.8, control 2.8 nmol TRH/l) suggesting depletion of an intracellular pool of TSH rather than 'desensitization'. After 6-h pretreatment with dbcAMP, subsequent TSH responses were augmented: basal release was 130% of the control, response to TRH (100 nmol/l) was 137% and to K+ it was 132% of the control, with a parallel upward shift of the TRH dose-response curve but no change in cellular TSH content.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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Thyrotropin-releasing hormone (TRH) has 3 effects on clonal strains of rat pituitary cells in culture (GH-cells). Two long-term effects of TRH on GH-cells, which are measurable after 3 h or longer, have been previously reported; these are an increase in prolactin synthesis and a decrease in growth hormone production. We report here that TRH also stimulates the rapid release of stored intracellular prolactin. We have investigated the role of cyclic AMP as a possible mediator of the effects of TRH on GH-cells. Cyclic AMP concentrations are higher in cells treated with TRH compared with paired controls; a maximum difference of greater than 150% of control values is detected at 15 min if the incubation is performed in serum-free medium in the presence of 1 mM theophylline. The concentration of TRH required to give half-maximum increases in both prolactin release and cyclic AMP accumulation is 0.3 nM; half-maximal increases in prolactin synthesis occur at 3 nM TRH. Exogenous cyclic AMP (1 mM) causes only a slight increase in prolactin release; 8-bromo-cyclic AMP and 8-methylthio-cyclic AMP (1 mM) do not cause significant release. Phosphodiesterase inhibitors (0.3 mM theophylline, 0.03 mM isobutyl-methylxanthine) increase prolactin release but their effects on hormone synthesis are more complicated. Isobutylmethylxanthine, 8-bromo-cyclic AMP and 8-methylthio-cyclic AMP (0.4 MM) increase prolactin synthesis, but do not significantly affect growth hormone synthesis. Theophylline increases the synthesis of both hormones. Dibutyryl cyclic AMP (0.5 mM or more) increases prolactin release and both growth hormone and prolactin synthesis, but equivalent amounts of sodium butyrate have the same effects. We conclude that in GH-cells under carefully defined experimental conditions: 1) TRH causes an increase in intracellular cyclic AMP concentrations; 2) the increase in endogenous cyclic AMP and the effects of phosphodiesterase inhibitors are consistent with a model with cyclic AMP as a mediator of the effects of TRH on prolactin release; however, they do not prove this model, because the interpretation of these results depends on assumptions which may not all be valid; and 3) none of the analogs of cyclic AMP or the phosphodiesterase inhibitors tested mimic the decrease in growth hormone production caused by TRH. 相似文献
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A modulatory role for cyclic AMP in the control of thyrotrophin release: studies with forskolin and dibutyryl cyclic AMP 总被引:1,自引:0,他引:1
We have studied the effects of cyclic AMP (cAMP) on TSH secretion by cultured rat pituitary cells, using forskolin and dibutyryl cAMP (dbcAMP) to raise the cellular cAMP content by different mechanisms. Forskolin (10 mumol/l), a stimulator of adenylate cyclase, raised the cAMP content within 10 min, but had a more delayed effect on TSH release, with no significant stimulation for at least 6 h, but a clear dose-dependent effect at 24 h. Incubation with dbcAMP likewise increased TSH release after 6-24 h. By contrast, high cellular cAMP levels induced by either forskolin or dbcAMP augmented the TSH response to TRH at an early stage, before any detectable change in unstimulated TSH release. Pretreatment of cells with forskolin led to a parallel upward shift in the subsequent TRH dose-response curve, without a significant change in median effective dose or any change in cellular TSH content. These findings suggest that cAMP acts to increase the availability of TSH for acute release by TRH by modulation of an intracellular releasable hormone pool, and indicate synergistic interactions between the adenylate cyclase system and the phospholipid-calcium stimulus-release coupling mechanism of TRH. 相似文献
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K Goshima 《Journal of molecular and cellular cardiology》1976,8(9):713-725
Cultured myocardial cells obtained from neonatal mouse ventricles beat spontaneously and rhythmically. Norepinephrine and dibutyryl cyclic AMP accelerated the rate of spontaneous beating. Dibutyryl cyclic GMP slightly decreased the rate of spontaneous beating. The acceleration of the beating rate of cultured myocardial cells by norepinephrine or dibutyryl cyclic AMP was counteracted by dibutyryl cyclic GMP. Preincubation of cultured myocardial cells with dibutyryl cyclic GMP prevented the positive chronotropic effect of dibutyryl cyclic AMP. 相似文献
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Evidence for the involvement of hypothalamic dopamine and thyrotrophin-releasing hormone in suckling-induced release of prolactin 总被引:1,自引:0,他引:1
The interactions of several mammalian follicle-stimulating hormones and luteinizing hormones with specific gonadotrophin receptors in macropodid marsupial testicular homogenates were investigated with a view to developing radioreceptor assays for marsupial FSH and LH. Testes from Eastern grey kangaroos and tammar wallabies possessed high affinity (dissociation constant congruent to 10(-10) mol/l) saturable receptor sites which were highly specific for LH or FSH. Luteinizing hormone receptor sites bound only highly purified LH preparations (human, ovine and rat) but did not bind highly purified FSH, TSH or prolactin while FSH receptor sites were equally specific for highly purified FSH preparations. These sites demonstrated a degree of species specificity in that marsupial pituitary extracts were relatively more potent in these assays than in assays using gonadotrophin receptors from rat testes. Serum from hypophysectomized female tammar wallabies had little effect on the slope and position of the LH standard curve but significantly depressed the dose-response curve for FSH. For this reason it was not possible to develop a radioreceptor assay for serum FSH using marsupial testicular FSH receptors. However, gonadotrophin receptors from both rat and marsupial testes have been employed in the successful development of radioreceptor assays for marsupial pituitary LH and FSH and marsupial serum LH. 相似文献
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Potentiation of the inotropic effects of norepinephrine and dibutyryl cyclic AMP by theophylline 总被引:1,自引:0,他引:1
C L Skelton F E Karch T J Hougen M L Marcus S E Epstein 《Journal of molecular and cellular cardiology》1971,3(3):243-253
The positive inotropic response of the heart to catecholamines has been postulated to result from an increase in the intracellular level of cyclic AMP (adenosine 3′,5′-monophosphate), produced by activation of myocardial adenylate cyclase. According to this hypothesis, inhibition of phosphodiesterase, the enzyme which hydrolyzes cyclic AMP to inactive 5′-AMP, should enhance the cardiac effects of catecholamines. We therefore examined the effects of theophylline, an inhibitor of cardiac phosphodiesterase, on the isometric contractile response of cat papillary muscles to varying concentrations of norepinephrine (10−11 to 10−5m), cyclic AMP (10−4 to 5 × 10−3m) and dibutyryl cyclic AMP (10−5 to 5 × 10−3m). The latter agent is a more lipid soluble derivative of cyclic AMP which is thought to reproduce the intracellular effects of the parent compound. Cyclic AMP produced no changes in isometric contractile function either in the presence or absence of theophylline. However, at a theophylline concentration (2.5 × 10−4m) which caused little increase in baseline contractile function (average increment in active tension less than 10%), a marked potentiation of the positive inotropic effects of norepinephrine and dibutyryl cyclic AMP was observed. The concentration of norepinephrine producing half-maximal increases in active tension and rate of tension development decreased from 10−7 to 10−8m while that of dibutyryl cyclic AMP decreased from 8 × 10−4 to 4 × 10−4m. Theophylline did not alter the positive inotropic effects of increasing extracellular calcium concentration (2.5 to 10 mm), an intervention which is not thought to directly influence intracellular cyclic AMP levels. Although indirect, these findings provide further evidence that the positive inotropic effects of catecholamines are mediated via the adenylate cyclase cyclic AMP system. 相似文献
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Y Hoshino 《Japanese heart journal》1988,29(6):771-779
Acute effects of dibutyryl cyclic AMP (DBcAMP) on hemodynamics, renal circulation and plasma catecholamine levels were examined in 8 patients with congestive heart failure, NYHA functional class II or III. Before and during intravenous infusion of dibutyryl cyclic AMP at 0.1 mg/kg/min for 30 min, hemodynamic variables, renal blood flow (RBF) and plasma catecholamine levels were investigated. 1) DBcAMP increased the cardiac index from 2.69 +/- 0.65 to 3.60 +/- 0.84 liter/min/m2 (+ 33.8%, p less than 0.001) and heart rate from 70.9 +/- 14.3 to 84.1 +/- 15.7 bpm (+ 18.6%, p less than 0.001) and decreased mean aortic pressure from 91.8 +/- 11.3 to 82.5 +/- 9.8 mmHg (-10.1%, p less than 0.001), and systemic vascular resistance from 1840 +/- 570 to 1260 +/- 370 dynes-sec-cm-5 (-31.6%, p less than 0.001). 2) RBF increased from 335 +/- 81 to 517 +/- 188 ml/min (+ 54.3%, p less than 0.05) and renal vascular resistance decreased from 2.33 +/- 0.61 to 1.52 +/- 0.68 x 10(4) dynes-sec-cm-5 (-34.5%, p less than 0.001). 3) Plasma norepinephrine levels increased significantly. The results indicate that DBcAMP is useful for the treatment of congestive heart failure because it improves cardiac hemodynamics by afterload reduction and has a strong vasodilating effect on renal vascular beds. 相似文献
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Structural changes inducted by follicle-stimulating hormone or dibutyryl cyclic AMP on presumptive Sertoli cells in culture. 总被引:3,自引:0,他引:3
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P S Tung J H Dorrington I B Fritz 《Proceedings of the National Academy of Sciences of the United States of America》1975,72(5):1838-1842
Cells isolated from testes of 20-day-old rats, maintained in primary culture in a defined medium, are shown to respond to follicle-stimulating hormone or 3:5-cyclic AMP with characteristic morphological changes. No response is observed in cells treated with luteinizing hormone or 5-?AMP. The cells form a mono-layer, and have been identified as presumptive Sertoli cells structurally by identification of unique tight junctions in electron micrographs of the preparations, along with other ultrastructural properties characteristic of Sertoli cells in situ. These cells do not undergo mitosis. The presumptive Sertoli cells are shown to be morphologically and functionally different from peritubular fibroblasts grown in parallel cultures. Fibroblasts have high rates of mitosis, do not respond to follicle-stimulating hormone, and frequently form multilayers. Other information on the biochemical responses of the cells is cited, which supports the conclusion that the cultured cell preparations consist primarily of Sertoli cells. 相似文献
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The aim of the present study was to determine whether or not somatostatin can directly affect amino acid transport and cyclic AMP (cAMP) release in isolated rat hepatocytes. Somatostatin at 1.5 microgram/ml (1mumol/l) had no effect on basal uptake of alpha-aminoisobutyric acid (AIB). Similarly, the peptide was without effect on basal cAMP release. Somatostatin exerted a slight but statistically not significant inhibitory effect on glucagon-stimulated AIB uptake and cAMP release. These observations do not support the possibility that somatostatin might directly interfere with hepatic glucose metabolism by altering the entry of amino acids into the liver and--or--by affecting the level of endogenous cAMP. 相似文献
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M Peracchi E Reschini L Cantalamessa A Catania G Giustina 《Metabolism: clinical and experimental》1976,25(3):321-328
The effect of somatostatin on the responses of blood glucose, plasma immunoreactive insulin (IRI), growth hormone (GH), and free fatty acids (FFA) to the injection of dibutyryl cyclic AMP (DBC) was studied in six normal volunteers. DBC, when injected alone, induced a rapid increase in blood glucose and plasma IRI levels, while GH concentrations showed a less marked and more delayed increase and plasma FFA showed a clear downtrend. Somatostatin infusion suppressed the GH and IRI release induced by DBC, potentiated its hyperglycemic effect and changed the pattern of FFA. These results suggest that somatostatin inhibits hormone secretion distal to the generation of cyclic AMP. 相似文献
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Glucocorticoids and estrogens each affect GH secretion in vivo. The effects of corticosterone and estradiol (E2) were studied singly and in combination on GH secretion and cell content of primary cultures of rat adenohypophyseal cells grown in media containing intact or hormone-deficient serum. Secretion was measured under basal conditions and in response to maximally stimulatory doses of ectopic GH-releasing factor (E-GHRF) derived from a carcinoid tumor and dibutyryl cAMP [(DBcAMP) 10(-3) M]. Basal GH release measured over a 4-h period was suppressed by 40% (P less than 0.001) when hormone-deficient serum was substituted for normal serum in the growth media, and the stimulatory responses to DBcAMP and E-GHRF were markedly attenuated (P less than 0.001). The GH content of unstimulated cells was also decreased [29 +/- (SE) 7%, P less than 0.001]. The addition of corticosterone, 3 X 10(-8) M to 3 X 10(-6) M, to the 4-day growth media resulted in dose-related increases in basal and DBcAMP-stimulated GH release during the 4-h test period which was proportional to the increases in total cellular GH content. In contrast, corticosterone exposure caused a dose-related enhancement of E-GHRF-stimulated release above that accounted for by the increase in total GH content alone. Concomitant exposure to the releasing stimuli and corticosterone during a 4-h incubation, however, reduced the effects of the releasing stimuli. The addition of E2, 10(-10) M to 10(-8) M, during the 4-day growth period and/or the 4-h stimulation period did not affect the secretion of GH either basally or in response to the stimuli. E2 did increase the cell content of GH, but the effects were not additive to those of corticosterone. These studies indicate that long term (4-day) exposure to corticosterone increases net GH synthesis and E-GHRF-stimulated release, but that acute (4 h) exposure inhibits stimulated release. Although E2 also increases cellular content of GH, it exhibits no demonstrable direct effects on GH secretion or content in the presence of corticosterone. 相似文献
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R L Ney 《Endocrinology》1969,84(1):168-170