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K M Gautvik

Publications and source records attributed to K M Gautvik.

At least 109 records · Page 6Linked to original sources
PubMed1985

Effects of bromocriptine on hormone production and cell growth in cultured rat pituitary cells.

Rat pituitary adenoma cells (GH3) that spontaneously synthesize and secrete both prolactin (Prl) and growth hormone (GH) were used in this study. Bromocriptine (5 X 10(-5) mol/l), a dopamine (DA) agonist, induced a rapid reduction in Prl and GH secretion with maximum effect (approximately 60%) after 15 min of treatment. Bromocriptine also inhibited Prl and GH production in a time- and dose-dependent manner with ED50 at 4 X 10(-6) mol/l and 7 X 10(-6) mol/l, respectively. Maximum effect was obtained at 5 X 10(-5) mol/l of bromocriptine which after 24 h of treatment reduced the production of Prl and GH by approximately 70 and approximately 50%, respectively. After 9 days of treatment both Prl and GH production was reduced by more than 95%. Bromocriptine also reduced cellular growth rate. The ED50 was approximately 1 X 10(-5) mol/l and the maximum effect (greater than 50%) was observed at 5 X 10(-5) mol/l. All effects of bromocriptine were reversible upon cessation of treatment. The antiproliferative effect of bromocriptine was also observed using a rat hepatoma cell line (MH1C1) and a human epithelial cell line (HE), suggesting a non-receptor mediated growth inhibition at high concentrations of the drug. In conclusion, the inhibitory effect of bromocriptine on secretion and production of both Prl and GH in GH3 cells occurs at a lower concentration than its effect on cell proliferation. The pharmacological effects of bromocriptine in vivo on Prl and GH producing adenomas may be explained by an action directly at the pituitary level.

Adenoma↗
PubMed1985

Effects of bromocriptine on cell cycle distribution and cell morphology in cultured rat pituitary adenoma cells.

The effects of bromocriptine, a dopamine (DA) agonist, on cell cycle distribution and cell morphology have been studied in a clonal strain of rat pituitary adenoma cells (GH3) which produce and secrete spontaneously both prolactin (Prl) and growth hormone (GH). DNA flow cytometry showed that bromocriptine caused a dose-dependent delay in cell cycle traverse concomitantly with a reduction in cellular growth rate. The lowest concentration of bromocriptine (5 X 10(-6) mol/l) significantly (P less than 0.05) increased the relative number of cells in the S phase and reduced the proportion of cells in the G1 phase. At higher concentrations (1 X 10(-5)-5 X 10(-5) mol/l) bromocriptine delayed cell cycle traverse through effects on cells in the S, G1 and G2 phases. These effects occurred already after 24 h of treatment. These results were supported by autoradiography of nuclear uptake of [3H]thymidine and by measurements of the number of cells arrested in metaphase after colcemide treatment (mitotic rate). Bromocriptine at 5 X 10(-5) mol/l altered profoundly GH3 cell structure inducing cell clustering and typical changes in mitochondrial and nuclear ultrastructures. Since Prl and GH production is a characteristic of cells in G1 phase, the inhibitory effect of the lowest antiproliferative concentration of bromocriptine (5 X 10(-6) mol/l) can only partly be explained by alterations in phase distribution. At the highest concentration of bromocriptine (5 X 10(-5) mol/l) hormone production and cell division are also inhibited due to general toxic effects as reflected by the ultrastructural changes.

Adenoma↗
PubMed1985

Immunoreactive parathyroid hormone and calcitonin in plasma and ultrafiltrate before and after haemodialysis.

The effects of haemodialysis on circulating immunoreactive parathyroid hormone (iPTH) and calcitonin (iCT) were determined in relation to alterations in total (Ca) and ionized (Ca2+) plasma calcium. The hormones were measured in plasma, in dialysate and in ultrafiltrate in eight patients with elevated iPTH concentrations. There was a small, but significant reduction in plasma iPTH during haemodialysis concomitant with an increase in Ca and Ca2+. Only small changes were found in plasma iCT during dialysis. Ultrafiltrate iPTH concentrations were reduced from 46% of plasma values at the beginning of dialysis to 27% of plasma values at the end of 4 h dialysis. Gel chromatography of plasma and ultrafiltrate showed corresponding molecular profiles of intact iPTH and hormone fragments suggesting that none of the PTH peptides were restricted by the dialysis membrane. Clearance of intact iPTH (dialysance) was as expected according to molecular weight. From the PTH clearance we calculated that only 5 to 10 micrograms of intact hormone were removed during dialysis. We therefore conclude that the reduction in plasma iPTH during dialysis is probably related to a relative suppression of PTH secretion rather than due to loss of hormone during dialysis.

Adult↗
PubMed1985

The diagnosis, occurrence and clinical aspects of primary hyperparathyroidism in patients with recurrent urolithiasis as registered in general practice.

Five patients with primary hyperparathyroidism (surgically verified) and one patient with probable normocalcaemic hyperparathyroidism were diagnosed in a series of 93 recurrent stone formers in general practice. The six case histories are presented. The initial diagnosis was based on repeated albumin corrected total serum calcium determinations. The condition had previously not been diagnosed in four of the six patients, despite one or more hospital admissions. The urinary calcium excretion index ad modum Peacock & Nordin is not recommended as a routine test for use in general practice. Serum immunoreactive parathyroidal hormone related to simultaneous serum calcium values did not give any further diagnostic information in 48 of these patients with, or without, formation of new stones during a mean follow-up period of 3.2 years. The clinical spectrum of primary HPT has apparently shifted during the last three decades from bone disease and renal calculi to more general symptoms.

Adult↗
PubMed1984

Vasoactive intestinal peptide causes a calcium-dependent stimulation of prolactin secretion in GH4C1 cells.

We have studied the effects of vasoactive intestinal peptide (VIP) on PRL secretion in a Bio-Gel column parafusion system containing rat pituitary tumour cells (GH4C1). A dose-dependent increase in PRL release was observed with half-maximal and maximal effect (2.1-fold) at 8 X 10(-8) and 5 X 10(-6) M, respectively. The PRL-stimulatory effect of VIP was instantaneous and maintained during the parafusion experiments (up to 60 min). On a molar basis VIP was always less effective than thyroliberin (THR), and the maximum stimulation of PRL release obtained with TRH was 1.2-3.0-fold higher (n = 12) than the maximum effect seen after VIP administration. The PRL-releasing effects of VIP, THR and high extracellular K+ were almost completely abolished in the presence of two inhibitors of voltage-sensitive Ca2+ channels, CoCl2 (10(-3) M) and verapamil (10(-4) M). In Ca2+-free buffer VIP, TRH and high extracellular K+ had only negligible effects, but the responses were fully restored in the presence of normal concentrations of extracellular Ca2+. In contrast to TRH, VIP had no demonstrable effect on the Ca2+-dependent action potentials of the GH4 cells.

Animals↗
PubMed1984

Prolactin desensitizes the prostaglandin E1-dependent adenylyl cyclase in the rat prostate gland.

Prior exposure of the rat ventral prostate to a high dose of ovine prolactin in vivo or in vitro caused the specific desensitization of the prostaglandin E1-dependent adenylyl cyclase. Maximal desensitization was achieved in vivo 6 h after exposure to 100 micrograms prolactin and complete resensitization occurred after 7 days. No heterologous desensitization of the response of the cyclase to other hormones tested was observed. Incubation of isolated secretory cells with prolactin and prostaglandin E1 desensitized the subsequent response to the same prostaglandin. Simultaneous exposure of the cells to indomethacin prevented the prolactin-induced effect. Prolactin could also induce similar changes in the prostaglandin E1-dependent cyclase of rat Leydig cell tumour cells in vivo, suggesting that this may represent a phenomenon shared by other prolactin target organs. This study supports the hypothesis that prostaglandins may constitute second messengers for prolactin effects on the prostate gland.

Adenylyl Cyclases↗
PubMed1984

Peripheral metabolism of parathyroid hormone in patients with primary hyperparathyroidism as judged by immunological and biological studies.

The present study characterizes the immunological and biological activity of circulating forms of parathyroid hormone (PTH) in patients with primary hyperparathyroidism. In addition, the rate of elimination of intravenously injected 125I-labelled bovine parathyroid hormone (125I-bPTH) was studied in patients with this disease before and after operation. The different molecular forms of serum PTH were characterized by gel chromatography followed by radioimmunoassay employing two antisera with specificities directed against the N-terminal and mid-region part of the peptide, respectively. The major part of immunoreactive PTH (iPTH; on the average above 50%) eluted corresponding to fragments with a molecular size about 7,500 daltons in both radioimmunoassays. Specific immunoreactivity coeluting with the intact hormone represented 9-15%. The biological activity of hyperparathyroid serum after gel chromatography was tested in a hormone-sensitive rat kidney adenylyl cyclase assay system. The basal and PTH-stimulated adenylyl cyclase activity (half-maximal) stimulation at 5 micrograms/l or 0.6 nM) was dependent on Mg2+ and ATP. Maximal responses to PTH, calcitonin, and prostaglandin E2 were 50-200% above basal activity and were obtained in the presence of both GTP and Gpp(NH)p (5 X 10(-4) M). Serum from patients with hyperparathyroidism and PTH extracted from parathyroid tissue stimulated the adenylyl cyclase in a dose-dependent manner, as did the chromatographic fraction representing the intact hormone. Elimination of 125I-bPTH from circulation after intravenous injection to patients with this disease suggested that the hormone, but not its degradation products, were removed more rapidly before than after successful surgery. We conclude that the major part of circulating iPTH in patients with primary hyperparathyroidism is unable to stimulate the rat kidney adenylyl cyclase, and that the biological PTH activity is represented by the intact hormone (15% or less of total iPTH). These patients degrade more rapidly the injected 125I-bPTH and this mechanism introduces a new concept to protect target cells against excessive hormone action.

Adenylyl Cyclases↗
PubMed1983

Thyroliberin receptor binding and adenylyl cyclase activation in cultured prolactin-producing rat pituitary tumor cells (GH cells).

A thyroliberin (TRH)-responsive particulate bound adenylyl cyclase is present in two rat anterior pituitary tumor cell strains (GH4C1 and GH3) which synthesize and secrete prolactin. At a given Mg2+ concentration, ATP and the guanyl nucleotides GTP and guanyl 5'-yl-imidodiphosphate (GMP-P(NH)P) caused a dose-dependent increase in adenylyl cyclase activity. The maximum response to thyroliberin occurred with ATP and GTP at concentrations above 0.30 mM and 2 microM, respectively. The maximal stimulatory effect of thyroliberin on adenylyl cyclase activity was 2-fold in the presence of GTP. GMP-P(NH)P increased the basal enzyme activity 4- to 10-fold over and above that of equimolar concentrations of GTP but supported poorly the TRH-induced response. Mg2+ caused a dose-dependent increase in the basal enzyme activity and reduced TRH and fluoride-induced responses. Also, Mn2+ and Co2+ stimulated the basal adenylyl cyclase activity while Zn2+, Ca2+, and Cu2+ inhibited the enzyme, and neither cations supported the TRH response. Half-maximal stimulation of the adenylyl cyclase by TRH and half-maximum binding of [3H]TRH to membranes at 35 degrees C were 102 and 56 nM, respectively. Pretreatment with TRH decreased the apparent Vmax of the enzyme and the maximal binding of [3H]TRH. Of 6 TRH analogs tested, only one was able to displace [3H]TRH from its receptor and to increase the adenylyl cyclase activity. We suggest that adenylyl cyclase activation is an early event in the stimulus secretion coupling between TRH and prolactin-producing GH cells.

Adenylyl Cyclases↗
PubMed1983

Calcitonin producing tumour. Effects on fracture repair and normal bone in rats.

The mechanical properties and the collagen metabolism of healing fractures and intact bones have been studied in rats with a transplanted, calcitonin (CT) secreting, medullary thyroid carcinoma (MCT). Sham operated animals served as controls. The MCT was transplanted beneath the kidney capsule. Seven months later, when the rats with MCT had increased circulating levels of CT, a standardized femoral fracture was produced in all the animals. The serum levels of CT were 3-40 times higher in tumour bearing rats than in controls in the period following the fracture. The fracture strength of rats with MCT was reduced by about 60 per cent compared to controls at 16 weeks after the fracture. The strength of intact femora (ultimate torsional moment) seemed to be progressively impaired by increasing levels of circulating CT. Also the strength of bone as a material (ultimate torsional stress) was reduced in the rats with MCT. The collagen synthesis was reduced in MCT rats, but the amounts of collagen in fractured or intact bones were not changed compared to controls. We conclude that chronic hypercalcitoninaemia due to MCT seems to have a negative influence both on fracture healing and on bone metabolism.

Animals↗
PubMed1983

Characterization of the molecular forms of immunoreactive parathyroid hormone in primary hyperparathyroidism and in hyperparathyroidism due to renal failure.

Radioimmunological determination of immunoreactive parathyroid hormone (iPTH) in sera of patients with primary and secondary hyperparathyroidism was carried out using antisera specific for the amino-terminal and the mid-region part of the hormone. In 58 patients with primary hyperparathyroidism and in 29 patients with the secondary form of the disease due to renal failure, there was a linear correlation between the concentration of serum iPTH determined with the two types of antiserum. In all cases the mid-region-specific antiserum measured the highest iPTH concentrations. The molecular forms of serum iPTH were examined after gel filtration of Sephadex G-75 followed by Bio-Gel P-60 in nine patients. Fractions which represented molecular forms equal to or smaller than intact PTH were collected. Using the mid-region-specific antiserum, the predominant immunoreactivity (50-80%) eluted corresponding to one or several large fragments in both forms of the disease. In contrast, iPTH activity co-eluting with the intact hormone represented 2-8% of the total. Similar elution profiles were observed when the amino-terminal-specific radioimmunoassay was used. However, this antiserum showed that in both disease states relatively higher concentrations of iPTH co-eluted with the intact hormone (about 20%). In conclusion, the higher serum iPTH concentrations measured with mid-region-specific antiserum are mainly due to quantitative differences due to the presence of large and intermediate sized fragments. The appearance of higher concentrations of iPTH in secondary hyperparathyroidism may be due to a reduced degradation and/or filtration by the kidney.

Adult↗
PubMed1982

Trifluoperazine blocks calcium-dependent action potentials and inhibits hormone release from rat pituitary tumour cells.

The effects of trifluoperazine (TFP) on basal and stimulated release of prolactin (PRL) and growth hormone (GH) and on the electrical properties of the membrane were studied in clonal rat pituitary tumour cells in culture (GH3 cells). The basal GH release was inhibited maximally 50% by TFP (13-30 microM) and the K+- and thyroliberin (TRH)-induced stimulation of both PRL and GH release was blocked significantly. The sustained depolarization caused by elevated extracellular K+ concentration and the biphasic membrane potential response to TRH (normally leading to spontaneous action potentials) were not affected by TFP. However, TFP inhibited the Ca2+-dependent action potentials, probably by blocking the voltage sensitive Ca2+ channels in the membrane. We therefore suggest that TFP inhibits hormone release by blocking the uptake of extracellular Ca2+. This action of TFP is probably due to direct membrane effects which are independent of calmodulin.

Action Potentials↗
PubMed1982

Uptake and localization of 131I-labeled anti-calcitonin immunoglobulins in rat medullary thyroid carcinoma tissue.

A medullary carcinoma of the thyroid gland (MCT) which has been transplanted repeatedly under the kidney capsule of Wag/Rij rats secretes calcitonin (CT) spontaneously. From 10--20 weeks after transplantation, immunoreactive serum calcitonin (iCT) is abnormally elevated and continues to rise parallel to tumor growth. The immunoglobulin fraction of the rabbit anti-CT antiserum raised against intact synthetic hormone, was purified and iodinated electrolytically. Specific activities of 131I-labeled immunoglobulin of 0.008--0.014 mCi/microgram protein were obtained with 80% preservation of CT binding activity. Wag/Rig rats with MCT tumor and increased serum iCT concentrations received intravenous injections of 131I-labeled immunoglobulins (0.054--0.811 mCi). The distribution of radioactivity in the rats was followed for 14 days using external scintigraphy in combination with radioactivity measurements of blood and different organs at the end of the observation period. The distribution of 113mIn was used as a marker for blood distribution. When the radioactivity ratios (131I/113mIn) in tumor and different organs were related to that of blood which was set equal to unity, tumor tissue contained 3--6 times higher activity. Nonhyperimmune rabbit immunoglobulins or rabbit antirat prolactin immunoglobulins were not concentrated in MCT tissue, nor did anti-CT immunoglobulins localize in rat prolactin adenomas.

Animals↗
PubMed1982

Relationship between stimulated prolactin release from GH cells and cyclic AMP degradation and formation.

We have studied the relationship between the prolaction (PRL) release induced by thyroliberin (TRH) and theophylline and the formation and inactivation of adenosine 3', 5'-cyclic monophosphate (cyclic AMP) in cultured rat-pituitary cells (GH3 cells). TRH, which stimulated prolactin release, increased cyclic AMP formation and stimulated transiently both the low- and high-Km cyclic phosphodiesterases. The maximal effect on the phosphodiesterase was observed at 30 mM TRH. The stimulatory effect of TRH on the activity of the cyclic AMP phosphodiesterases was duplicated by incubation of the cells with cyclic AMP (2-10 mM). In washed particulate GH3 cell fractions, TRH increased the adenylyl cyclase activity up to 180%. Treatment of GH3 cells with theophylline stimulated the release of PRL and inhibited cyclic AMP degradation probably leading to the measured increase in cellular concentrations of the nucleotide. The effects of TRH and theophylline on cellular cyclic AMP concentrations and on PRL release were additive. There was a positive correlation between PRL release and cellular cyclic AMP concentration (r = 0.97). The elevations observed in cellular cyclic AMP concentration after TRH treatment are due to increased formation which in turn leads to phosphodiesterase activation. Therefore, cyclic AMP formation appears to be an intermediary step in the stimulus-secretion coupling caused by the tripeptide.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1982

Immunochemical and biological characterization of calcitonin originating from transplanted medullary thyroid carcinoma in rats.

The immunoreactive and biological activities of calcitonin (CT) produced by transplanted rat medullary thyroid carcinomas (MCT) have been studied. Immunoreactive CT (iCT) in serum and in MCT tissues of rats carrying tumours of generations 5-8 was characterized by gel filtration on Sephadex G-100 followed by radioimmunological measurements using region specific antiserum. The hypocalcaemic effect of sera and tumour extracts was tested in a rat bioassay. Rats with transplanted MCT of the 5th and 6th generations had mainly (70-84%) circulating iCT species of molecular size comparable to intact hormone. However, in rats with tumours of the 7th and 8th generations corresponding circulating iCT forms comprised less than 52% of total immunoreactivity while 32-38% eluted earlier. In comparison, iCT corresponding to intact hormone represented 30-50% of total immunoreactivity in the tumour extracts and no differences were observed between the generations. Subcutaneous injections of sera from MCT rats and of tumour extracts reduced the serum levels of ionized calcium in test rats. The sera containing mainly intact iCT showed the strongest biological potency. We conclude that rat MCT transplanted under the kidney capsule is able to secrete biologically active CT. However, the heterogeneity of circulating iCT increases in rats with transplanted tumours of older generations, approaching the heterogeneity of stored hormone in the gland.

Animals↗
PubMed1982

Progestin receptors in prolactin and growth hormone producing tumours in rats.

Progesterone and corticosterone have a similar effect on the production of growth hormone (GH) and prolactin (Prl) by pituitary tumour cells (GH3 cells) in culture. Previously we have shown that progesterone has a high affinity for the glucocorticoid receptors in these cells. Progesterone may therefore exert its effects through binding to the glucocorticoid receptor. The aim of the present study was to investigate if the GH3 tumour cells and an oestrogen induced pituitary tumours, which also produce GH and Prl, possess specific receptors for progesterone. Both the GH3 tumours and the oestrogen induced pituitary tumour were in fact found to possess cytoplasmatic receptor molecules for progesterone by using the potent progestin R5020 as a marker. Isoelectric focusing revealed one binding component (pH 5.9), which was of protein nature. The binding was of high affinity (KD 2 X 10(-9) mol/l). In the oestrogen induced tumour, the maximal binding was 70 fmol/mg cytosol protein. In female rats with GH3 tumours the binding was 55 fmol/mg cytosol protein. Priming of the animals with 1 mg oestradiol-valerate increased the binding to 116 fmol/mg cytosol protein, whereas very little binding was found in GH3 tumours from rats castrated 7 days before sacrifice. The receptors in the oestrogen induced pituitary tumour and the GH3 tumours exhibited high affinity for R5020 and progesterone, whereas corticosterone had no significant affinity for the receptors. Using exchange assay, it was demonstrated that the cytoplasmic progestin receptors could be translocated to the nucleus after administration of progesterone to the animals. Thus, the presence of specific progesterone receptors, different from the glucocorticoid receptors, strongly indicates that athe effects of progesterone on GH and Prl production are mediated through the progesterone receptors.

Animals↗