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PubMed2002

Parathyroid hormone 1 receptor: insights into structure and function.

The parathyroid hormone (PTH) and parathyroid hormone type 1 receptor (PTH1-Rc) are major players in regulating blood calcium homeostasis. PTH1-Rc is a G protein-coupled receptor (GPCR) and it is also activated by PTH-related protein (PTHrP), which has potent effects in several target tissues including bone, via endocrine, paracrine, and autocrine mechanisms in prenatal and adult stages of life, and in several diseases. Another layer of complexity is added by the recently discovered PTH2-Rc subtype displaying unique tissue distribution and ligand specificity, and the potential presence in mammals of a third receptor subtype. Understanding of the mechanisms regulating PTH1-Rc gene expression, receptor desensitization, endocytosis, recycling, and intracellular signaling is advancing and provides insights to understand PTH1-Rc's role in both normal and pathophysiology. In addition, development of an experimentally based model of the PTH-PTH1-Rc complex by combining photoaffinity crosslinking, mutagenesis, conformational analysis, and molecular modeling sheds light, at the atomic resolution, on the molecular mechanisms involved in ligand binding, receptor activation, and coupling to intracellular effectors. Taken together, these lines of investigation offer not only a better understanding of GPCR mechanisms of action in general, but also contribute to the treatment of PTH/PTHrP-PTH1-Rc-related disease states and to the rational development of novel mechanism-based drugs to treat them.

Animals↗
PubMedDate not supplied

Surgical approaches to solitary parathyroid adenoma: state of the art. Our early experience with intraoperative parathyroid hormone measurement.

We report our early experience with focused radioguided parathyroidectomy with intraoperative parathyroid hormone measurement in patients affected by primary hyperparathyroidism. Over a period of 2 months we performed 4 consecutive focused parathyroidectomies with intraoperative parathyroid hormone measurement, 3 of which radioguided. All patients had a preoperative localization of single gland disease by sestamibi scanning and/or ultrasound. Blood samples for parathyroid hormone measurement were taken at baseline (induction of anaesthesia), 10 minutes after adenoma excision and the day after surgery. Three of the 4 patients were discharged within 24 hours. In all cases a solitary adenoma was successfully identified and removed. As predicted by the appropriate fall in intraoperative parathyroid hormone levels, all patients were considered cured on the basis of normal levels of calcium and parathyroid hormone at 1-month follow-up. Targeted parathyroidectomy can be successfully performed in patients with preoperatively localized solitary adenoma. The appropriate decrease in intraoperative parathyroid hormone levels assures a curative operation. The use of radioguidance should be recommended when difficulties with gland identification are foreseen.

Adenoma↗
PubMed1980

Effect of cimetidine on circulating parathyroid hormone in primary hyperparathyroidism.

In twelve patients with primary hyperparathyroidism the raised parathyroid hormone (PTH) levels consistently returned to normal with cimetidine ("Tagamet"), 300 mg four times a day, orally. As PTH levels returned to normal, signs and symptoms improved. Reduction of hypercalcaemia varied with the time, dose, and route of administration of cimetidine. Whenever cimetidine was discontinued, there was a rebound of PTH levels to approximately twice the initial value, which suggests that cimetidine blocks the synthesis and/or secretion of parathyroid hormone, so that parathyroid hormone or its precursor accumulates in the gland. A solitary parathyroid adenoma has been confirmed surgically in the five patients so far operated on. In all surgical patients the PTH levels were brought to normal by cimetidine preoperatively; these levels were maintained postoperatively. The adenomas were unusually large, firm, and congested; there was no atrophy of the rest of the glands. These last two observations further support our hypothesis that cimetidine blocks the synthesis or release of parathyroid hormone; they also support the concept that in primary hyperparathyroidism the parathyroid adenoma becomes autonomous or there is an abnormal hormone.

Adenoma↗
PubMed1987

Effect of verapamil on plasma parathyroid hormone.

The effects of the Ca antagonist, verapamil, on the behaviour of parathyroid hormone was studied in normal and uraemic male Wistar rats. Parathyroidectomy was by cautery. Acute uraemia was induced by bilateral nephrectomy, and moderate uraemia by s.c. injection of gentamicin (200 mg/kg). Ethylendiamine tetracetic acid (50 mg/kg X d) was injected subcutaneously. Parathyroid hormone was determined by radioimmunoassay. The degree of uraemia was determined from plasma urea levels. Renal failure resulted in a significant increase in plasma parathyroid hormone (mean +/- SEM, ng/l) (84 +/- 6, n = 10, in the control; 277 +/- 39, n = 7, in the moderate uraemics and 667 +/- 128, n = 6, in the acute uraemics). Injection of verapamil significantly increased plasma levels of parathyroid hormone, ranging from 21% in the controls to 62% in the moderate uraemia group. In the acute uraemics, parathyroid hormone levels were very high and verapamil did not cause any further elevation of the hormone in the blood. Parathyroidectomy significantly lowered plasma parathyroid hormone, and verapamil resulted in a mean increase of 29%. EDTA caused an increase of 64%, compared with the control group.

Acute Kidney Injury↗
PubMed1975

Human parathyroid autotransplantation: proved function by radioimmunoassay of plasma parathyroid hormone.

The possibility of transplanting parathyroid gland fragments into accessible muscle as functioning autografts in the human being has been supported but unproved. During operations in the thyrocervical area, the parathyroid glands frequently are removed, either intentionally or inadvertently. We have had occasion to transplant slices of parathyroid glands in five instances; four parathyroid glands were proved to be normal, and a benign adenoma appeared in the fifth. The parathyroid gland was positioned in a muscular bed in the patient's forearm. Plasma parathyroid hormone (PTH) measurements by radioimmunoassay were made from the implant venous effluent. The venous outflow from the contralateral arm was used for control. We have concluded that parathyroid tissue can be transplanted, does function, and might be capable of providing calcium homeostasis.

Adenoma↗
PubMed1992

Dopamine enhances the phosphaturic response to parathyroid hormone in phosphate-deprived rats.

Phosphate deprivation results in a resistance to the phosphaturic effect of parathyroid hormone. Dopamine is phosphaturic and is synthesized by kidney proximal tubule, the nephron subsegment where parathyroid hormone inhibits phosphate transport. Thus, to test the hypothesis that phosphate deprivation is associated with low intrarenal dopamine synthesis and that dopamine infusion will overcome the resistance to the phosphaturic response to parathyroid hormone, the following study was performed. The effect of dietary phosphate intake on intrarenal dopamine synthesis, as reflected by urinary dopamine excretion, was determined. Rats were placed in metabolic cages (N = 5) and were fed a low-phosphate diet (0.07% Pi) for 4 days and then a high-phosphate diet (1.8% Pi) for 4 days. Twenty-four-hour urinary dopamine excretion was significantly lower in rats fed a low-phosphate diet (2.53 +/- 0.06 versus 4.10 +/- 0.30 micrograms/day). Further, the effect of dopamine infusion on the blunted phosphaturic response to parathyroid hormone was studied in rats fed a low-phosphate diet for 1, 2, and 3 days. Control clearances were taken 2 h after thyroparathyroidectomy; then, parathyroid hormone (33 U/kg plus 1 U/kg/min), dopamine (25 micrograms/kg/min), or parathyroid hormone plus dopamine were infused for 60 min. Changes in the fractional excretion of phosphate were significantly greater in rats fed a low-phosphate diet infused with parathyroid hormone plus dopamine than in rats fed a low-phosphate diet infused with parathyroid hormone alone (delta 27.9 +/- 5.8 versus 11.2 +/- 2.6% for day 1; 28.4 +/- 1.4 versus 7.1 +/- 3.6% for day 2; and 10.7 +/- 2.8 versus -0.2 +/- 0.2% for day 3; N = 5 for all groups).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Hypotensive action of parathyroid hormone in hypoparathyroid and hyperparathyroid rats.

Experimental and clinical data suggest an association between chronic hyperparathyroidism and hypertension, but acute infusion of parathyroid hormone causes vasodilation and hypotension. These observations imply that chronic and acute parathyroid states affect blood pressure through different mechanism(s), either by modification of vascular receptors or by an ionophoretic effect of parathyroid hormone. The effect of parathyroid status induced by dietary calcium manipulations or by surgical ablation of the parathyroid gland on the hypotensive response of parathyroid hormone infusion was studied in rats. At 4 weeks of age 24 male rats were divided into four equal groups. Three groups were sham-operated, and one group was thyroparathyroidectomized. Only the thyroparathyroidectomized group was treated with thyroxine, 10 micrograms/kg/day. The control and thyroparathyroidectomized groups were raised on a 1.4% calcium diet; the other two groups were raised on 0.005% and 2.8% calcium diets. After 8 weeks on the diets, parathyroid hormone was infused through a venous cannula at 5 and 10 micrograms/kg doses and blood pressure was measured through arterial cannulas. The results indicate that hyperparathyroidism and hypocalcemia induced by the low calcium diet attenuated the hypotensive response to parathyroid hormone compared with responses in rats raised on a 1.4% calcium diet. In hypoparathyroid rats (2.8% Ca diet) with hypercalcemia, the hypotensive response was also reduced. However, in hypoparathyroid (thyroparathyroidectomized) rats with hypocalcemia, the hypotensive response was enhanced. The data suggest that chronic parathyroid status, as well as hypercalcemia, alters the hypotensive response to parathyroid hormone infusion, presumably by altering the vascular parathyroid hormone receptors or by some other mechanism.

Animals↗
PubMed1974

The amino-acid sequence of the amino-terminal 37 residues of human parathyroid hormone.

The sequence of the amino-terminal 37 residues of human parathyroid hormone has been established. The hormone used in these studies was isolated in highly purified form from parathyroid adenomata and was subjected to automated degradation in a Beckman sequencer. A high-sensitivity sequencing procedure employing (35)S-labeled phenylisothiocyanate of high specific activity as the coupling agent was used. The sequence obtained differs from that of bovine parathyroid hormone in three of the first 37 positions, and from that of porcine parathyroid hormone in two positions. A single human-specific residue was found (asparagine 16). The sequence obtained differs at three positions (22, 28, and 30) from the structure for human parathyroid hormone reported recently by Brewer et al. [(1972) Proc. Nat. Acad. Sci. USA 69, 3585-3588] and synthesized by Andreatta et al. [(1973) Helv. Chim. Acta, 56, 470-473] We have carefully reviewed our data, reported here in detail, on the sequence positions in dispute. We must conclude, on the basis of all available data, that the structure that we propose is the correct structure. The objective resolution of these discrepancies in structural analysis through further chemical and immunochemical studies is important, since synthesis of human parathyroid hormone, in which there is widespread interest for physiological and clinical studies, must be based on the correct sequence of the human hormone if the peptide is to be genuinely useful.

Adenoma↗
PubMed1977

Renal effects of native parathyroid hormone and synthetic biologically active fragments in pseudohypoparathyroidism and hypoparathyroidism.

To gain further insight into the biological significance of parathyroid hormone (PTH) metabolism, native parathyroid hormone and synthetic peptides, similar to PTH metabolites generated in vivo, have been given intravenously to human subjects. The resultant changes in renal excretion of adenosine 6':5' monophosphate (cyclic AMP) and inorganic phosphate have been measured in five pseudohypoparathyroid, four hypoparathyroid, and one pseudopseudohypoparathyroid patient. As anticipated, native PTH promptly increased urinary cyclic AMP and phosphate excretion in the hypoparathyroid and pseudo-pseudohypoparathyroid patients, and had little or no effect on their excretion in the pseudohypoparathyroid patients. Synthetic bovine parathyroid hormone 1-34 and synthetic human parathyroid hormone 1-34 had effects essentially identical to each other and to native PTH. We conclude that the PTH resistance of pseudohypoparathyroidism is probably not caused by a defect in PTH metabolism. We further conclude that synthetic human or bovine parathyroid hormone 1-34 could be used for diagnostic evaluation of patients.

Creatinine↗
PubMed2004

Parathyroid hormone: evolving therapeutic concepts.

PURPOSE OF REVIEW: Osteoporosis results from a loss of bone mass and structure such that bones break with very little trauma. To reduce bone loss and improve strength, antiresorptive agents have been instituted. Just more than a year ago, a 34-amino acid fragment of parathyroid hormone (recombinant human parathyroid hormone 1-34) was approved for the treatment of osteoporosis. The parathyroid hormone treatment works by stimulating bone formation on all bone surfaces and is referred to as an osteoanabolic agent. The purpose of this article is to review initial phase 2 and phase 3 studies that establish the effectiveness of this agent to treat osteoporosis. RECENT FINDINGS: In addition, studies that use parathyroid hormone in combination with antiresorptive agents and sequentially are reviewed. Last, unresolved issues related to the duration of use of parathyroid hormone are discussed. SUMMARY: In summary, parathyroid hormone compounds are a major advance in the treatment of osteoporosis. Additional research will enlighten clinicians on the most efficacious way to use them.

Clinical Trials as Topic↗
PubMed2001

Is there an optimal parathyroid hormone level in end-stage renal failure: the lower the better?

Skeletal resistance to parathyroid hormone is well defined in patients with chronic renal failure. In recent years, with the increased frequency of development of adynamic bone disease, it has been recognized that secondary hyperparathyroidism must exist as a 'trade off' mechanism to maintain skeletal bone remodeling in this patient population. An optimal level of intact parathyroid hormone to maintain the normal skeletal bone turnover is believed to be between 2.0 and 2.5 times the upper limit of normal parathyroid hormone. It has very recently been argued that the optimal parathyroid hormone level for maintenance of skeletal bone remodeling may be insufficient to prevent the extraskeletal complications of coronary artery calcifications, calcific valvular heart disease, and cardiac death. To provide optimal health care for these patients several new treatments have been developed, including use of new vitamin D analogs, calcimimetic agents, and noncalcium-based phosphorus binders. It is anticipated that with lower suppression of parathyroid hormone by these vitamin D analogs, intermittent suppression of parathyroid hormone with calcimimetic agents, and the use of noncalcium phosphorus binders (Renageltrade) by regulating serum calcium, the resultant phosphorus concentrations will provide an optimal parathyroid hormone activity to maintain skeletal bone remodeling, while preventing extraskeletal complications.

Bone and Bones↗
PubMed1991

Parathyroid hormone, platelet calcium, and blood pressure in normotensive subjects.

Relations between platelet cytosolic calcium, parathyroid hormone, and blood pressure were investigated in 91 normotensive subjects: 47 men and 44 women ranging in age from 24 to 70 years. The men had higher mean arterial blood pressure, serum creatinine, and body mass index than the women. Serum total calcium, plasma ionized calcium, and parathyroid hormone (measured as both intact hormone and mid-molecule fragment) were not different between men and women; however, serum phosphate was higher in women than in men. Basal platelet cytosolic calcium was higher in men than in women (113.7 +/- 1.9 versus 105.9 +/- 1.7, respectively; p less than 0.01), but there was no difference in the peak platelet cytosolic calcium responses to thrombin between the two groups. In the combined group of male and female subjects, platelet cytosolic calcium correlated with diastolic blood pressure and mean arterial pressure (r = 0.37, p less than 0.001 and r = 0.32, p less than 0.01, respectively). Intact parathyroid hormone correlated with systolic and mean arterial blood pressure (r = 0.41, p less than 0.001 for both). Age correlated with both systolic blood pressure (r = 0.40, p less than 0.001) and intact parathyroid hormone (r = 0.51, p less than 0.001). When multiple regression analysis was performed using mean arterial pressure as the dependent variable, platelet cytosolic calcium and intact parathyroid hormone maintained significant correlations with mean arterial pressure. Platelet cytosolic calcium did not correlate with intact parathyroid hormone. These results suggest that both platelet cytosolic calcium and intact parathyroid hormone are associated with blood pressure regulation in normotensive subjects. However, the influences of these two factors on blood pressure are not interrelated.

Adult↗
PubMed1979

Effect of parathyroid hormone on bicarbonate absorption by proximal tubules in vitro.

The effect of parathyroid hormone on bicarbonate absorption was tested in rabbit proximal renal tubules perfused in vitro. In proximal straight tubules 0.05 U/ml of parathyroid hormone caused a large and reversible increase in the steady-state bicarbonate concentration in tubule fluid. Further, the rates of bicarbonate and fluid absorption (measured at faster flow rates) were inhibited approximately 50% by the hormone. We conclude that parathyroid hormone directly inhibits fluid and bicarbonate absorption by proximal straight tubules, causing an increase in the bicarbonate concentration in the tubule fluid, and we suggest that this action of the hormone contributes to the increase in renal bicarbonate excretion that is generally caused by the hormone. In proximal convoluted tubules, parathyroid hormone was previously demonstrated by other investigators to inhibit fluid and bicarbonate absorption approximately proportionally, so that there was little or no change in the bicarbonate concentration in tubule fluid. In agreement we found in the present studies that 0.05 U/ml of the hormone did not affect the steady-state bicarbonate concentration in proximal convoluted tubule fluid and that 5 U/ml caused only an equivocal increase in tubule fluid bicarbonate concentration.

Absorption↗
PubMed1991

Intact parathyroid hormone assay is superior to mid region assay in the EDTA-infusion test in hyperparathyroidism.

We examined the use of an intact parathyroid hormone two-site immunoradiometric assay compared with a mid region parathyroid hormone radioimmunoassay in ethylene diamine tetraacetic acid-infusion test in 15 patients with hyperparathyroidism. During the test, plasma intact parathyroid hormone levels increased by 240 +/- 43%, whereas the plasma levels of mid molecule parathyroid hormone increased by only 65 +/- 17%, which is significantly lower (P less than 0.01). Four patients had no increase in plasma mid molecule parathyroid hormone level but still a large increase in plasma intact parathyroid hormone level (P less than 0.01). Thus, plasma measurement of intact parathyroid hormone is superior to that of mid molecule parathyroid hormone in the ethylene diamine tetraacetic acid-infusion test in patients with hyperparathyroidism.

Adult↗
PubMed1992

Lack of effect of parathyroid hormone on calcium homeostasis in rat platelets.

The in vitro effects of parathyroid hormone on Ca2+ handling by fura-2 loaded rat platelets were studied. The incubation of these platelets with rat parathyroid hormone (1-34) for 10 min had no effect on intracellular fura-2 metabolism or [Ca2+]i in the resting state. The [Ca2+]i response to 0.1 U/mL thrombin was unaffected by preincubation with parathyroid hormone in the presence or absence of extracellular Ca2+. Furthermore, the recovery rate of [Ca2+]i after the thrombin-induced peak in Ca(2+)-depleted media was not altered with parathyroid hormone. These data indicate that parathyroid hormone may not have a significant effect on Ca2+ homeostasis in rat platelets in unstimulated and stimulated conditions.

Animals↗
PubMed1984

Age, strain and species differences in circulating parathyroid hormone.

A new, sensitive parathyroid hormone (PTH) radioimmunoassay that appears specific for the intact hormone, and its validation for measuring rat PTH are described. The assay is based on antibody C2-7 from chicken immunized with bovine PTH; it has a detection limit of 6 pg of bPTH per assay tube and measures basal PTH in most rats; it is responsive to provoked changes in endogenous PTH concentration, and the intra-assay and inter-assay coefficients of variation are 6.0% and 7.2%, respectively. Multiple dilutions of rat serum and parathyroid gland extract, result in competitive inhibition curves that are parallel to that of highly purified bPTH. Under our assay conditions the C2-7 antibody cross-reacts well with intact PTH but synthetic fragments of the hormone (1-34bPTH, 1-34hPTH, 28-48hPTH, 44-68hPTH, 53-84hPTH) do not depress tracer (125l-bPTH) binding to the antibody. Studies designed to validate the assay gave predictable results such as enhanced secretion of the hormone in response to EDTA infusion, and failure to detect the hormone in serum following thyroparathyroidectomy. In addition, we made the novel observation that in F344 rats circulating immunoreactive PTH increases progressively with aging.

Aging↗