calcimycin and Adenoma

To investigate the disturbance in the function of SRIF receptor, Gi protein and Ca2+ channel in hGH adenoma cells and to evaluate their significance in the pathogenesis of pituitary hGH adenomas.. All 25 patients with pituitary hGH adenoma who were involved in this study had typical acromegalic manifestation and high fasting serum hGH levels of > 5.0 micrograms/L which were not suppressed to < 3.0 micrograms/L by oral glucose tolerance test. The pituitary hGH adenoma tissue obtained from transphenoidal operation was digested by collagenase and the dispersed adenoma cells were cultured in the monolayer. The effects of octreotide (SMS), a long-acting agonist of somatostatin, on hGH secretion and intracellular cAMP level were observed and the influences of pertussis toxin (PT), an inhibitor of Gi protein, and Ca2+ ionophore A23187 or KCl on the inhibitory action of octreotide on hGH secretion were also investigated in the cultured pituitary hGH adenoma cells.. A total of 16.0% (4/25) of cultured pituitary hGH adenomas did not respond to octreotide (100 nmol). The inhibitory effect of octreotide on hGH secretion was not blocked by PT (50 ng/ml) and A23187 (10 mumol) or KCl (22.5 nmol) in 31.6% (6/19) and 35% (7/20) of hGH adenomas, respectively. The effects of octreotide on hGH secretion and intracellular cAMP levels were studied in 10 cultured hGH adenomas. Octreotide suppressed both hGH secretion and cAMP levels in 5 cases; inhibited only hGH secretion or the cAMP level in 3 cases and 1 case respectively; and affected neither hGH secretion nor cAMP level in the last case.. There were abnormalities in the SRIF receptor and/or postreceptor signal transduction in 16.0% of hGH adenomas which did not respond to octreotide. The defects in Gi and/or Ca2+ channels were found in 52.4% (11/21) of hGH adenomas which had responded to octreotide. These defects might induce diminution of the inhibitory action of SRIF on hGH secretion and might be the causes of hypersecretion in some pituitary hGH adenomas.

Topics: Adenoma; Calcimycin; Growth Hormone; GTP-Binding Protein alpha Subunits, Gi-Go; Hormones; Humans; Ionophores; Octreotide; Pertussis Toxin; Pituitary Neoplasms; Receptors, Somatostatin; Signal Transduction; Somatostatin; Tumor Cells, Cultured; Virulence Factors, Bordetella

The oxidative processes (oxygen consumption, superoxoid anion generation, arachidonic acid cascade) of human polymorphonuclear granulocytes (PMNs) obtained from patients suffering from thyroid disorders of autoimmune origin (Graves' disease and Hashimoto's thyroiditis), and non autoimmune origin (toxic adenoma) were investigated. All Graves' and toxic adenoma patients were hyperthyroid. Hashimoto's thyroiditis patients were euthyroid. Healthy age and sex matched volunteers served as controls. The results are as follows: 1) In PMNs from both hyperthyroid groups (Graves' disease and toxic adenoma), independently from the autoimmune origin of the disease, a significantly increased Antimycin A sensitive mitochondrial oxygen consumption and a slightly increased superoxide anion generation were detected. 2) In both autoimmune thyroid disease groups (Graves' disease and Hashimoto's thyroiditis)--depending on the functional state of the thyroid gland--a significantly altered intracellular killing activity was measured. 3) An increased arachidonic acid cascade--triggered by opsonized zymozan (OZ)--was detected in both autoimmune thyroid diseases. The increased arachidonic acid cascade was sensitive to phospholipase A2 inhibiting Mepacrin treatment. 4) The PMNs from both autoimmune thyroid diseases produced large amount of leukotriens (LTs)--LTC4 and LTB4--after stimulation through their Fc receptors but the synthesis of prostagalandins (PGs) has not changed. There are no data indicating local, specific effects of circulating leukotriens in the thyroid gland itself, but based on authors' data, their general, regulating role on both the endocrine-- as well as on the immune system--seems to be plausible.

Topics: Adenoma; Adult; Arachidonic Acids; Calcimycin; Candida albicans; Dinoprostone; Female; Graves Disease; Humans; In Vitro Techniques; Leukotriene B4; Leukotriene C4; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Oxygen Consumption; Phagocytosis; Reference Values; Respiratory Burst; Superoxides; Thyroid Neoplasms; Thyroiditis, Autoimmune; Thyroxine; Zymosan

Effects of Ca2+ channel blockers (nicardipin and nifedipin) and Ca2+ ionophore A23187 on the basal secretion and on the secretion stimulated by GRH or inhibited by SMS, a SRIF analogne of GH were investigated in monolayer cell cultures of 23 cases of human pituitary GH-secreting adenomas. The roles of GRH and SMS in 45Ca influx were investigated also. The GH secretion of most GH adenomas was depended on Ca2+, but the abnormality in different link of GH secretion mediated by Ca2+ was observed. The defects of receptor and post-receptor including Ca2+ channel and Ca(2+)-GH secretion couple regulated by GRH and SRIF were found in 66.7% and 55.6% of GH adenomas respectively. These abnormalities may contribute to GH hypersecretion in GH adenomas.

Topics: Adenoma; Biological Transport, Active; Calcimycin; Calcium; Calcium Channel Blockers; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Ionophores; Nicardipine; Nifedipine; Octreotide; Pituitary Neoplasms; Somatostatin; Tumor Cells, Cultured

Synthesis of leukotriene B4 (LTB4) upon stimulation of peripheral blood samples with the calcium ionophore A 23187 was studied in patients with primary hyperparathyroidism who underwent parathyroidectomy. Preoperatively, an increased LTB4 concentration of 1.76 +/- 0.19 ng/ml plasma was found, vs. 0.95 +/- 0.28 ng/ml in healthy individuals. On the fourth day after operation, the LTB4 concentration was almost normalized, reaching 1.25 +/- 0.23 ng/ml plasma. At the same time, mean serum calcium levels were reduced from 6.1 +/- 0.6 meq/liter before operation to 4.53 +/- 0.28 meq/liter after operation. In a control group, euthyroid patients with thyroid adenomas who underwent adenomectomy had normal LTB4 levels before operation (0.84 +/- 0.11 ng/ml) and did not show significant changes in LTB4-synthesizing capacity. The results indicate that synthesis of LTB4 in vivo may depend in part on factors related to serum calcium concentration or calcium metabolism.

Topics: Adenoma; Calcimycin; Calcium; Humans; Hyperparathyroidism; Leukotriene B4; Neutrophils; Parathyroid Glands; Thyroid Neoplasms

In an attempt to delineate the mechanism(s) of PRL secretion from human lactotrophs, the effects of dopamine and somatostatin on PRL release from adenomatous and nonadenomatous human pituitary cells in culture was studied. High K+ and the divalent cation ionophore A23187 both elevated PRL secretion, which was blocked by dopamine and somatostatin. When the cells were incubated in low calcium medium, PRL secretion was significantly inhibited. The addition of dopamine or somatostatin to low calcium medium further decreased PRL release. The stimulatory action of ionophore A23187 on PRL release was found even in the absence of extracellular calcium. Theophylline and isobutylmethylxanthine, when added to the incubation medium, increased PRL secretion, and dopamine as well as somatostatin again inhibited PRL release induced by phosphodiesterase inhibitors. No qualitative difference in these PRL responses was found in adenomatous and nonadenomatous human lactotrophs. In prolactinoma cells obtained from three different patients, cAMP generation was correlated with hormone release. Exposure of the cells to dopamine or somatostatin resulted in a parallel decrease in intracellular cAMP content and PRL secretion. The inhibitory effect of dopamine on PRL secretion and cAMP accumulation was blocked by coincubation of the cells with haloperidol. These results suggest that an increase in cytosol calcium caused by either mobilization from intracellular calcium pools or influx from the extracellular compartment and intracellular cAMP accumulation may be involved in the mechanism of PRL secretion from human lactotrophs, and dopamine and somatostatin may influence these two messengers to suppress PRL secretion.

Topics: 1-Methyl-3-isobutylxanthine; Adenoma; Adolescent; Adult; Calcimycin; Calcium; Cells, Cultured; Cyclic AMP; Dopamine; Female; Humans; Male; Middle Aged; Pituitary Gland, Anterior; Pituitary Neoplasms; Potassium; Prolactin; Radioimmunoassay; Somatostatin; Theophylline

To examine whether alterations in parathyroid adenylate cyclase might be associated with glandular hyperfunction, we compared enzyme activity in membranes from 7 normal glands with activity from 18 abnormal and 5 noninvolved glands from patients with primary hyperparathyroidism. Compared with the normal glands, the specific enzyme activity after full stimulation with guanyl-5'yl imidodiphosphate was significantly decreased in both hyperplastic and noninvolved glands from the hyperparathyroid subjects. While the enzyme activity of all tissues could be suppressed by calcium, a twofold higher calcium concentration was required for comparable suppression of the enzyme from adenomas as compared with normal or noninvolved glands. Alterations in the adenylate cyclase complex of hyperplastic parathyroid glands may explain, in part, the elevated "set point" for calcium homeostasis in primary hyperparathyroidism.

Topics: Adenoma; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Adult; Aged; Calcimycin; Calcium; Child; Dose-Response Relationship, Drug; Female; Guanylyl Imidodiphosphate; Humans; Hyperparathyroidism; In Vitro Techniques; Male; Middle Aged; Parathyroid Glands; Parathyroid Neoplasms

We have investigated the regulation of the human throid gland based on controls discovered in the dog thyroid gland. TSH and thyroid-stimulating immunoglobulin enhanced cAMP accumulation, which supports the validity of the Sutherland model for the action of TSH on the human thyroid. Iodide inhibited TSH- and thyroid-stimulating immunoglobulin-activated cAMP accumulation and this effect was reduced by methimazole, showing that, in this tissue, iodide, through an oxidized derivative, depresses the TSH-cAMP system. Contrary to the hypothesis of a short feedback loop of thyroid hormone, no thyroid effect of T3 or T4 was found. Adrenergic agents (norepinephrine and isoproterenol) enhanced cAMP accumulation; this effect was inhibited by dl-propranolol but not by d-propranolol or phentolamine. This suggests a positive control of the thyroid cAMP system by beta-adrenergic receptors. Histamine also increased cAMP accumulation. However, the role of these controls is unknown. Acetylcholine, by a muscarinic type effect, enhanced cGMP accumulation and prostaglandin E2 and prostaglandin F2 alpha release. These effects were mimicked by ionophore A23187 and abolished in a calcium-deprived medium, which suggests that they are secondary to a raised Ca++ influx. The results are summarized in a general working model of human thyroid regulation. These biochemical controls have been compared in normal tissue and autonomous nodules. No evidence of increased sensitivity to TSH of the nodular tissue was found. On the other hand, this tissue was less sensitive to acetylcholine (cGMP accumulation) and more sensitive to norepinephrine (cAMP accumulation).

Topics: 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; Acetylcholine; Adenoma; Adult; Atropine; Calcimycin; Carbachol; Cholera Toxin; Cyclic AMP; Cyclic GMP; Female; Fluorides; Humans; Middle Aged; Physostigmine; Prostaglandins; Prostaglandins E; Thyroid Gland; Thyroid Neoplasms; Thyrotropin