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PubMed1989

Renal responsiveness to synthetic human parathyroid hormone 1-38 in healthy subjects.

Renal responsiveness to synthetic human parathyroid hormone (HPTH) 1-38 was examined in seven healthy volunteers. Each subject received three different doses (35 micrograms, 17.5 micrograms, 8.75 micrograms) as bolus intravenous injections. Rapid, transient, dose-dependent decreases in diastolic blood pressure and increases in heart rate were observed, as reported previously in animal studies, suggesting an acute vasodilatory effect of the hormone. The extracellular cyclic AMP responses were brisk and dose-dependent in the group as a whole as well as in the individual subjects. In contrast, the phosphaturic responses, though statistically significant with all three doses, were of a lesser magnitude and showed an individual variability. Nearly maximal decreases in TmP/GFR were found even after the lowest dose with minimal increases in cyclic AMP in some subjects. The injections of HPTH 1-38 also induced a dose-dependent natriuresis which was accompanied by an increase in excreted calcium. It seems that under these experimental conditions the sodium-dependent renal calcium transport cannot be compensated by the effects of the hormone on the distal tubule. HPTH 1-38 can be safely and predictably used for the assessment of renal responsiveness to PTH in routine clinical practice.

Adult↗
PubMed1988

Effects of salicylate and zinc deficiency on the serum concentrations of magnesium, calcium, and parathyroid hormone.

Oral application of 700 mg/kg salicylic acid to pregnant and non-pregnant female rats caused an increase of serum Mg2+ and a decrease of serum Ca2+ concentration. The salicylate effect was drastically enhanced by Zn deficiency. The increase in serum Mg2+ is probably caused by the nephrotoxicity of salicylate. The decrease of serum Ca2+ concentration is combined with an increase of parathyroid hormone concentration in serum. Probably, salicylate and Zn deficiency inhibit Ca2+ mobilization by parathyroid hormone in bone.

Animals↗
PubMed1979

A patient with pseudohypoparathyroidism with increased serum calcium and 1 alpha, 25-dihydroxyvitamin D after exogenous parathyroid hormone administration.

The cause for the normal calcemic response to exogenous parathyroid hormone (PTH) was explored in a case of pseudohypoparathyroidism. The diagnosis of pseudohypoparathyroidism in this 29-yr-old woman was well established, since she had hypocalcemia (6.6 mg/dl), hyperphosphatemia (5.0 mg/ dl), high serum immunoreactive PTH, and negligible urinary cAMP response to exogenous PTH. Treatment with Amphojel slightly increased serum calcium (to 7.4 mg/dl) and lowered serum phosphorus (to 4.1 mg/dl) without altering the serum concentration of 1 alpha, 25-dihydroxyvitamin D [1,25(OH)2D]. After im administration of parathyroid extract (400 U/day for 4 days), serum calcium increased to 9.2 mg/dl, commensurate with significant elevations in serum 1,25(OH)2D (from 1.2 to 2.6 ng/dl) and fractional (intestinal) calcium absorption (from 0.22 to 0.43). The results suggest that the synthesis of 1,25(OH)2D upon PTH challenge was relatively intact and may have accounted for the normal calcemic response.

Adult↗
PubMed1996

Full activation of chimeric receptors by hybrids between parathyroid hormone and calcitonin. Evidence for a common pattern of ligand-receptor interaction.

Calcitonin (CT) and parathyroid hormone (PTH), whose receptors belong to the same family of G protein-coupled receptors, share no amino acid sequence homology and selectively activate either CT or PTH receptors. We now show, however, that reciprocal hybrid ligands (CT/PTH and PTH/CT), which do not activate the "wild-type" receptors, activate PTH/CT and CT/PTH receptor chimeras, respectively. Our findings indicate that PTH and CT share a similar architecture with at least two functional, receptor-specific domains. These domains are sufficiently independent to permit synthetic hybrid ligands to efficiently activate appropriate receptor chimeras. Therefore, both ligands follow, despite their very different primary sequences, a common pattern of ligand-receptor interaction.

Animals↗
PubMed2005

Aluminum posttranscriptional regulation of parathyroid hormone synthesis: a role for the calcium-sensing receptor.

BACKGROUND: Calcium regulates parathyroid hormone (PTH) gene expression by a posttranscriptional mechanism, as well as parathyroid gland growth through the activation of the calcium-sensing receptor. Aluminum decreases both parathyroid cell proliferation and PTH levels by an unknown mechanism. METHODS: To investigate the possible role of calcium-sensing receptor in the aluminum-induced PTH inhibition we used human embryonic kidney (HEK-293) cells transiently transfected with the human calcium-sensing receptor. We used a parathyroid gland tissue culture model to investigate whether the effect of aluminum in PTH mRNA was a transcriptional mechanism and also its possible role in calcium-sensing receptor expression. RESULTS: We found that Al activated the calcium-sensing receptor with higher efficiency than calcium, its biologic ligand. Aluminum inhibited PTH gene expression by a posttranscriptional mechanism, but only when low calcium is present in the medium. Finally, we found that aluminum is also able to decrease calcium-sensing receptor mRNA levels by a posttranscriptional mechanism; however, no effect was observed on calcium-sensing receptor protein. CONCLUSION: These findings indicate that aluminum impairs parathyroid function through a calcium-like mechanism due to the lack of specificity of the calcium-sensing receptor. Additionally, aluminum decreases parathyroid calcium-sensing receptor mRNA levels, and the regulatory mechanism was posttranscriptional. These findings demonstrate for the first time a regulatory effect in the calcium-sensing receptor by one of its ligands.

Aluminum Chloride↗
PubMed1990

Parathyroid-hormone-related protein in tumours associated with hypercalcaemia.

Parathyroid-hormone-related protein (PTHrP) messenger RNA was identified by in-situ hybridisation in seven tumours complicated by hypercalcaemia. In addition, among samples from normocalcaemic patients, it was commonly found in tumours of types frequently complicated by hypercalcaemia but was not found in tumours that are rarely complicated by hypercalcaemia. Positive results were obtained with both freshly frozen and archive paraffin-embedded material. These findings support the view that PTHrP is a common cause of hypercalcaemia in malignant disorders.

DNA Probes↗
PubMed1997

Bioactivities and secondary structures of constrained analogues of human parathyroid hormone: cyclic lactams of the receptor binding region.

In a search for analogues of human parathyroid hormone (hPTH) with improved activities and bioavailabilities, we have prepared the following three lactam analogues of hPTH-(1-31)-NH2 (1) or [Leu27]hPTH-(1-31)-NH2 (2): [Leu27]cyclo(Glu22-Lys26)-hPTH-(1-31)-NH2 (3), [Leu27]cyclo(Lys26-Asp30)-hPTH-(1-31)-NH2 (4), and cyclo(Lys27-Asp30)-hPTH-(1-31)-NH2 (5). Analogues 1, 2, and 5 had seven or eight residues of alpha-helix, as estimated from their circular dichroism (CD) spectra, in contrast to 12 residues in cyclic analogues 3 and 4. Thus, lactams 3 and 4 stabilized a helix previously shown to exist within residues 17-29. The adenylyl cyclase activity (EC50), measured in rat osteosarcoma 17/2 cells, of 5 (40.3 +/- 2.3 nM) was half that of its linear form 1 (19.9 +/- 3.9 nM). The linear Leu27 mutant 2 was twice as active (11.5 +/- 5.2) as analogue 1, and lactam analogue 3 was 6-fold more active (3.3 +/- 0.3 nM). Lactam analogue 4 had less activity (16.9 +/- 3.3 nM) than 2, its linear form. Peptides hPTH-(1-30)-NH2 (6), [Leu27]hPTH-(1-30)-NH2 (7), and [Leu27]cyclo(Glu22-Lys26)-hPTH-(1-30)-NH2 (8) all had AC-stimulating activities similar to that of 1. When injected intravenously, with a dose of 0.8 nmol/100 g of analogue in acid saline, hypotensive effects paralleled their adenylyl cyclase activities. They behaved quite differently when applied subcutaneously. Analogues 1, 5, and 6, the weakest, showed about half the drop in blood pressure observed with 3 and 4, the most active. In contrast, the time required to reach a maximum drop in blood pressure of 4-8, after subcutaneous administration, was 2-4 times that of the other analogues. Thus, the bioavailabilities of the lactam analogues, unlike their adenylyl cyclase-stimulating activities, were highly dependent on the presence or conformation of Val31.

Adenylyl Cyclases↗
PubMed2002

Parathyroid hormone as a therapeutic agent.

Recent advances in the use of parathyroid hormone as a therapeutic agent include a controlled trial that assessed vertebral and non-vertebral fracture risk reduction in women, trials in men, and assessment of treatment on cortical and trabecular bone structure. The occurrence of osteosarcoma in long-term toxicology studies in rats is briefly reviewed.

Animals↗
PubMed1988

The beta-subunit of the bovine mitochondrial F1 ATPase specifically binds the amino terminal domain of parathyroid hormone.

A protein which specifically binds the amino terminal domain of parathyroid hormone (PTH) on nitrocellulose blots of polyacrylamide gels was fragmented with cyanogen bromide (CNBr), and two fragments were sequenced through 20 residues. The sequence obtained was 100% homologous with the beta-subunit of bovine F1 mitochondrial ATPase. Purified F1 ATPase from bovine heart and Escherichia coli were obtained and the binding of PTH examined on the blots. The beta-subunit of the bovine enzyme bound PTH specifically through its amino terminal domain. However, both the alpha- and beta-subunit of the E. coli enzyme were found to bind the hormone. This binding was also specific for the amino terminal domain of the hormone. The subcellular distribution of the PTH-binding protein from bovine kidney was also examined further. While the mitochondria and plasma membrane appear to possess similar PTH-binding capability, submitochondrial particles enriched in F1 ATPase were also enriched in PTH-binding activity.

Amino Acid Sequence↗
PubMed2002

Calcium homeostasis and intact plasma parathyroid hormone during exercise and training in young Standardbred horses.

Physical exercise is known to affect calcium homeostasis in horses, but there is little information on the hormonal regulation of calcium metabolism during exercise. In order to evaluate the effects of exercise and training on calcium homeostasis and intact plasma parathyroid hormone, 7 untrained Standardbred horses were studied in a 6 week training programme. These horses were accustomed to running on the treadmill 3 weeks before onset of training and were exercised on a high-speed treadmill with an initial incremental standardised exercise test (SET 1: 6 incremental steps of 5 min duration each; first step 5 m/s, increase 1 m/s). SET 1 was followed by a lactate-guided training programme (6 weeks in total) with 2 types of exercise in alternating order with a day of rest after each work day: high-speed exercise (HSE) of 15 min duration, starting at VLa4, continuous increase in speed every 60 s by 0.3 m/s (14 incremental steps); and low-speed exercise (LSE) at a constant velocity at VLa2.5, duration approximately 60-90 min. The whole training programme consisted of 8 HSE and 8 LSE sessions. HSE and LSE were calculated to require the same energy expenditure. A final SET (SET 2) finished the training programme. Blood samples for lactate, plasma total calcium [Ca], blood ionised calcium [Ca2+], blood pH, plasma inorganic phosphorus [P(i)] and plasma intact parathyroid hormone [PTH] were collected before, during and after SETs 1 and 2, before and after the first and eighth HSE and LSE. During SETs 1 and 2, HSEs 1 and 8 there was a decrease in ionised Ca2+ and pH and a rise in lactate, intact PTH and P(i). LSEs 1 and 8 resulted in an increase in pH, whereas lactate, ionised Ca2+, total Ca, P(i) and intact PTH were not affected. No changes in calcium metabolism were detected during training. Results of this study suggest that intact PTH is a mediator in counter-regulation of exercise-induced hypocalcaemia.

Animals↗
PubMed1989

Effect of parathyroid hormone, centrally or peripherally injected, on gastric activity in male rats.

Parathyroid hormone (PTH) injected peripherally did not interfere with the development of experimental ulcers. Conversely, when PTH was administered i.c.v. the development of ulcers was significantly inhibited. The gastric secretory volume and acid output were also reduced. The possibility is discussed that this antisecretory activity of PTH may be due to a direct effect at the CNS level.

Animals↗
PubMed1989

The effects of protein kinase-C agonists on parathyroid hormone release and intracellular free Ca2+ in bovine parathyroid cells.

High extracellular Ca2+ stimulates the accumulation of inositol trisphosphate and diacylglycerol in parathyroid cells and suppresses PTH release. Since diacylglycerol is an endogenous activator of protein kinase-C, these observations would suggest that activation of protein kinase-C is associated with inhibition of PTH release. However, phorbol esters, which stimulate protein kinase-C activity, have been reported to enhance PTH release. To clarify the role of protein kinase-C in the regulation of PTH secretion, we studied the responses of parathyroid cells to phorbol myristate acetate (PMA), bryostatin-1, and 1,2-dioctanoylglycerol (diC8). PMA and bryostatin-1 translocated protein kinase-C activity from the soluble to particulate fractions of cell homogenates. Phosphotransferase activity in the particulate fractions increased from 21 +/- 4% to 93 +/- 6% of the total activity after 10 min of exposure to PMA (10(-6) M) and from 21 +/- 2% to 69 +/- 2% after 5 min of exposure to bryostatin-1 (10(-7) M). These three structurally different agonists of protein kinase-C also altered the typical secretory response to Ca2+ in parathyroid cells. At 2.0 mM extracellular Ca2+, PMA (10(-6) M) bryostatin-1 (10(-7) M), and 1,2-dioctanoylglycerol (3 x 10(-4) M) blunted the suppressive effects of high Ca2+ on secretion, thus stimulating PTH release 252 +/- 45%, 122 +/- 20%, and 485 +/- 95% over control levels, respectively. However, at low extracellular Ca2+, these agents inhibited maximal PTH release. Since changes in the intracellular free Ca2+ concentration ([Ca2+]i) may be important in the control of PTH release, we investigated whether protein kinase-C agonists changed the relationship between extracellular Ca2+ and PTH release by affecting [Ca2+]i. In PMA-treated cells, the intracellular Ca2+ response to raising extracellular Ca2+ from 0.5 to 1.5 and 2.0 mM was reduced to 50 +/- 1% and 63 +/- 3% of that in control cells, respectively (P less than 0.005; n = 7-11). Specifically, PMA preincubation reduced the initial intracellular Ca2+ transient with raising extracellular Ca2+ from 0.5 to 2.0 mM and with adding 4.0 mM Sr2+. The sustained phase response to high Ca2+, but not to Sr2+, was also attenuated after incubation with PMA. We conclude that protein kinase-C agonists suppress PTH release at low extracellular Ca2+ and enhance PTH release at high extracellular Ca2+. The effects on secretion at high extracellular Ca2+ may be related to the ability of protein kinase-C agonists to change the sensitivity of [Ca2+]i to high extracellular Ca2+ in these cells.

Animals↗
PubMed1992

Intact parathyroid hormone overestimates the presence and severity of parathyroid-mediated osseous abnormalities in uremia.

To examine the possibility that uremia alters the relationship between bioactive PTH serum concentrations and its osseous end-organ response, we evaluated the relationship between circulating intact PTH and bone turnover in 39 end-stage renal disease patients with hyperparathyroid-mediated bone disease of varying severity. We excluded from analysis patients with coexistent defects in mineralization to insure that bone remodeling indices primarily reflected the effects of PTH. The distribution of serum PTH levels ranged from normal to markedly elevated. Regression analysis between circulating intact PTH concentrations, measured by a two-site immunoradiometric assay, and osseous indices of hyperparathyroidism, determined by quantitative bone histological analysis of iliac crest bone biopsies, showed that bioactive serum PTH levels correlated linearly with bone formation (r = 0.836), woven osteoid volume (r = 0.718), and marrow fibrosis (r = 0.856), and nonlinearly with parameters of bone resorption (r = 0.760). From these functional relationships, we found that the average serum intact PTH level of approximately 165 pg/mL, a value that exceeds the upper limit of intact PTH in nonuremic subjects (65 pg/mL) by 2.5-fold, defines the upper normal limit of bone turnover in uremic subjects. Indeed, the average serum PTH concentrations reached 500 pg/mL before histological evidence of severe hyperparathyroidism developed in uremic subjects. These findings demonstrate that elevated PTH concentrations are necessary to maintain normal bone remodeling in the uremic setting. Consequently, it may not be necessary to attain normal serum intact PTH levels to control the osseous manifestations of PTH excess in uremic subjects.

Adult↗