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PubMed1984

Effect of cimetidine on serum carboxyl and aminoterminal fragments of parathyroid hormone in chronic uraemic patients.

The effect of cimetidine on abnormally elevated serum levels of parathyroid hormone was studied in 21 patients with secondary hyperparathyroidism due to chronic renal failure, receiving regular dialysis treatment. The concentrations of carboxyl (-COOH) and aminoterminal (-NH2) fragments of circulating immunoreactive parathyroid hormone (iPTH) were determined before and after 2 months af treatment with cimetidine 400 mg/day. All patients had, on admission, raised levels of either hormonal fragment. The mean pre-treatment value was 17.2 mU/ml for -COOH terminus (upper normal limit 6.5 mU/ml) and 5.7 mU/ml for -NH2 terminus (upper normal limit 1.9 mU/ml). At the end of cimetidine treatment the mean values were 19.9 and 5.7 mU/ml respectively for the two forms of circulating iPTH. No changes in total serum calcium, phosphate or alkaline phosphatase activity were recorded during the study. These results do not indicate any lowering effect of cimetidine on serum iPTH in chronic uraemic patients with secondary hyperparathyroidism.

Adult↗
PubMed1993

Postoperative studies on parathyroid hormone secretion in patients operated on for primary hyperparathyroidism.

The secretion of intact parathyroid hormone (PTH) was investigated in 11 patients operated on for parathyroid adenoma at 1 year after surgery and compared with that of seven healthy individuals and five patients operated on because of clinical and biochemical signs of primary hyperparathyroidism with equivocal diagnosis after surgery. The investigation was performed by infusing Na2EDTA and CaCl2 at constant rates. No significant difference was found in the suppressibility of PTH secretion by calcium. The set point (the calcium concentration required for half-maximal inhibition of PTH secretion) was slightly lower in patients (1.20 +/- 0.02 mmol/l) compared with healthy subjects (1.23 +/- 0.03 mmol/l; P < 0.05). During the hypocalcemic EDTA infusion, the secretion of PTH was higher in controls compared with patients (P < 0.01). By comparing the data from the infusion tests in patients operated on for parathyroid adenomas with the data obtained from the patients with equivocal diagnosis after parathyroid surgery, a good probability for the diagnosis could be obtained.

Adenoma↗
PubMed1989

Concurrent hyperthyroidism and hyperparathyroidism: influence of hyperthyroidism on serum magnesium, free calcium and parathyroid hormone.

A patient with concomitant primary hyperparathyroidism and Graves' disease with hyperthyroidism was observed during treatment with carbimazole. His serum free calcium levels was initially elevated (6.3mg/dl, normal 4.5-5.3 mg/dl) whereas his serum magnesium level was depressed (1.6 mg/dl, normal 1.7-2.8 mg/dl), but immunoreactive parathyroid hormone levels were only slightly increased (96 pg/ml, normal less than 86 pg/ml). During therapy with carbimazole, the patient became euthyroid and serum free calcium levels decreased to 6.0 mg/dl whereas serum magnesium levels increased to 2.3 mg/dl, and parathyroid hormone increased to values clearly indicative of hyperparathyroidism (185 pg/ml). A subtotal thyroidectomy and parathyroidectomy corrected both diseases in this case. These observations suggested that hyperthyroidism per se causes a decrease in serum magnesium levels and also potentiates the osteoclastic effects of parathyroid hormone resulting in an exacerbation of hypercalcemia which in turn produced a relative inhibition of hormone secretion by the abnormal parathyroid tissue.

Adult↗
PubMed2002

Origin of parathyroid hormone (PTH) fragments detected by intact-PTH assays.

BACKGROUND: Intact parathyroid hormone (I-PTH) assays react with non-(1-84)PTH, large carboxyl-terminal (C) fragments with a partially preserved amino-terminal (N) structure. They account for up to 50% of I-PTH in renal failure and may be implicated in PTH resistance. We wanted to know if they were secreted by the parathyroid glands and generated by peripheral metabolism of PTH(1-84). METHODS: Anesthetized normal and nephrectomized (NPX) rats were injected i.v. with 1.5 microg human (h) PTH(1-84). Blood was obtained from 8 rats at 2, 4, 6, 8, 12, 24, 48 and 96 min. I-PTH (Allegro I-PTH) was measured in all samples. Pools of serum were fractionated by HPLC at each time point and the fractions assayed to quantitate hPTH(1-84) and non-(1-84)PTH. Secretion studies were performed with dispersed cells from 5 parathyroid adenomas. The serum of 10 patients with primary hyperparathyroidism and cell supernatants were fractionated by HPLC and were analyzed as described. RESULTS: hPTH(1-84) disappeared from serum biexponentially. The half-life of the first exponential was similar in normal (2.08 min) and NPX (1.94 min) rats, while that of the second was longer in NPX rats (32.4 vs 20.9 min). The residual quantity of hPTH(1-84) under the curve was greater in NPX (6964+/-2392 pmol) than in normal rats (3229+/-561 pmol; P<0.001). Non-(1-84)PTH concentration was maximal at 8 min in both groups and was higher in NPX (92.8+/-13.8 pmol/l) than in normal rats (38.8+/-7.2 pmol/l; P<0.01). The area under the curve of non-(1-84)PTH was also greater in NPX (1904+/-405 pmol) than in normal rats (664+/-168 pmol; P<0.001). All parathyroid adenomas secreted non-(1-84)PTH. It represented 21.1+/-3.9% of secreted and 32.5+/-1.3% of circulating I-PTH in primary hyperparathyroidism. CONCLUSIONS: Non-(1-84)PTH, like other C-PTH fragments, originates from both the peripheral metabolism of hPTH(1-84) and from parathyroid gland secretion. Renal failure influences its concentration by increasing the amount of substrate available and by reducing non-(1-84)PTH clearance. Its higher proportion in serum relative to cell supernatants in primary hyperparathyroidism reflects the added role of peripheral metabolism and the longer half-life of fragments.

Acute Kidney Injury↗
PubMed1981

[Angiographic investigation with parathyroid hormone administration as functional gauge of liver blood flow (author's transl)].

Parenteral administration of parathyroid hormone causes dilatation of the main hepatic artery adn the intrahepatic branches, as demonstrable on coeliacography. This applies to healthy persons as well as to patients suffering from cirrhosis of the liver. When hormone is given intraarterially, i.e. into the coeliac trunk, the effect on the hepatic arteries is stronger than after intravenous administration. No effect can be be shown on the splenic, upper mesenteric or gastroduodenal arteries. The reaction of the hepatic arteries to parathyroid hormone seems to be a good parameter of the degree of dilatory capacity of these vessels in cirrhosis. Relevant conclusions can probably be drawn as to the prognosis of porto-systemic shunt operations and their indication. This haemodynamic hormone effect, the cause of which is still unknown enabled better visualisation of primary liver tumours on coeliacography.

Adult↗
PubMed1995

Heparin-insensitive calcium release from intracellular stores triggered by the recombinant human parathyroid hormone receptor.

1. In the present study we have characterized the parathyroid hormone (PTH)-induced calcium signalling in 293 cells stably transfected with the human PTH receptor cDNA. In these cells, human PTH-1(1-38) strongly stimulates adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation (EC50 = 0.39 nM) but fails to activate phosphoinositide (PI) turnover. The latter pathway is strongly activated, however, by carbachol (CCh) acting through endogenous M3-muscarinic receptors. 2. Despite the lack of detectable inositol phosphate (IP) formation, hPTH-(1-38) elicited calcium transients (EC50 = 11.2 nM) which were comparable to the signals evoked by CCh. These signals are independent of cyclic AMP generation as cyclic AMP elevating agents did not mimic or modify the PTH response. 3. The PTH-stimulated calcium signal still occurred in calcium-free medium but was absent in cells pretreated with thapsigargin, an inhibitor of the calcium pump of the endoplasmic reticulum (ER). hPTH-(1-38) did not accelerate Mn(2+)-influx through the plasma membrane. These data indicate that PTH releases calcium from intracellular stores. 4. Using heparin, an inhibitor of the IP3-activated calcium release channel of the ER, we tested whether the formation of a low amount of IP3, escaping detection by our biochemical assay, might be the origin of the PTH-induced calcium response. However, intracellular infusion of heparin through patch pipettes in voltage clamp experiments failed to block hPTH-(1-38)-induced calcium signals, whereas it abolished the CCh response. 5. The PTH response, like the CCh response, was insensitive to micromolar concentrations of ryanodine and ruthenium red, eliminating the possibility that hPTH-(1-38) stimulates calcium-induced calcium release through ryanodine receptors.6. We conclude that the recombinant human PTH receptor stimulates calcium release from intracellular stores through a novel pathway not involving IP3- or ryanodine receptors.

Calcium↗
PubMed1983

A homologous biological probe for parathyroid hormone in human serum.

A method of measuring the biological activity of parathyroid hormone (PTH) in human serum that depends on the activation of its natural target enzyme, human renal cortical adenylate cyclase, is described. Optimal sensitivity ranging in different assays from 14 to 20 pg 1-34 hPTH/ml was achieved in the presence of the GTP-analogue GppNHp (10 mumol/L), 5 mmol/L MgCl2 and 1.25 mmol/L EGTA. Basal and stimulated cAMP production was reproducible within assays (c.v. below 7%, S.E.M., n = 3) and between assays (c.v. 5 to 14%, S.E.M., n = 4). The recovery of 1-34 hPTH added to individual test sera averaged 94%. The specificity of the method was established as follows: 1.) Other tested hormones, at 100 ng/ml, were ineffective; 2.) In the majority of peripheral sera from patients with hyperfunctioning parathyroid glands elevated bio-activity was detected; 3.) The circulating bio-activity fell rapidly after removal of parathyroid adenomata; 4.) Treatment with antisera for hPTH reduced the bio-activity; 5.) A PTH-antagonist inhibited the bio-activity.

Adenoma↗
PubMed1982

In vitro studies on an antagonist of parathyroid hormone [Nle-8, Nle-18, Tyr-34]bPTH-(3-34)amide.

1 The actions of parathyroid hormone (PTH) are antagonized in vitro by the peptide [Nle-8, Nle-18, Tyr-34]-bPTH-(3-34)amide, an analogue of PTH. In this paper, the actions of the inhibitory peptide were investigated in vivo. 2 Native parathyroid hormone (bPTH-(1-84)), administered i.v. (0.17-1.51 nmol in volume of 0.3 ml) to 7 day old chicks produced hypercalcaemia but administration of the analogue in doses up to 173 nmol was ineffective in this respect. 3 The analogue failed to antagonize the hypercalcaemia produced by bPTH-(1-34) when injected, in 10 fold molar excess, 2 min before or simultaneously with bPTH-(1-34). 4 Normocalcaemia was restored in parathyroidectomized rats by intravenous infusion of bPTH-(1-84) at 32 pmol kg-1 h-1. Addition of the analogue to the infusion fluid in a 200 fold molar excess did not affect the concentrations of calcium and phosphate in the plasma, cyclic adenosine 3',5'-monophosphate (cyclic AMP) in the urine or phosphate clearance but produced a significant (P less than 0.05) rise in urinary calcium clearance. 5 The results suggest that the peptide [Nle-8, Nle-18, Tyr-34]-bPTH-(3-34)amide does not antagonize the actions of PTH in vivo and demonstrate an important dichotomy between in vitro and in vivo biological properties of the PTH analogue.

Animals↗
PubMed1999

Parathyroid hormone-(1-34) enhances aggrecan synthesis via an insulin-like growth factor-I pathway.

During endochondral bone formation, the growth plate chondrocytes proliferate, become hypertrophic, lose the cartilage phenotype, undergo mineralization, and provide a scaffold upon which subsequent longitudinal bone growth occurs. Parathyroid hormone (PTH), a calcium-regulating hormone, and parathyroid hormone-related peptide (PTHrP), which shares several properties with PTH, have profound effects on skeletal growth and new bone formation. In order to define further the mechanism by which PTH/PTHrP promotes the cartilage phenotype, chondrocytes isolated from the rib cages of developing rat embryos were evaluated for the biosynthesis of aggrecan. Cells treated with PTH-(1-34) for a 4-h period followed by a 20-h recovery period showed a significant increase in cartilage proteoglycan (aggrecan) synthesis in a dose-dependent manner. Only N-terminally intact PTH and PTHrP were effective in stimulating aggrecan synthesis. Addition of a neutralizing antibody to insulin-like growth factor-I (IGF-I) during PTH treatment resulted in the inhibition of PTH-stimulated aggrecan synthesis, whereas the addition of a neutralizing antibody to insulin-like growth factor-binding protein-2 (IGFBP-2) resulted in an increase in synthesis in both the control and PTH-treated cells. In addition, PTH treatment resulted in an increase in the mRNA for aggrecan, a reduction in IGFBP-3 mRNA, and no discernible changes in IGF-I mRNA levels, which was complemented by quantitative changes in IGFBP-3 and free IGF-I levels. The reciprocal relationship in the expression of aggrecan and IGFBP was further confirmed in chondrocytes from various gestational stages during normal development. Collectively, our results indicate that the effect of PTH may be mediated at least in part through the regulation of the IGF/IGFBP axis, by a decrease in the level of IGFBP-3, and an increase in free IGF-I levels. It is likely that the local increase in IGF-I may lead to an increase in cartilage type proteoglycan synthesis and maintenance of the cartilage phenotype. The consequence of the prolonged maintenance may be to halt mineralization while a new scaffolding is created.

Aggrecans↗
PubMed1976

Relative biologic activities of human and bovine parathyroid hormones and their synthetic, NH2-terminal (1-34) peptides, as evaluated in vitro with renal cortical adenylate cyclase obtained from three different species.

The relative biologic activities of native human parathyroid hormone, hPTH (1-84), native bovine parathyroid hormone, bPTH (1-84), and their respective synthetic, NH2-terminal, biologically-active (1-34) fragments were compared in vitro using adenylate cyclase preparations from human, chicken, and rat renal cortex. The concentrations of the hormones required for half-maximal stimulation of the enzymes were determined from dose response curves. bPTH (1-84) had greater apparent activity than hPTH (1-84), using rat or chicken renal adenylate cyclase, but, with human renal adenylate cyclase, the apparent activities of the two hormones were equal. Synthetic hPTH (1-34) possessed about 1/10 of the apparent activity of hPTH (1-84) in all three adenylate cyclase systems. However, (GLU22)bPTH (1-34) was about equal inapparent activity to bPTH (1-84) in the three systems. We propose that different rates of hormone degradation at or near renal receptor sites may be responsible for the dependence of the relative biologic activity on the assay system used. In the case of hPTH a peptide chain longer than (1-34) may be required for the full biologic activity of the hormone...

Adenylyl Cyclases↗
PubMed1992

A novel, mild, specific and indirect maleimido-based radioiodolabeling method. Radiolabeling of analogs derived from parathyroid hormone (PTH) and PTH-related protein (PTHrP).

In an effort to design a mild, non-oxidative and site-specific means of radiolabeling bioactive molecules we have employed maleimido-sulfhydryl chemistry to produce bioactive hormone radioligands. We have prepared two novel radioiodolabeled reagents, 3'-maleimidopropanoyl-3-125I-tyramide and its retro analog, N-maleoyl-N'-3-(4-hydroxy-3-125I-phenyl)propanoyl ethylenediamide, by either oxidative radioiodination of the precursors or radiolabeling of the phenolic component prior to its incorporation into the radiolabeling reagents. These reagents were then used to radiolabel analogs of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) in an efficient way, yielding reaction mixtures which were easily purified. The radioligands obtained are stable upon storage and bind in a reversible manner to a single population of binding sites displaying affinity in the low nanomolar range. The potencies of these analogs are comparable to the non-modified PTH and PTHrP analogs. This study demonstrates the utility of the novel maleimido-based indirect radioiodination approach and highlights some of its advantages over either direct oxidative procedures or acylation using the Bolton-Hunter reagent.

Adenylyl Cyclases↗
PubMed2003

Large carboxy-terminal parathyroid hormone (PTH) fragment with a relatively longer half-life than 1-84 PTH is secreted directly from the parathyroid gland in humans.

OBJECTIVE: It was discovered that an immunoreactive large carboxy-terminal parathyroid hormone (PTH) fragment (large C-PTH), likely 7-84 PTH, is present in the circulation. However, very little is known about the production and metabolism of this large C-PTH. Combining a whole molecule PTH (whole PTH) immunoradiometric assay (IRMA) specifically for 1-84 PTH and an intact PTH (iPTH) IRMA for the sum of 1-84 PTH and large C-PTH, we were able to assess the circulating level of this large C-PTH as well as the glandular secretion and metabolism of this large C-PTH in primary hyperparathyroidism (pHPT). METHODS: This study consisted of two patient groups consisting of 77 pHPT patients with a single adenoma. Of these, 43 comprised the venous sampling study group and 70 comprised the intra-operative PTH study group. (Seven patients belonged only to the former group, 34 patients to only the latter group, and 36 patients to both groups.) Preoperatively, blood samples were drawn from the bilateral internal jugular vein by ultrasonographic guidance and from the peripheral vein (n=43). During surgery, blood samples were drawn after anesthesia (basal level), before excision (pre-excision level) of one enlarged parathyroid gland, and at 5, 10, and 15 min post-excision (n=70). RESULTS: There were 26 patients whose iPTH assay levels differed by more than 10% between the right and left internal jugular. In 24 of the 26 patients, the large C-PTH levels obtained from the adenoma side were significantly higher than those from the contralateral side (117+/-135 vs 43+/-33 pg/ml, P<0.001). The plasma whole PTH values decreased more rapidly than the iPTH values after parathyroidectomy (P<0.001). CONCLUSIONS: Our study has demonstrated that the large C-PTH, likely 7-84 PTH, is directly released from the parathyroid gland in humans. Since the half-life of 1-84 PTH is much shorter than large C-PTH, likely 7-84 PTH, it would be advantageous to use an assay that specifically measures 1-84 PTH for intra-operative monitoring of parathyroidectomy.

Adenoma↗
PubMed1991

Parathyroid hormone secretory reserve in patients submitted to 131-iodine therapy for hyperthyroidism.

Twelve euthyroid patients who had been treated with 131I for hyperthyroidism due to Graves' disease and six normal controls were submitted to an EDTA infusion test. Ionized calcium and parathyroid hormone were measured in serum samples collected every 10 min during the 2-h test. Basal values for calcium (1.22 +/- 0.03 vs 1.23 +/- 0.03 pmol/l, mean +/- SD, controls vs patients) and parathyroid hormone (3.3 +/- 0.65 vs 5.1 +/- 2.32 pmol/l) as well as maximum response during infusion (1.01 +/- 0.04 vs 1.01 +/- 0.05 for calcium and 12.0 +/- 2.2 vs 13.1 +/- 3.7 for parathyroid hormone) were not significantly different. We conclude that 131I treatment for hyperthyroidism due to Graves' disease had no effect on the parathyroid gland secretory reserve of the patients studied.

Adolescent↗
PubMed1988

Vasorelaxant effect of parathyroid hormone on isolated segments of porcine coronary artery.

Parathyroid hormone and it's aminoterminal 1-34 fragment, PTH-(1-34), are potent vasodilators of the coronary circulation in vivo. In order to fully characterize the mechanism of this effect on coronary vascular resistance, it was necessary to determine whether isolated coronary arteries would respond to the action of PTH-(1-34) in vitro. Porcine coronary arteries were cut into cylindrical segments, mounted in a muscle bath containing physiological salt solution, and precontracted with prostaglandin F2. After obtaining stable contractions, PTH-(1-34) was added over the dose range of 10(-10)-10(-7) M. The results showed that PTH-(1-34) produced a dose-dependent vasorelaxation of the coronary segments. A statistically significant relaxation was obtained at a concentration of 10(-10) M. The near-maximal relaxation was 77% with respect to control values. Thus, it has been shown for the first time that PTH-(1-34) relaxes precontracted coronary arteries in vitro, a finding which was consistent with the potent vasodilator action of the polypeptide hormone in vivo.

Animals↗
PubMed1981

Sulfur-free parathyroid hormone analogues containing D-amino acids: biological properties in vitro and in vivo.

Three sulfur-free analogues of bovine parathyroid hormone (bPTH) containing D-amino acids were synthesized by the solid-phase method and their biological properties compared in an in vitro bioassay (rat renal adenylate cyclase assay), a receptor assay for parathyroid hormone (PTH) (canine renal membranes), and an in vivo bioassay (chick hypercalcemia assay). The analogue [Nle8,Nle18,D-Tyr34]-bPTH-(1-34)-amide, which was found to be more than 4 times as potent in vitro as unsubstituted PTH, is the most potent analogue of PTH yet synthesized. The enhanced potency was largely attributable to increased affinity for the PTH receptor. In vivo, however, this analogue was only one-third as potent as bPTH-(1-34). Cumulative evidence suggests that the nearly 15-fold decline in the relative potency when the compound was assayed in vivo is due to the substitution of norleucine for methionine. The other analogues, [D-Val2,Nle8,D-Tyr34]bPTH-(1-34)-amide and [D-Val2,Nle8,Nle18,D=Tyr34]bPTH-(2-34)-amide, were only weakly active in vitro and in vivo, indicating that substitution with D-amino acids at the NH2 terminus of PTH causes markedly diminished receptor affinity. In fact, the placement of a D-amino acid at the NH2 terminus is more deleterious to biological activity than is omission of amino acids at positions 1 and 2.

Adenylyl Cyclases↗
PubMed2004

The role of intraoperative rapid parathyroid hormone monitoring for predicting thyroidectomy-related hypocalcemia.

OBJECTIVE: To determine if the intraoperative rapid parathyroid hormone (PTH) assay can be used to accurately predict postoperative calcium levels following total or completion thyroidectomy. DESIGN: A prospective study. SETTING: Tertiary care referral center. PATIENTS: One hundred four patients following a total or completion thyroidectomy.Intervention Intraoperative rapid plasma PTH levels were determined for patients undergoing a total or completion thyroidectomy. MAIN OUTCOME MEASURES: Parathyroid hormone levels were recorded after the induction of anesthesia, before excision, and 5, 10, and 20 minutes after thyroidectomy. Postoperative calcium levels were monitored every 6 hours until hospital discharge. Intraoperative PTH levels were correlated with postoperative calcium levels and clinical symptoms of hypocalcemia. RESULTS: Twenty-two patients (21.2%) required short-term postoperative calcium supplementation, and 2 (1.9%) required long-term calcium replacement. There was a statistically significant difference between those patients requiring calcium replacement and those who did not require calcium supplementation, for postoperative total calcium level (7.2 vs 8.1 mg/dL [1.8 vs 2.0 mmol/L]; P<.001) and ionized calcium level (3.76 vs 4.36 mg/dL [0.94 vs 1.09 mmol/L]; P<.001). In addition, the PTH changes from baseline demonstrated statistically significant differences at 5, 10, and 20 minutes after the excision between the 2 groups (P<.005). In those patients requiring calcium supplementation, 14 (64%) of 22 demonstrated a change in PTH level at 20 minutes of greater than 75% from baseline, and in those patients who did not require postoperative calcium supplementation, 61 (74%) of 82 demonstrated a change in PTH level of less than 75% from baseline (P<.005). CONCLUSION: Intraoperative PTH monitoring may be a useful tool in identifying patients who will not require postoperative calcium supplementation following total or completion thyroidectomy.

Adolescent↗
PubMed1992

Serum levels of intact parathyroid hormone in elderly patients with hip fracture living at home.

The serum levels of intact parathyroid hormone and cholecalciferol metabolites have been measured in patients with hip fracture above 70 years of age admitted to hospital from home-living conditions and compared with serum levels in age- and sex-matched home-living control subjects. It was found that patients with hip fracture had significantly lower levels of calcidiol (29.7 +/- 15.9 vs 46.0 +/- 27.8 nmol/l) and calcitriol (63.6 +/- 25.0 vs 91.1 +/- 39.5 pmol/l) with no difference in serum levels of intact parathyroid hormone (4.7 +/- 2.1 vs 5.3 +/- 3.3 pmol/l). The data suggest that secondary hyperparathyroidism is not an important risk factor in our population of patients with hip fracture.

Aged↗