Effect of stress on calcium homeostasis in sheep

The acute effect of stress on the plasma and cerebrospinal fluid (CSF) immunoreactive parathyroid hormone (PTH) response was studied in 6 merino sheep. Stress was exerted by weak periodical electric square waves (PESW). In addition, the effect of intravenous injection of adrenaline was studied. Under stress conditions (PESW or adrenaline injection), plasma PTH increased up to 30% and up to 50%, respectively. Weak periodical electric square waves of 3-4 mA decreased CSF PTH concentrations by up to 50%. The effect of adrenaline injection on the CSF PTH was not significant. Total calcium and magnesium in plasma and CSF did not change. Our results showed that the effect of stress on the CSF PTH is opposite to the effect on plasma PTH, and suggest that both, PESW and adrenaline, affected PTH in plasma and CSF by a Ca-independent mechanism.     

睾酮对去睾丸家兔骨密度及血清钙磷的影响

目的:观察去睾丸和睾酮补充对雄兔骨密度和血清钙、镁、磷的影响.方法:周龄相同的雄性新西兰白兔随机分成对照组、去睾丸组和睾酮补充组(去睾丸后肌注十一酸睾酮).同等条件下饲养20周后测量各组兔全身骨密度、腰椎骨密度、股骨颈骨密度,并检测血清总睾酮(TT)、雌二醇(E2),脱氢表雄酮(DHEA)水平以及血清钙(Ca2 )、游离钙([Ca2 ]i)镁(Mg2 )、磷(P)和碱性磷酸酶(AKP)浓度.结果:去睾丸组血清TT水平明显下降(P<0.01),睾酮补充组血清TT水平升高接近对照组(P>0.05).去睾丸组血清E2和E2/TT比明显高于对照组(P<0.01),睾酮补充组血清E2和E2/TT下降,接近对照组水平(P均>0.05).与对照组相比,去睾丸组血清Ca2 、[Ca2 ]i、Mg2 以及AKP浓度明显升高(P均<0.01),睾酮补充组血清Ca2 、[Ca2 ]i、Mg2 以及AKP浓度较去睾丸组低,接近对照组水平(P>0.05).股骨颈骨密度在去睾丸组明显低于对照组和睾酮补充组(P<0.01),而后两组无差别(P>0.05).结论:去睾丸后雄兔血清TT明显下降,E2和E2/TT比以及Ca2 、[Ca2 ]i、Mg2 和AKP浓度明显升高,骨密度显著下降,睾酮补充使上述异常明显改善.     

Effect of aluminium hydroxide on serum ionised calcium,immunoreactive parathyroid hormone,and aluminium in chronic renal failure.

According to the Bricker-Slatopolsky theory, secretion of parathyroid hormone (PTH) is switched on in chronic renal failure by hypocalcaemia due to phosphate retention. In an attempt to reverse this process 20 patients in preterminal renal failure (plasma creatinine 569 +/- 195 mumol/l) were given aluminium hydroxide, 3.8 g daily. They were studied for four weeks and all measurements were made at the start and weekly, except measurements of serum aluminium concentration, which were made at the start and at the end of the fourth week. Mean serum phosphate fell from 1.89 to 1.47 mmol/l (5.9 to 4.6 mg/100), mean serum calcium rose from 2.07 to 2.24 mmol/l (8.3 to 9.0 mg/100 ml), and serum ionised calcium rose from 1.07 to 1.20 mmol/l (4.3 to 4.8 mg/100 ml), but serum immunoreactive PTH did not fall. Thirteen patients had initial serum immunoreactive PTH concentrations at or near to normal and 11 were taking beta-blockers but even in those with neither explanation, PTH concentrations did not fall. Serum aluminium concentrations rose from 0.4 to 1.02 mumol/l (10.9 to 27.4 microgram/l). Aluminium hydroxide corrects serum phosphate, total calcium, and ionised calcium at the price of a rise in serum aluminium concentration; in this study it did not affect serum immunoreactive PTH. The Bricker-Slatopolsky theory still needs verification in studies of patients with chronic renal failure.     

Ultrasound-guided laser thermal ablation for parathyroid adenomas: analysis of three cases with a three-year follow-up

BACKGROUND: In patients with primary hyperparathyroidism (pHPT) the therapeutical choice is surgery. In patients with high surgical and anesthetic risks, ultrasound-guided laser ablation (LTA) of parathyroid adenoma has been reported to reduce parathyroid hormone (PTH) hypersecretion without relevant side effects. No data are available from patients followed for >6 months. We report our 3-year follow-up experience with LTA in 3 patients affected by pHPT due to a parathyroid tumor. METHODS: LTA was performed under color-Doppler ultrasound guidance with a continuous pulse at 2 W (total treatment duration: 300 s in each session; total energy: 1,200 J in two sessions). RESULTS: In the first patient who refused to undergo the second LTA session, calcium, PTH levels and parathyroid lesion volume showed a slight reduction, returning to baseline values in a month. In the second patient, no modification of parathyroid lesion was obtained even if calcium levels temporarily normalized. In the third patient, LTA led to normalization of calcium and PTH levels and to a 99% reduction of parathyroid volume. CONCLUSION: After LTA procedures the long-term disease remission of pHPT is achievable in a minority of patients. Data from larger samples are needed to verify the usefulness of this procedure.     

The influence of PTH, calcium gluconate and EDTA on the parotid saliva in the goat

1. The role of exogenous parathyroid hormone (PTH) and stimulation or inhibition of endogenous hormone release, on the parotid gland of normal and thyroparathyroidectomized (t.x.p.t.x.) goats was studied. 2. The intravenous infusion of PTH and EDTA produced a transitory rise in saliva flow rate in intact animals. In t.x.p.t.x. goats the flow of saliva decreased transiently throughout the infusion. 3. The calcium levels in parotid saliva was unchanged throughout the infusion of PTH, EDTA, calcium gluconate both alone or with propranolol, in either intact or t.x.p.t.x. animals. 4. The parathyroid hormone infusion caused an increase in salivary phosphate concentration in both intact and operated goats. The effects of PTH upon the salivary flow and concentration of P are discussed.     

The Vitamin D,Ionised Calcium and Parathyroid Hormone Axis of Cerebral Capillary Function: Therapeutic Considerations for Vascular-Based Neurodegenerative Disorders

Blood-brain barrier dysfunction characterised by brain parenchymal extravasation of plasma proteins may contribute to risk of neurodegenerative disorders, however the mechanisms for increased capillary permeability are not understood. Increasing evidence suggests vitamin D confers central nervous system benefits and there is increasing demand for vitamin D supplementation. Vitamin D may influence the CNS via modulation of capillary function, however such effects may be indirect as it has a central role in maintaining calcium homeostasis, in concert with calcium regulatory hormones. This study utilised an integrated approach and investigated the effects of vitamin D supplementation, parathyroid tissue ablation (PTX), or exogenous infusion of parathyroid hormone (PTH) on cerebral capillary integrity. Parenchymal extravasation of immunoglobulin G (IgG) was used as a marker of cerebral capillary permeability. In C57BL/6J mice and Sprague Dawley rats, dietary vitamin D was associated with exaggerated abundance of IgG within cerebral cortex (CTX) and hippocampal formation (HPF). Vitamin D was also associated with increased plasma ionised calcium (iCa) and decreased PTH. A response to dose was suggested and parenchymal effects persisted for up to 24 weeks. Ablation of parathyroid glands increased CTX- and HPF-IgG abundance concomitant with a reduction in plasma iCa. With the provision of PTH, iCa levels increased, however the PTH treated animals did not show increased cerebral permeability. Vitamin D supplemented groups and rats with PTH-tissue ablation showed modestly increased parenchymal abundance of glial-fibrillary acidic protein (GFAP), a marker of astroglial activation. PTH infusion attenuated GFAP abundance. The findings suggest that vitamin D can compromise capillary integrity via a mechanism that is independent of calcium homeostasis. The effects of exogenous vitamin D supplementation on capillary function and in the context of prevention of vascular neurodegenerative conditions should be considered in the context of synergistic effects with calcium modulating hormones.     

Parathyroid hormone causes a transient rise in intracellular ionized calcium in vascular smooth muscle cells

The effect of parathyroid hormone on intracellular calcium concentration in vascular smooth muscle cells in culture was studied. Human PTH 1-34 (hPTH (1-34)) caused a transient rise in intracellular calcium in a dose-dependent manner at physiological concentrations. The effect of PTH was mimicked by dibutyryl cyclic AMP and inhibited by a PTH receptor antagonist. The effect of PTH was increased in parallel with extracellular calcium concentration and a sustained response was observed when extracellular calcium was 2 mM or higher. The PTH action was blocked by nisoldipin, a calcium antagonist, but not by ouabain, a Na, K-ATPase inhibitor. These data indicate that PTH increases intracellular calcium through its receptor via opening calcium channels. A possible role of this effect in the regulation of vascular tone is also discussed.     

PIXE study on the effects of parathyroid hormone on elemental content in rat bones

Parathyroid hormone (PTH) has attracted considerable interest as a bone anabolic agent. PTH plays a central role in regulating calcium phosphate metabolism and its increases in production in response to low serum calcium levels. A continuous hypersecretion of PTH, as occurs in primary hyperparathyroidism, leads to bone resorption. In this study, the effect of different doses of parathyroid hormone (PTH) on bone mineral content (BMC) in rats was investigated by particle-induced X-ray emission (PIXE). This study will help in investigating further the toxicity of extremely high doses of PTH on BMC. For this study, PTH at doses of 15, 45, or 135 μg/kg/day were applied to 9-month-old male and female Sprague Dawley (SD) rats. The concentrations of calcium (Ca), phosphorus (P), strontium (Sr), and zinc (Zn) were measured for bone treatment of PTH. From the results of the research, it was revealed that the biomechanical characteristics of the bone as well as the bone mass were enhanced after the treatment. It was further found that the concentrations of other elements also increased, excluding Zn. This research proved that PTH assists in the treatment of osteoporosis as revealed by the characteristics of different elements. PIXE can be used to determine the concentrations of bone mineral content.     

Direct and indirect assessment of the parathyroid hormone response to pamidronate therapy in Paget's disease of bone and hypercalcaemia of malignancy

In patients with either Paget's disease or hypercalcaemia associated with malignancy (HCM) we have assessed the parathyroid response to pamidronate therapy, both by immunoassay of serum intact parathyroid hormone PTH (1–84) and by measurement of indirect parameters of PTH bioactivity, tubular maximum reabsorption of phosphate (TmPO₄/GFR) and nephrogenous cyclic AMP (NcAMP).In 12 patients with Paget's disease, therapy with pamidronate produced a small but significant decrease in adjusted serum calcium within the reference interval which was accompanied by a progressive increase in PTH (1–84) secretion and a corresponding fall in TmPO₄/GFR and increase in NcAMP.In 12 patients with HCM pretreatment, PTH (1–84) concentrations were suppressed, whilst mean TmPO₄/GFR was reduced and NcAMP was increased, compatible in most patients, with parathyroid hormone-related peptide (PTHrP) driven hypercalcaemia. Therapy with pamidronate produced the expected fall in serum calcium but caused an increase in PTH (1–84) secretion in the presence of absolute hypercalcaemia. The initial subnormal TmPO₄/GFR decreased further to a nadir on day 5, and there was a corresponding further increase in NcAMP. By day 7, however, when PTH (1–84) concentrations were maximal, there was a significant paradoxical rise in TmPO₄/GFR and a corresponding decrease in NcAMP.These data are consistent with a variable trigger point for PTH (1–84) secretion, one consequence of which is a reduction in the risk of hypocalcaemia following pamidronate.The results have major clinical implications for the interpretation of PTH (1–84) measurements in patients who are being treated or about to be treated for bone disease or for hypercalcaemia of malignancy (HCM). A pretreatment sample is essential in making the correct diagnosis in such patients, preventing confusion and possible unnecessary investigation.     

Unimpaired membrane dynamics in parathyroid cells in insulin deficient rats

The responsiveness of parathyroid cells in insulin deficient and short-term diabetic rats was investigated by morphometric analysis. Insulin deficiency was produced by intravenous injection of D-mannoheptulose and short-term (7 days) diabetes mellitus by intraperitoneal application of streptozotocin. Parathyroid glands were stimulated for parathyroid hormone secretion by decreasing the serum calcium concentration through intravenous infusion of EGTA. Parathyroid cells of controls, insulin deficient, and short-term diabetic rats responded to reduced serum calcium by a 45% increase of the cell surface area. This increase is assumed to be the result of the membrane-bound transport of parathyroid hormone from the Golgi complex and secretory granules to the plasma membrane and subsequent exocytic release of parathyroid hormone induced by the low serum calcium concentration. Therefore, the unimpaired increase in the cell surface area of parathyroid cells in insulin deficient and short-term diabetic rats indicates that insulin does not modulate the release of parathyroid hormone. It is also considered likely that synthesis of parathyroid hormone is not suppressed in short-term diabetes but that fat metabolism is disturbed leading to accumulation of lipid vacuoles.     

Calciotropic hormones and lipolysis of human adipose tissue: role of extracellular calcium as conditioning but not regulating factor

The influences of different calcium concentrations (0, 0.924 and 2.772 mMol/l) on lipolysis of in vitro incubated human adipose tissue slices or adipocytes were studied under the conditions of stimulation with isoproterenol and parathyroid hormone preparations or inhibition by insulin. Extractive bovine PTH (as well as synthetic PTH 1--34) stimulated glycerol release in a biphasic pattern similarly to isoproterenol; PTH was about half as potent as isoproterenol. The optimal conditions for lipolysis were observed using a calcium concentration of 0.924 mMol/l, whereas lipolysis was distinctly impaired at concentrations of 0 or 2.772 mMol/l; this was true for basal as well as isoproterenol- and PTH stimulated lipolysis or the inhibitory effect of insulin. In contrast to partially purified extractive calcitonin, pure synthetic calcitonin did not inhibit lipolysis. Isoproterenol- and PTH-administrations led to cAMP accumulation in the adipose tissue, this process was also diminished at the non-optimal calcium concentrations. The results suggest a conditioning, but not a regulating significance of extracellular calcium for lipolysis, whereas the importance of the lipolytic potency of PTH remains to be elucidated.     

Bone mineral density is inversely related to parathyroid hormone in adolescent girls.

Preventive programs aimed at maximizing peak bone mass as a way of reducing the risk of osteoporotic fractures later in life should take into account the contribution of nutritional factors to bone mass accumulation in young age. The role of calcium and energy intakes on radial mineral density was investigated in 200 healthy girls (aged 11-15 yr) simultaneously evaluating serum changes of insulin-like growth factor-I (IGF-I), parathyroid hormone (PTH) and osteocalcin (OC). Dietary calcium and energy intakes were assessed by a 3-day food record method, bone mineral density (BMD) was performed at ultradistal (ud) and proximal (pr) radial sites using dual energy X-ray absorptiometry. Calcium consumption below the levels suggested by Dietary Reference Intakes in more than 80% of population studied was not related to BMD, which in turn markedly increased in post-compared to premenarcheal girls. Interestingly, in a multiple regression analysis PTH was inversely related to BMD after adjustment for calcium intake, bone age and menarche. Serum IGF-I was positively associated to energy intakes and bone age in girls before menarche, who exhibited the highest values of OC. Our data highlighted the role of food habits in modulating some hormonal response that might influence bone mineral apposition during adolescent age. Low calcium consumption associated to enhanced PTH values, if persisting, could be responsible for reduced rate of gain in bone mineral density. Thus, to optimize bone mineralization during the critical period of rapid body growth adequate intakes of calcium and energy should be recommended.     

Calcium homeostasis: solving the solubility problem

This report summarizes the evidence that the control of the concentration of free calcium ions in body fluids is centered at mineralized bone surfaces. This process involves an increase in the solubility of bone mineral produced by the non-collagenous proteins existing in the bone extracellular fluid (ECF) and on the adjacent surfaces of bone. The result is a basic equilibrium level produced in the absence of parathyroid hormone (PTH), which is well above the solubility of bone mineral. The effect of PTH is to increase the solubility of bone mineral still further, but the mechanism by which the hormone acts is unknown. The lining cells of the bone contain receptors for PTH and can be observed to respond to this hormone, but the relationship between this response and the increased solubility of bone remains to be discovered. Further research in this field is strongly urged.     

Rapid activation of the medullary bone osteoclast cell surface by parathyroid hormone

Quantitative transmission electron microscope methods were used to determine the response of functionally inactive avian medullary bone osteoclasts to parathyroid hormone (PTH). Egg-lying Japanese quail were used during a period of the egg cycle when medullary bone was not being resorbed for egg shell calcification and when medullary bone osteoclasts were functionally inactive. Ruffled borders adjacent to bone surfaces were rarely, if ever, found on these cells. 20 min after the administration of PTH, over 70% of the osteoclast profiles had ruffled borders adjacent to bone surfaces. These ruffled borders were bounded by filamentous-rich "clear zones" and resembled ruffled borders found on functionally active cells. There was also a marked increase in plasma calcium levels after PTH administration. This study demonstrates that PTH stimulates the de novo generation of ruffled borders on osteoclasts in vivo and suggests that osteoclasts may be involved in the acute regulation of calcium metabolism by exogenous PTH.     

Plasma parathyroid hormone during acute volume expansion in the rat

Various studies have suggested the possibility that volume expansion may increase parathyroid hormone (PTH) secretion. PTH appears to have renal effects consistent with the actions of a natriuretic and diuretic and the possibility exists that PTH may play a physiological role in volume homeostasis. The present studies were designed to examine whether PTH levels in plasma from rats was influenced by acute volume expansion and whether such effects were independent of alterations in plasma ionized calcium concentration. Volume expansion with calcium-free bicarbonate Ringers (10% of body weight, IV) led to a drop in plasma ionized calcium from 1.08 to 0.92 mMol/l (p less than 0.01) while plasma PTH concentration was increased from 67.2 to 114.2 pMol/l. Volume expansion with bicarbonate Ringers solution (also 10% of body wt, IV) which contained 1.8 mM CaCl2 was not associated with any significant change in either plasma ionized calcium or plasma PTH concentration. However, measurements of blood packed cell volume (PCV) revealed that infusion resulted in a drop in PCV from 49.7 to 41.1% (p less than 0.01). This represents a dilution of plasma of approximately 42%. The absence of any drop in plasma PTH during isocalcemic volume expansion suggests an underlying stimulus to PTH secretion during volume expansion independent of plasma ionized calcium levels.     

A dual effect of calcitonin gene-related peptide on plasma calcium levels in the chick

Calcitonin gene-related peptide (CGRP) lowers plasma calcium in the rat and inhibits bone resorption by isolated rat osteoclasts. In our preliminary studies we found that rat CGRP elevates plasma calcium levels in the chick, a response that was somewhat similar to that of parathyroid hormone. Here, we report that human CGRP (alpha) produces a concentration-dependent elevation of plasma calcium levels. The two peptides did not follow precisely the same time course. Whereas at 15 minutes CGRP produced hypocalcaemia relative to the control plasma calcium levels, at 30 minutes both CGRP and PTH were found to be hypercalcaemic. These studies suggest that CGRP initially interacts with the calcitonin receptor to produce a calcitonin-like effect, which is followed by hypercalcaemia presumably by antagonising the action of endogenous circulating calcitonin.     

Effect of long-term phenytoin treatment on the levels of calcium and magnesium in rat femurs]

In young male rats, long-term treatment with phenyto?n reduces the amount of calcium and magnesium in the femurs and provokes a stimulation of the parathyroi?ds witnessed by the hypertrophy and hyperplasy of the parathyroid cells. Neither plasma calcium nor plasma and erythrocyte magnesium are modified.     

Calcium homeostasis and bone surface proteins, a postulated vital process for plasma calcium control

This report is a more in-depth explanation of a recently reported hypothesis for controlling the ionic calcium content of plasma and extracellular fluids (ECF). The hypothesis proposes a two-step process for returning calcium to the ECF against the established gradient continuously moving calcium from plasma to bone surfaces. The first step in this process is the predicted transfer of calcium directly from bone surfaces to the non-collagenous proteins, which are in contact with bone mineral. This calcium would be complexed to existing proteins and a portion would automatically become available for equilibration with ionic calcium in the ECF. The basis of the hypothesis is that the equilibration level helps to set the ionic calcium concentration of plasma. The gradient toward bone and the proposed two-step return occur in the ECF of bone and would be considered normal physiochemical processes. Thus, these processes are critical for mineral ion homeostasis in mammals. In this hypothesis, parathyroid hormone (PTH) is not required for the basic process. However, PTH works within the process to raise and set a precise plasma calcium concentration. The report to follow describes the process and discusses its relationship to normal and pathological conditions affecting human health.     

Light- and electron microscopic observations on parathyroid glands in different age groups of rats

The parathyroid hormone (PTH) acts on bones, intestines, and kidneys to maintain the calcium homeostasis which, in turn, is a main factor in controling the parathyroid (PT) gland activity. In all mammals studied, the chief cells of PT glands changed their size, shape, and cytoplasmic structure due to different functional states which vary the serum calcium levels. The chief cells of the rat PT glands were classified as dark and light. The dark cells may constitute an active form, characterized mainly by the abundant free ribosomes, conspicuous rough endoplasmic reticulum, and GOLGI complexes, greater number of secretory granules (SG) and increased tortuosity of the plasma membranes as compared to the light ones which were considered as a less active type of cells. Due to different calcium requirements in newborn and young rats for the ossification of growing skeleton and in adult and senile rats with consolidate mature bones, the PT glands studied with electron microscope showed various cytological features. The parenchyma of newborn and young PT glands was composed by dark chief cells. The light chief cells were more frequent in adult and senile animals as a less active type of cell. Mature SG were only occasionally observed in dark cells of newborn, young and adult PT glands. They may constitute a reserve supply of PTH but probably not the main way of secretion, according to their little number. Another pool of PTH probably answers the needs for the small basal variations in the steady-state secretion and may be represented by the vesicles observed in the chief cells cytoplasm.     

Clinical use of calcimimetics in the treatment of hyperparathyroidisms

Recognition of the role of the extracellular calcium sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The activation of this receptor by small changes in the extracellular ionized calcium concentration (Ca(2+)ec) regulates parathormone (PTH) and calcitonin secretion, urinary calcium excretion and ultimately bone turnover. Cloning of CaR and discovery of mutations making the receptor less or more sensitive to calcium allowed a better understanding of several hereditary disorders characterized either by hyperparathyroidism or hypoparathyroidism. CaR became an ideal target for the development of compounds able to modulate the activity of CaR, activators (calcimimetics) as well as inhibitors (calcilytics). The calcimimetics are able to amplify the sensitivity of the CaR to Ca(2+)ec, suppressing PTH levels with a resultant fall in blood Ca2+. They dose-dependently reduce the secretion of PTH in vitro in cultured parathyroid cells, in animal models and in humans. In uremic animals, these compounds prevent parathyroid cell hyperplasia, normalize plasma PTH levels and bone remodelling. In uremic patients undergoing hemodialysis, the calcimimetics reduce plasma PTH concentration at short-term (12 weeks) as well as at long-term (2 years), serum calcium-phosphorus product and bone remodelling. After one year of treatment, these patients show a gain of bone mass of 2-3% at the femoral neck and at the total body. Contrarily, the calcilytics, by inhibiting CaR, can intermittently stimulate the secretion and the serum concentration of PTH. This results in an skeletal anabolic effect with a substantial increase in bone mineral density. They are potentially very interesting for the treatment of post-menopausal osteoporosis.