Cholera toxin stimulates 3',5'-adenosine monophosphate accumulation and parathyroid hormone release from dispersed bovine parathyroid cells.
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Animals↗
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Beta-adrenergically stimulated adenosine 3',5'-monophosphate accumulation in and parathyroid hormone release from dispersed human parathyroid cells.
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Bucladesine↗
Human parathyroid cryopreservation: in vitro testing of function by parathyroid hormone release.
The functional viability of cryopreserved human parathyroid tissue was assessed by determining suppressibility of parathyroid hormone release by evaluation of ambient calcium concentration. Parathyroid hormone release from dispersed human parathyroid cells prepared from both fresh tissue and tissue cryopreserved for up to 200 days was suppressed 0-90% in response to four-fold increases in calcium concentration. In the tissue that demonstrated suppression precryopreservation, the suppression curve was similar in form postcryopreservation. The ability to retain functional integrity within human parathyroid cells by cryopreservation, allows preservation for periods of time probably sufficient to determine the presence of the aparathyroid state, and allows for subsequent successful parathyroid autotransplantation. This technique has particular applicability to patients reoperated upon for persistent hyperparathyroidism where the remaining amount of normal parathyroid tissue is obscure or unknown.
Calcium↗
Comparative response to parathyroid hormone in hyperthyroidism and hypothyroidism.
The effects of exogenous parathyroid hormone, administered for 3 days, were compared in six hyperthyroid and six hypothyroid subjects. Maximum increments were much greater in hyperthyroid than in hypothyroid subjects for serum calcium (3.5 mg/100 ml versus 1.6 mg/100 ml), urine calcium (476 mg versus 79 mg), urine hydroxyproline (56 mg versus 11 mg), and urine phosphorus (671 mg versus 192 mg). Maximum decrease in serum phosphorus (minus0.9 mg/100 ml versus minus 0.1 mg/100 ml) was also greater in hyperthyroid subjects. Serum parathyroid hormone immunoreactivity was significantly higher in hypothyroid subjects (0.48 ng/ml) that either normals (0.21 ng/ml) or hyperthyroid subjects (0.19 ng/ml). The data support the concept that excess thyroid hormone sensitizes and deficient thyroid hormone blunts the responsiveness of bone to parathyroid hormone. This may lead to a state of hypoparathyroidism in hyperthyroidism and hyperparathyroidism in hypothyroidism.
Adult↗
Hormonal control of bone collagen synthesis in vitro: effects of parathyroid hormone and calcitonin.
The effects of parathyroid hormone (PTH) on bone collagen synthesis were assessed in organ cultures of fetal rat calvaria by measuring the incorporation of [3H]proline into collagenase-digestible (CDP) and non-collagen protein (NCP) using purified bacterial collagenase. 1) PTH decreased the incorporation of labeled proline into CDP at concentrations similar to those which stimulate bone resorption in vitro. 2) This effect was observed in bones treated for 6 h, but not for 3 h; it was maximal at 24 h and was maintained for 96 h. Bones treated with PTH for 48 h and transferred to control media for 48 h showed recovery of CDP labeling to control values. 3) the effect was specific for bone collagen. There was little alteration in the incorporation of proline into NCP, and incorporation into collagen was not inhibited. 4) The effect could be ascribed to decreased collagen synthesis and not to changes in amino acid uptake, precursor pool size, or degradation of newly synthesized CDP. In 3 hour experiments, PTH did increase the labeling of CDP and NCP, but only at tracer concentration of proline in the medium, compatible with an early stimulation of amino acid uptake. 5) Similar inhibition was observed with purified bovine (1-84) PTH and synthetic bovine PTH (1-34) as well as with crude homologous PTH obtained from rat parathyroid gland culture fluid. Human (hCT) and salmon (sCT) calcitonin did not inhibit the effect of PTH on the labeling of CDP nor did they stimulate CDP labeling directly at concentrations which inhibited bone resorption. Dibutyryl cyclic-3',5'-adenosine monophosphate (D3cAMP) inhibited labeling of CDP at concentrations of .03 to .3 mM, thus mimicking the action of PTH. However, in this system DBcAMP inhibited 45Ca release, thus mimicking CT. We conclude that the direct effect of PTH on bone collagen synthesis is a slow reversible inhibition, not opposed by CT. This effect may be mediated by cAMP formation in bone cells.
Animals↗
Adenylate cyclase of human fat cell ghosts. Stimulation of enzyme activity by parathyroid hormone.
Some of the effects of native bovine parathyroid hormone and of the synthetic aminoterminal 1-34 fragment on the adenylate cyclase activity of human fat cell ghosts were studied. Saturating concentrations of both hormone preparations caused a significant increase of enzyme activity by about 200-300%. Guanosine 5'-triphosphate (0.1 mM) inhibited basal enzyme activity but had no substantial effect on parathyroid hormone-stimulated enzyme activity. The guanosine 5'-triphosphate analogue, 5'-guanylyl-imidodiphosphate, produced about a threefold enhancement of basal and parathyroid hormone-stimulated enzyme activities under standard conditions (5 mM Mg+2, 1mM ATP, pH 8.0, 30 degrees C). Activation by parathyroid hormone was not influenced by beta-adrenergic blockade in contrast to stimulation by epinephrine. The sensitivity of the enzyme system to the native and the synthetic parathyroid hormone was, however, abolished after pretreatment of the fat cells with trypsin (1 mg/ml). The stimulatory effects of epinephrine and NaF were not affected by pretreatment with trypsin. The results suggest that human fat cells, like rat adipocytes, contain a multireceptor-coupled adenylate cyclase.
Adenylyl Cyclases↗
Inhibition of parathyroid hormone secretion by isoproterenol.
Intravenous infusion of the beta-adrenergic agonist isoproterenol produced a fall in the serum concentration of parathyroid hormone. It also produced a pronounced fall in the serum phosphate concentration, and significant increases in blood glucose and serum insulin concentration and in pulse rate. The fall in serum parathyroid hormone was abolished by beta-adrenergic blockage with propranolol. Oral glucose loads produced a pronounced fall in serum phosphate concentration, comparable to the fall after isoproterenol infusion, but no significant changes in serum parathyroid hormone. It is concluded that the fall in serum parathyroid hormone after isoproterenol is due to a beta-adrenergic effect. It is unknown, if isoproterenol acts directly on the parathyroid hormone secreting cell, or the fall in serum parathyroid hormone is secondary to the effect of isoproterenol on other endocrine glands or the cardiovascular system.
Adult↗
Renal adenylate cyclase and the interrelationship between parathyroid hormone and vitamin D in the regulation of urinary phosphate and adenosine cyclic 3',5'-monophosphate excretion.
This study examined the role of cyclic AMP in the phosphaturic response to parathyroid hormone in vitamin D-deficient rats. Infusion of purified bovine parathyroid hormone (13.3 mug/h) into control, D-fed, or D-deficient, thyroparathyroidectomized rats produced a sixfold increase in renal phosphate and cyclic AMP excretion in D-fed rats, but only a two- to threefold increase in both parameters in D-deficient animals. Intravenous injection of parathyroid hormone over the dosage range from 1-50 mug/kg resulted in a dose-dependent increase in phosphate and cyclic AMP excretion with both D-fed and D-deficient thyroparathyroidectomized rats. However, the D-deficient rats responded to these injections of parathyroid hormone with a two- to threefold increase in both renal phosphate and cyclic AMP excretion at the highest dose of 50 mug/kg, whereas the D-fed animals' response was 35-fold and 11-fold over control excretion levels of phosphate and cyclic AMP, respectively. To directly examine the role of the renal cortical adenylate cyclase system in the blunted phosphaturic and urinary cyclic AMP responses to parathyroid hormone in D-deficient rats, we prepared a plasma membrane fraction enriched in this enzyme activity from the renal cortex of D-fed and D-deficient thyroparathyroidectomized rats. The renal cortical adenylate cyclase of D-deficient rats showed significantly (P less than 0.001) less activation by parathyroid hormone over the hormone concentration range from 0.3 to 7.0 mug/ml than was observed with the enzyme prepared from D-fed animals. Basal adenylate cyclase activity and the fluoride-stimulated enzyme activity were not altered by the state of D-deficiency. These experiments demonstrate that the blunted phosphaturic response to parathyroid hormone observed in D-deficient rats is associated with the reduced responsiveness of the renal cortical adenylate cyclase to the hormone. Moreover, the defect in the renal membrane adenylate cyclase system appears to be localized at the level of PTH binding to membrane receptors or, alternatively, at the level of transmission of the hormone-receptor binding signal to the catalytic moiety of this membrane enzyme.
Adenylyl Cyclases↗
Influence of calcium infusion on calcitonin and parathyroid hormone concentrations in normal and hemodialyzed subjects.
Plasma calcitonin and parathyroid hormone concentrations were compared before and after calcium infusion in both hemodialyzed patients and control subjects. Levels of both hormones were significantly higher in patients with chronic renal failure. In the uremic group, calcium infusion inhibited parathyroid hormone secretion but did not affect calcitonin. In the control group, calcium infusion stimulated calcitonin secretion but had no effect on parathyroid hormone.
Adult↗
[Postoperative behavior of parathyroid hormone dependent parameters after the removal of parathyroid adenomas].
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Adenoma↗
Acquired resistance to parathyroid hormone.
Studies are presented in a patient with pseudohypoparathyroidism who showed a partial response to parathyroid extract. Resistance to the extract was observed after its short-term administration for the gourth time. Serum from the patient contained antibodies of the gamma G globulin class which bound 125I-labelled bovine parathyroid hormone. Prior incubation of parathyroid hormone with the serum prevented the activation in vitro of adenylate cyclase from pork renal cortex. The antibodies were directed primarily toward the C-terminal portion of the molecule. Thus, clinical resistance to parathyroid hormone is attributed to specific antibodies.
Adenylyl Cyclases↗
Comparison of the effects of calcium and magnesium on parathyroid hormone secretion rate in calves.
Parathyroid hormone (PTH) secretion rate was measured in seven calves by using a technique which involved RIA of parathyroid venous blood collected during timed intervals and measured volumetrically. Infusion of solutions of NA2EDTA and MgCl2 into the jugular vein was used to alter plasma calcium and magnesium concentrations. In four calves, elevation of plasma magnesium concentration rapidly decreased the PTH secretion rate that had been stimulated by induced hypocalcemia. In three calves, equimolar and opposite changes in plasma calcium and magnesium concentrations were induced by simultaneous infusions of Na2EDTA and MgCl2. Despite the equimolar increase in plasma magnesium concentration, PTH secretion was increased in response to the decline in plasma calcium concentration. In three experiments, the concentration of each cation was kept constant during periods in which the concentration of the other cation was varied. The effect of variations in plasma magnesium concentration on PTH secretion rate was approximately 1/3-1/2 as great as that observed with changes in plasma calcium concentration. These observations indicate that the effect of magnesium on PTH secretion rate is similar to that of calcium, but not equipotent.
Animals↗
Anabolic effect of low doses of a fragment of human parathyroid hormone on the skeleton in postmenopausal osteoporosis.
Parathyroid hormone, injected daily in low dosage, exerted anabolic effects on the human skeleton, just as it does in the rat. Four postmenopausal women with primary osteoporosis were treated for six months with a synthetic fragment of human parathyroid hormone (hP.T.H. 1-34), given as a daily injection of 100 mug. This treatment caused a remarkable acceleration of bone turnover, indicated both by isotopic tracer and histological methods. At this normocalcaemic dose level, the increases in bone formation outweighed increases in resorption. Three of the four patients showed more positive calcium balances, and mean increases in calcium and phosphorus balances were statistically significant for the group as a whole, the changes being principally due to increased intestinal absorption of both elements. Many modifications of the present method of hormone administration are possible which could further increase the preponderance of anabolic effects. These results suggest that low doses of hP.T.H. 1-34, alone or in combination with other agents, may prove useful in the treatment of osteoporosis.
Absorption↗
Metabolism of radioiodinated bovine parathyroid hormone in the rat.
Metabolism of bovine 125I-labeled parathyroid hormone was studied in the rat by gel filtration and by sequence analysis of the iodinated fragments. Analysis of the kinetics of hormone metabolism shows that iodinated intact hormone has a multiexponential disappearance curve with a rapid (3 min) initial and a slower (48 min) second component. Iodinated fragments, which rapidly increase during the first 12 min after injection of the intact hormone, subsequently disappear from the circulation with a t1/2 of no greater than 48 min. Plasma samples collected at various time-intervals after intravenous injection of bovine 125I-labeled parathyroid hormone were gel filtered on Bio-gel P-100. Four radioactive peaks were seen. The first and second peaks eluted, respectively, at the void volume of the column and at the position of intact hormone. The third peak consisted of iodinated fragments, and the last peak eluted at the salt volume of the column. Sequence analysis of the iodinated fragments in the third peak showed that it was heterogeneous, containing several different, but closely related, polypeptides. Before 48 min after injection, the most-abundant fragment is one whose amino-terminal amino acid is residue 34. The amino-terminal residue of the next most-common fragment is the amino acid at position 37. No fragments representing cleavages closer to the amino-terminus than residue 34 were seen. The results of these studies are virtually identical with those previously obtained in the dog. The similarities found in the sites of hormone proteolysis and in the kinetics of hormone metabolism in the rat and dog, coupled with the less direct evidence indicating that similar cleavages are also present in man and bovine, are consistent with the view that proteolysis of parathyroid hormone is peripheral tissues is specific, at least in mammalian species, and may be a critical step in controlling the availability of biologically active hormone.
Animals↗
The diagnostic value of a radioimmunoassay for parathyroid hormone in human serum.
A radioimmunoassay for the measurement of immunoreactive parathyroid hormone (PTH) in human serum is described. The assay is based on the ability of human parathyroid hormone (h-PTH) to compete with 125I-labelled bovine parathyroid hormone (b-PTH) for binding to a guinea-pig antiserum directed against b-PTH. The linear part of the standard curve was parallel with dose response curves for anti-b-PTH serum reacting with dilutions of sera from patients with primary hyperparathyroidism and from h-PTH purified from human parathyroid adenomas, indicating that levels of immunoreactive PTH could be expressed as b-PTH equivalents. The range in 62 healthy blood donors was 1.1-2.5 ng b-PTH Eg./ml. The reproducibility was satisfactory, and the sensitivity permitted the measurement of PTH concentrations down to 0.8 ng b-PTH Eg./ml. No crossreaction with h-CT, h-STH or h-ACTH was observed. The clinical value of the assay has been considered in a number of patients with various disorders of calcium metabolism, diagnosed and treated conventionally. About 80 per cent of patients with primary hyperparathyroidism had elevated PTH levels on one or more occasions before surgery. In patients with chronic renal failure of other aetiology than primary hyperparathyroidism the levels were usually far higher. Patients with primary hyperparathyroidism and increased S-creatinine had higher PTH levels than those with normal S-creatinine. After parathyroidectomy all previously increased PTH levels became normal or low. High PTH concentrations were found in 3 patients with normocalcaemic hyperparathyroidism who at operation were shown to have parathyroid adenomas. However, in normocalcaemic patients there were also some falsely elevated PTH values which limit the diagnostic value of the assay in this group of patients. Low PTH values were observed in patients with hypercalcaemia due to malignant disorders, indicating that PTH determination may be of some value in the diagnosis of patients with hypercalcaemia of unknown origin.
Adult↗
Calcium-dependent intracellular degradation of parathyroid hormone: a possible mechanism for the regulation of hormone stores.
The dynamics of parathyroid hormone (PTH) biosynthesis, storage, and secretion in bovine parathyroid slices in vitro in response to alterations in the concentrations of extracellular calcium were studied. Hormone biosynthesis was evaluated by using polyacrylamide gel electrophoresis to measure incorporation of [3H]leucine into newly synthesized PTH and proparathyroid hormone (ProPTH) during short (35 min) incubations. Amounts of newly synthesized PTH stored in and secreted from the tissue slices were determined by electrophoretic analysis of [3H]PTH in extracts of tissue and media. Total PTH and ProPTH is slices and media were measured by specific radioimmunoassays. PTH secretion rates changes 5-fold when calcium was lowered from 2mM to 1mM. Secretion of some PTH continued despite high concentrations of calcium (5 mM). Biosynthesis of ProPTH was changed only slightly, and conversion of ProPTH to PTH was independent of the extracellular calcium concentration. Tissue stores of PTH increased during incubation of parathyroid slices in medium containing high amounts of calcium. The increase in stores was much less, however, than predicted by the findings of marked suppression of secretion and little change in rates of PTH biosynthesis. In high concentrations of calcium, a large fraction (up to 50%) of newly synthesized PTH was degraded within the tissue, whereas in low concentrations of calcium, little (less than 10%) of the PTH was degraded. No fragments of PTH or ProPTH were identified in either extracts of tissue or media, suggesting that degradation occurred rapidly by general proteolysis rather than by limited, specific endopeptidase activity. The data suggest that the parathyroid cell contains a calcium-sensitive degradative pathway for PTH and that this pathway may be involved in the regulation of hormone production and secretion.
Animals↗
Demonstration that cyclic adenosine 3',5'-monophosphate mediates the lipolytic action of parathyroid hormone.
Studies were carried out with rat epididymal fat pads first to compare the effects of the synthetic N-terminal 1-34 peptide of bovine parathyroid hormone and of the native hormone to determine whether this portion of the molecule is responsible for the lipolytic action of the hormone and second to determine whether this biologic action of parathyroid hormone is mediated by cyclic adenosine 3',5'-monophosphate. The N-terminal polypeptide was as effective as the native hormone in stimulating lipolysis in the concentration range between 10(-8) M and 10(-6) M. Parathyroid hormone stimulated lipolysis by isolated fat cells. The concentration of cyclic adenosine 3',5'-monophosphate in the fat pads was significantly increased by the hormone (10(-6)M). Lipolytic stimulation by parathyroid hormone (10(-6)M) was diminished by insulin (100 muU/ml) and prostaglandin E1 (1 mug/ml), both of which are known inhibitors of lipolysis. The findings indicate that the amino-terminal 1-34 peptide portion of parathyroid hormone is responsible for the lipolytic action and that this effect is mediated through cyclic adenosine 3',5'-monophosphate.
Adipose Tissue↗
Effects of parathyroid hormone on H+ and NH+4 excretion in toad urinary bladder.
The urinary bladder of Bufo marinus excretes H+ and NH+4, and the H+ excretion is increased after the animal is placed in metabolic acidosis. The present study was done to determine if parathyroid hormone could stimulate the bladder to increase the excretion of H+ and/or NH+4. Parathyroid hormone added to the serosal solution in a final concentration of 10 mug/ml was found to increase H+ excretion by 50 per cent above the control hemibladders, while there was no effect on NH+4 excretion. Parathyroid hormone had no effect on H+ excretion when added to the mucosal solution. We also performed experiments utilizing theophylline and dibutyryl cyclic AMP which mimicked those of the parathyroid hormone experiments. A dose-response analysis was performed and the results indicate that 1 mug/ml of parathyroid hormone was the minimal effective dose. These results suggest that parathyroid hormone can stimulate H+ excretion in the toad urinary bladder and this effect seems to be mediated by cyclic AMP. In addition, it was found that parathyroid hormone has no effect on NH+4 excretion.
Ammonia↗