[Research on the rectal absorption of calcium and parathyroid hormone].
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Calcium↗
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Reversible resistance to the renal action of parathyroid hormone in man.
1. Normal subjects showed a highly reproducible, rapid increase in plasma adenosine 3':5'-cyclic monophosphate (cyclic AMP) after an intravenous injection of 200 MRC units of highly purified bovine parathyroid hormone. 2. No significant increase in plasma cyclic AMP was observed after administration of bovine parathyroid hormone to patients with severe chronic renal failure. 3. Even when renal function was not impaired, some patients with primary hyperparathyroidism, who had high concentrations of endogenous parathyroid hormone, showed resistance to bovine parathyroid hormone and when this was injected intravenously it caused only a small increase in plasma cyclic AMP. This resistance was reversible since there was marked improvement in the response after parathyroidectomy, when endogenous parathyroid hormone concentration had fallen. 4. It was possible to reproduce this resistance to the hormone by intravenous infusion of bovine parathyroid hormone into normal subjects. When the hormone (1000 MRC units) was infused over 2 h, after an initial increase there was a progressive decline in plasma cyclic AMP concentration and a fall in urinary cyclic AMP excretion. The response to a standard test stimulus (200 MRC units of bovine parathyroid hormone given as a rapid intravenous injection) was examined at intervals after 1000 units of bovine parathyroid hormone had been infused. Initially, the response was severely impaired; at 4 h, partial recovery had occurred and, 24 h after the infusion, recovery of the response was complete. The resistance was therefore reversible. Infusion of the amino-terminal peptide, fragment 1-34, gave the same effect as infusion of intact hormone. Region-specific assays for the hormone were used to show that the concentration of immuno-assayable hormone remained high during the infusions. 5. The mechanism of this reversible resistance to parathyroid hormone remains to be elucidated; it seems unlikely that circulating hormone fragments could account for the prolonged impairment in the responsiveness to the intact hormone. It is possible that alteration in the formation, intracellular degradation or, perhaps, release of cyclic AMP from the cells, is the cause. Changes in the characteristics of the hormone receptor sites might also explain the phenomenon.
Aged↗
Renal responsiveness to parathyroid hormone in a case of nonfamilial hypophosphatemic osteomalacia.
Plasma immunoreactive parathyroid hormone level, urinary excretion of adenosine cyclic 3',5'-monophosphate (cyclic AMP) and the sensitivity of the renal tubule to calcium infusion and to parathyroid extract were investigated in a patient with nonfamilial hypophosphatemic osteomalacia. Plasma immunoreactive parathyroid hormone concentration was normal and basal urinary excretion of cyclic AMP was increased. Renal cortical adenylate cyclase, as measured by urinary cyclic AMP excretion, was certainly as sensitive to exogenous parathyroid extract as in normal subjects. After a previous calcium infusion, a greater parathyroid-hormone-sensitive component of phosphorus transport in the kidney was present than in two control subjects. Our results indicate that in nonfamilial hypophosphatemic osteomalacia the renal tubule could be hyperresponsive to parathyroid hormone.
Calcium↗
Genetic and synteny mapping of parathyroid hormone and beta hemoglobin in cattle.
Parathyroid hormone and the beta hemoglobin gene cluster, which are closely linked on human chromosome 11p15, were localized to bovine syntenic group (U7) with the gene for catalase by the use of bovine x hamster hybrid somatic cells. Restriction fragment length polymorphisms (RFLPs) were followed through informative pedigrees to determine a linkage map distance of 15.6 +/- 5.4 cM between the parathyroid hormone and hemoglobin genes. Allelic frequencies of the DNA fragment were compared in a small sampling of cattle from five different breeds.
Animals↗
Chemical and biological properties of synthetic, sulfur-free analogues of parathyroid hormone.
Several analogues of the biologically active fragment of bovine parathyroid hormone (bPTH), based on the sequence of the NH2-terminal 34 amino acids, were prepared by solid phase synthesis and bioassayed in the in vitro adenylyl cyclase assay to provide further information concerning structure-activity relations in parathyroid hormone. In two analogues both methionines of the natural hormone were replaced with the sulfur-free and closely isosteric amino acid norleucine (Nle). The synthetic analogue [Nle-8, Nle-18]bPTH-(1-34) was highly active in the in vitro rat adenylyl cyclase bioassay, thus demonstrating that neither of the methionines, found in the native sequence, is indispensable for biological activity. Tyrosine was substituted for phenylalanine at position 34 in the synthesis of two other hormone analogues, [Try-34]bPTH-(1-34) and [Nle-8,Nle-18,Tyr-34]bPTH-(1-34). Both derivatives were exposed to conventional iodination procedures involving use of the oxidant chloramine T. Although iodination of [Try-34]bPTH-(1-34) resulted in virtually complete loss of biological activity, [Nle-8,Nle-18,Tyr-34]-bPTH-(1-34), which lacks methionine, could be exposed to oxidants and labeled efficiently with iodine with retention of nearly complete biological activity. These findings confirm that the loss of biological activity after oxidation of bPTH, as previously observed with the native hormone, is indeed attributable to the oxidation lability of methionine rather than to any other modifications. This sulfur-free, radioiodinated, biologically active analogue of parathyroid hormone may prove useful in studies of interaction of the hormone with the membrane receptors of target tissues and in studies of the metabolism of parathyroid hormone.
Adenylyl Cyclases↗
Effect of parathyroid hormone on bicarbonate secretion in the guinea-pig stomach and the amphibian isolated gastric mucosa.
1. The effect of parathyroid hormone on gastric bicarbonate secretion was determined in the anaesthetized guinea pig. Subcutaneous injections of bovine parathyroid hormone (75 U.S.P units day-1 kg-1) for 7 days caused a significant increase in HCO3- output. There was also a rise in K+ output and a slight elevation of H+ secretion. A similar increase in HCO3- output occurred after acute intravenous injection of the hormones (75 U.S.P. units/kg). 2. Both chronic and acute administration of parathyroid hormone caused a significant increase in serum calcium concentration and it is likely that the changes in gastric ion outputs reflect raised calcium levels. Given alone intravenous calcium (1.5 mg/kg body wt.) stimulated gastric secretion of both HCO3- and H+. 3. To determine whether parathyroid hormone had a direct action on gastric ion transport experiments were performed in the amphibian isolate mucosa. Antrum transports HCO3- spontaneously while HCO3- transport in fundus was studied after inhibition of the greater H+ secretion by the histamine H2-receptor antagonist metiamide. Parathyroid hormone at a concentration of 0.2 United States Pharmacopea (U.S.P.) unit/ml in the nutrient-side bathing solution inhibited both antral and fundic HCO3- transport. A higher concentration (2.0 units/ml) had no effect on fundic H+ secretion. 4. The inhibitory effect in vitro was greater in the antrum and parathyroid hormone may almost abolish the active component of HCO3- transport in this tissue. It is likely that any similar inhibition of gastric HCO3- secretion by parathyroid hormone in vivo is masked by the stimulatory effects of released calcium.
Animals↗
The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects.
We measured serum concentrations of calcium and parathyroid hormone in seven pregnant women who were receiving intravenous magnesium sulfate for the suppression of premature labor. After administration of magnesium sulfate, the mean (+/- S.E.M.) serum magnesium level rose rapidly from the normal base-line level of 2.0 +/- 0.2 mg per deciliter to 6.1 +/- 0.4 mg per deciliter (0.8 +/- 0.1 to 2.5 +/- 0.2 mmol per liter) (P less than 0.001) at 30 minutes and remained markedly elevated. Concentrations of total and ionized calcium fell gradually in all subjects from normal base-line concentrations, 8.6 +/- 0.2 and 4.4 +/- 0.1 mg per deciliter (2.2 +/- 0.1 and 1.1 +/- 0.03 mmol per liter), respectively, into the hypocalcemic range, reaching a nadir of 7.6 +/- 0.2 and 3.9 +/- 0.1 mg per deciliter (1.9 +/- 0.1 and 0.98 +/- 0.03 mmol per liter), respectively, at three hours (P less than 0.001). Parathyroid hormone levels fell rapidly in response to magnesium infusion, from 13.1 +/- 2.5 to 7.8 +/- 0.7 pg per milliliter at 30 minutes, and were significantly below base-line levels for two hours despite frank hypocalcemia. These results suggest that hypermagnesemia rapidly decreases the secretion of parathyroid hormone in vivo in human subjects and that parathyroid hormone levels remain depressed despite concomitant hypocalcemia. The results also suggest that the hypocalcemia associated with hypermagnesemia may be due in part to the suppressive effects of hypermagnesemia on parathyroid hormone secretion.
Adult↗
Parathyroid hormone receptors of renal cortex: specific binding of biologically active, 125I-labeled hormone and relationship to adenylate cyclase activation.
Biologically active (125)I-labeled bovine parathyroid hormone (prepared by electrolytic iodination) and its synthetic NH(2)-terminal (1-34) biologically active fragment bound rapidly and specifically to a purified plasma membrane preparation from bovine renal cortex. Binding of labeled intact hormone or labeled NH(2)-terminal (1-34) peptide was inhibited competitively by unlabeled (1-34) peptide in the same range of concentrations that activated renal cortical 3':5'-adenylate cyclase (EC 4.6.1.1) in these membranes. The concentrations of synthetic (1-34) peptide for half-maximal inhibition of binding of labeled hormone as well as half-maximal activation of the enzyme were about 0.6 muM (2.5 mug/ml). Therefore it is likely that the binding activity studied represents a physiologically important renal receptor for parathyroid hormone. Biologically inactive (oxidized) forms of parathyroid hormone and (1-34) NH(2)-terminal peptide as well as calcitonin, glucagon, insulin, and epinephrine failed to competitively inhibit the binding of labeled (1-34) parathyroid hormone or activate adenylate cyclase in the renal cortical membrane preparation. Observations with the NH(2)-terminal (1-34) biologically active fragment of parathyroid hormone suggest that the COOH-terminal region of the molecule is not required for receptor binding.
Adenylyl Cyclases↗
Primary hyperparathyroidism: four- to eight-year postoperative follow-up demonstrating persistent functional insignificance of microscopic parathyroid hyperplasia and decreased autonomy of parathyroid hormone release.
Thirty-nine patients with primary hyperparathyroidism were studied four to eight years after their initial operation. In six patients, both the pathologist and surgeon agreed on the diagnosis of solitary adenoma; in 16 patients, the surgeon diagnosed solitary adenoma and the pathologist parathyroid hyperplasia (microscopic hyperplasia). In 16 patients, primary chief cell hyperplasia was agreed upon by the pathologist and surgeon. In the 16 patients with microscopic hyperplasia, there have been no long-term recurrences of hypercalcemia, but, in two patients, plasma parathyroid hormone levels are high. Parathyroid hormone--total calcium regression curves demonstrate significant preoperative correlation in solitary adenoma, p less than 0.01, and primary chief cell hyperplasia, p less than 0.05. After operation, significant correlations were not found between parathyroid hormone and total calcium. T-testing slope differences of pre- and postoperative parathyroid hormone--total calcium regression curves demonstrates a significant (p less than 0.01) shift to the right of the microscopic hyperplasia patients after operation, moving them to a broader range of total calcium per picogram parathyroid hormone. We conclude that 1) in primary hyperparathyroidism, positive regulation of total calcium by autonomously released parathyroid hormone exists in patients with solitary adenoma and chief cell hyperplasia; 2) autonomously functioning parathyroid tissue has been removed by operation for solitary adenoma with coexistent microscopic parathyroid hyperplasia. In this four- to eight-year follow-up period, it is clear that microscopic parathyroid hyperplasia is not associated with recurrent hypercalcemia. Two functionally distinct forms of parathyroid suppression are suggested; positively regulated microscopic hyperplasia and negatively regulated pathologically suppressed glands.
Adenoma↗
Parathyroid hormone inhibits collagen synthesis and the activity of rat col1a1 transgenes mainly by a cAMP-mediated pathway in mouse calvariae.
We examined the effect of parathyroid hormone and various signaling molecules on collagen synthesis and chloramphenicol acetyltransferase activity in cultured transgenic mouse calvariae carrying fusion genes of the rat Col1a1 promoter and the chloramphenicol acetyltransferase reporter. After 48 h of culture, parathyroid hormone, forskolin, dibutyryl cAMP, 8-bromo cAMP, and phorbol myristate acetate inhibited transgene activity, while the calcium ionophore ionomycin had no effect. Pretreatment of calvariae with the phosphodiesterase inhibitor isobutylmethylxanthine potentiated the inhibitory effect of 1 nM parathyroid hormone on transgene activity and collagen synthesis. Parathyroid hormone further inhibited transgene activity and collagen synthesis in the presence of phorbol myristate acetate. Parathyroid hormone inhibition of transgene activity and collagen synthesis was not affected by indomethacin or interleukin-6. After 48 h of culture, parathyroid hormone inhibited chloramphenicol acetyltransferase activity by 50-85% in cultured calvariae carrying transgenes having progressive 5' upstream deletions of promoter DNA down to -1683 bp. These data show that the inhibitory effect of parathyroid hormone on Col1a1 expression in mouse calvariae is mediated mainly by the cAMP signaling pathway. Prostaglandins and IL-6 are not local mediators of the parathyroid hormone response in this model. Finally, regions of the Col1a1 promoter downstream of -1683 bp are sufficient for parathyroid hormone inhibition of the Col1a1 promoter.
Animals↗
Characterization of parathyroid hormone fragments produced by cathepsin D.
Cleavage of parathyroid hormone by cathepsin D was studied. Four primary products were detected and separated by high performance liquid chromatography. Two of the fragments are fluorescent and therefore contain residue 23 (tryptophan). These fragments are NH2-terminal in origin. The other two cross-react with antisera directed against COOH-terminal portions of the hormone; they are the complementary COOH-terminal fragments. Microsequencing and amino acid analysis showed that the two COOH-terminal fragments are 35-84 and 38-84 bovine parathyroid hormone. By CNBr cleavage and amino acid analysis, the two NH2-terminal fragments were shown to be the complementary 1-37 and 1-34 fragments. The 1-37 fragment is transitory and is rapidly hydrolyzed to 1-34, so that only relatively small amounts are detected at any one time. However, 34-84 was not converted to 38-84, although cleavage at other sites in the COOH-terminal fragments was observed with more exhaustive digestion. The 1-34 fragment appears to be the final product of the action of cathepsin D on parathyroid hormone. Both enzymatically produced NH2-terminal fragments were fully active in the renal membrane adenylyl cyclase assay system.
Adenylyl Cyclases↗
Parathyroid hormone and isoproterenol stimulation of adenylate cyclase in rat osteosarcoma clonal cells. Hormone competition and site heterogeneity.
A clonal cell line from rat osteosarcoma was found to possess parathyroid hormone and isoproterenol sensitive adenylate cyclase. This study examines the relationship between the two hormones and triphosphoguanine nucleotide with respect to enzyme activation. Concentration-dependence curves, analyzed by computer-aided curve fitting, revealed: (1) in the presence of 5 microM GTP there were two apparent affinities for parathyroid hormone (Km 9 and 89 nM) and isoproterenol (Km 72 and 340 nM; (2) and two affinities for guanosine-5' (beta, gamma-imido)triphosphate (Km 0.25 and 1.3 microM); (3) hormones and guanine nucleotides reciprocally shifted each other's concentration dependence curve to the high affinity sites; (4) parathyroid hormone and isoproterenol interacting with high affinity sites competed for the same adenylate cyclase; (5) parathyroid hormone and isoproterenol, acting on low affinity sites had additive effects and also stimulated adenylate cyclase in the absence of added guanine nucleotides. The findings are consistent with (i) competition of parathyroid hormone and isoproterenol for the activation of the high (hormone) affinity complex containing: receptors, nucleotide subunit, triphosphoguanine nucleotide, catalytic unit (ii) the apparent presence of receptor-nucleotide sub-unit GDP-catalytic unit complexes with low hormone affinity which are stimulated by parathyroid hormone and isoproterenol separately.
Adenylyl Cyclases↗
Effect of parathyroid hormone and calcitonin on cholinergic markers in rat parathyroid gland.
The effect of parathyroid hormone (PTH) and calcitonin on 3H-choline uptake and on 3H-acetylcholine synthesis by rat parathyroid glands were examined. Incubation of tissue for 120 min with PTH or calcitonin resulted in an inverted bell-shaped, dose-dependent inhibition of 3H-choline uptake, with a maximal effect at 10(-9) M concentration. The effect of PTH on parathyroid choline uptake was blunted by preincubation with the PTH antagonist NLe(8-18)-PTH (3-34) amide. PTH brought about a dose-dependent inhibition of 3H-choline conversion to 3H-acetylcholine, with significant effects at 10(-8) M concentration or higher. This inhibitory effect of PTH on 3H-acetylcholine synthesis was blocked by co-incubation with the PTH antagonist NLe(8-18)-PTH (3-34) amide. Only at a 10(-7) M concentration calcitonin was effective to impair the in vitro conversion of radioactive choline into 3H-acetylcholine by parathyroid fragments. The results indicate that, in vitro, PTH, and to a less extent, calcitonin, inhibit cholinergic activity in rat parathyroid glands.
Acetylcholine↗
Absence of parathyroid hormone messenger RNA in nonparathyroid tumors associated with hypercalcemia.
We used a sensitive and specific hybridization assay that detects evidence of parathyroid hormone synthesis in tumors to investigate whether this hormone mediates the hypercalcemia of malignant disease. The assay uses radiolabeled, cloned parathyroid hormone DNA to hybridize selectively with parathyroid hormone messenger RNA. We assayed 13 human and 3 animal tumors of diverse cell origins that are frequently associated with the hypercalcemia of cancer. Five of the human tumors were obtained from patients known to be hypercalcemic at the time of tumor excision, two were from normocalcemic patients, and six were from patients with breast cancer whose serum calcium levels were unknown. Messenger RNA was prepared from cultured cell lines or tumors; active RNA fractions were hybridized with either human or bovine cloned parathyroid hormone DNA that had been labeled to a high specific activity with [32P]nucleotide. We were unable to detect parathyroid hormone RNA transcripts in any of the tumors. Our results indicate that parathyroid hormone rarely, if ever, causes hypercalcemia in malignant disease.
Adult↗
Binding of bovine parathyroid hormone to surface receptors of cultured B-lymphocytes.
Binding of parathyroid hormone onto B-lymphocytes is detected by the utilization of the labelled antibody membrane assay. The amount of parathyroid hormone bound to the receptor sites was depending on the quantity of cells in the incubation milieu. Each cell line showed typical characteristics in time course of parathyroid hormone binding and maximal receptor capacity. Fragmentation of intact parathyroid hormone, also varying with the cell line tested, was very rapid, even at 24 degrees C. Within 20 min most of the cell lines destroyed 20% of the native hormone in the incubation mixture, indicating a fragmentation rate of up to 2.25 ng/min at 37 degrees C. Bmax and KD for the different lymphocytes was 5.3--19 . 10(11) M and 1.8--18,5 . 10(11) M, respectively. These values are in the range of reported plasma concentrations and may therefore represent more physiological values for the capacity and affinity of membrane receptors.
Animals↗
Parathyroid hormone and vitamin D receptors.
Parathyroid hormone (PTH), an 84-amino-acid polypeptide hormone, interacts with plasma membrane-bound receptors on bone and kidney cells, thereby increasing intracellular cAMP. Although the synthetic amino terminal 1-34 fragment of PTH possesses full biological activity, there is no firm evidence that hormone cleavage is a requisite step in the biological action of PTH. In contrast, vitamin D must undergo hydroxylations in the 1 and 25 positions in order to become fully active on target organs. 1,25(OH)2D, a steroid-like hormone, interacts with cytoplasmic receptors in small intestinal and bone cells. The 1,25(OH)2D-receptor complex (in the same manner as other steroid hormones) directs the synthesis of specific proteins. The integrated actions of PTH and vitamin D maintain serum calcium within narrow limits, thereby permitting normal neuromuscular and secretory function, as well as normal bone mineralization. Abnormalities in hormone secretion (PTH) or metabolic activation (vitamin D) lead to clinical disturbances in hormone action. Abnormalities at the level of the receptor-effector system for PTH and vitamin D also lead to clinical disturbances characterized by resistance to hormone action. Specific examples of the latter include pseudohypoparathyroidism, in which deficient activity of a component (the G unit) of the adenylate cyclase complex may lead to resistance to PTH, and hereditary vitamin D-dependent rickets type II, in which abnormalities in the nuclear uptake of 1,25(OH)2D may lead to impaired response to 1,25(OH)2D.
Animals↗
[Histomorphometric data in 5 cases of pseudohypoparathyroidism: discussion on bone sensitivity to parathyroid hormone].
We studied 5 patients (aged 8 to 18) presenting chronic calcipenia with hyperphosphatemia and an increase in C terminal-specific immunoreactive parathyroid hormone. Systematic radiography of the hands revealed 2 cases with signs of subperiosteal resorption characteristic of hyperparathyroidism and 2 cases of cortical fibrillation. These cases were monitored by measuring phosphate levels in the urine after injection of parathyroid hormone (Ellsworth-Howard test), by determining urinary elimination of cyclic AMP after injection of parathyroid hormone (Chase-Aurbach test) and by assaying cyclic AMP levels in the plasma after intravenous administration of parathyroid hormone (Tomlinson-Hendy test). These 3 measurements revealed no changes upon injection of parathyroid hormone, even after administration of vitamin D, thus suggesting renal resistance to parathyroid hormone. The absence of cyclic AMP secretion is suggestive of perturbation of the membrane receptor. Histomorphometric study of the bones showed an increase in resorption and osteoid areas and in the relative osteoid volume without modification of osteoid thickness, which is very suggestive of an effect of parathyroid hormone on the bone. Pseudohypoparathyroidism was, then, characterized by renal resistance to parathyroid hormone and an effect of the latter on bone cells.
Adolescent↗
Minerals, vitamin D, and parathyroid hormone in continuous ambulatory peritoneal dialysis.
The effects of continuous ambulatory peritoneal dialysis on parathyroid hormone (PTH) and mineral metabolism were evaluated in ten patients. Utilizing a PTH radioimmunoassay, which measures both intact hormone and carboxyl-terminal PTH fragments, it was found that the mean clearance of immunoreactive parathyroid hormone was 1.5 +/- 0.73 ml/min (SEM) yielding a daily net removal of 13.6 +/- 3.2% of estimated total extracellular parathyroid hormone. Gel electrophoresis of the dialysate revealed the presence of both intact parathyroid hormone and fragments in a similar pattern to that of peripheral plasma. Normal levels of 25-(OH) vitamin D and vitamin D binding protein were observed prior to the initiation of continuous ambulatory peritoneal dialysis and following 6 months of treatment. Timed dialysate collections (N = 93) demonstrated a daily calcium influx of only 9.9 +/- 9.7 mg. The daily removal of phosphorus was 308.4 +/- 15.5 mg. Despite elevated serum magnesium levels in all patients, the net daily removal was inadequate (31.2 +/- 15.5 mg). It was concluded that: (1) Unlike chronic hemodialysis, continuous ambulatory peritoneal dialysis removes significant amounts of parathyroid hormone. (2) Normal 25-(OH) vitamin D and vitamin D binding protein levels are maintained with continuous ambulatory peritoneal dialysis despite large protein losses. (3) Substantial amounts of phosphorus are removed with continuous ambulatory peritoneal dialysis but not to an extent that precludes use of phosphorus binders. (4) Dialysate containing lower magnesium and possibly higher calcium concentrations should be made available to improve mineral homeostasis.
Calcifediol↗