Changes In Parathyroid Hormone Secretion Research Articles

Rare Case of Severe Hypocalcemia Due to PTH Resistance Related to Diet Pill

Introduction: The production of parathyroid hormone (PTH) is essential for calcium the maintenance of normal mineral metabolism. Parathyroid cells have cell-surface calciumsensing receptors, even small changes in extracellular Ca induce rapid changes in PTH secretion. Hypocalcaemia is a well-recognized manifestation of magnesium deficiency. We present rare case of severe hypocalcemia due to PTH resistance caused by hypomagnesemia related to diet pill. Case Report: 61 year old Hispanic obese female with chronic gastritis on omeprazole 20 mg daily, no other significant past medical and surgical history, not taking any prescribed medications presents to ED with complaints of tingling and numbness around the mouth, abdominal cramps, chest pain, shortness of breath and anxiety. On arrival calcium was found to be 6.0mg/dl(8.2–10.2mg/dl) with ionized calcium of 0.60mmol/l(1.13-1.32mmol/l) and EGFR>90ml/min, Albumin-4.0g/l, Magnesium-1.1mg/dl(1.6–2.3mg/dl), Phosphorus-6.1mg/dl(2.4–4.5mg/dl),rest of the electrolytes were normal. Patient was given IV calcium gluconate 2g and magnesium which helped improving her symptoms. PTH was 1700pg/ml(23-73pg/ml), low Vitamin D 25-hydroxy 20ng/dl(30-100ng/dl). Urinary calcium was <1mg/dl(2.0–17.5mg/dl). Vitamin D1,25- dihydroxy 34pg/ml(18-78pg/ml), PTH-like peptide levels 0.6pmol/l(<4.2pmol/l). EKG was normal no QT interval changes. For 4 weekspatient was taking weight loss medication was given to her by her brother called nucific-bio-x4. Patient had lost 4 pounds while taking the medication and had suppression of appetite. Physical features of pseudohypoparathyroidism were not seen. Patient had poor dietary intake of calcium, denied taking vitamin D supplements. Patient was given calcium acetate 2001 mg TID with meals, calcitriol 0.5mcg daily and calcium gluconate 2g IV intermittently was given. That improved her calcium levels to 6.8mg/dl with ionized calcium-0.90mmol/l. Magnesium was replaced IV and discharged on magnesium oxide 400mg BID to maintain magnesium the normal range. The patient was given loading dose of ergocalciferol 50,000 IUfor 8 weeks. At the time of discharge repeat PTH levels were 1600 pg/ml and calcium levels were 8.2mg/dl. 3D CT of the neck did not parathyroid mass. After discharge patient continued on oral calcium and magnesium to maintain calcium levels between 8.4–10.2mg/dl. After discharge calcium levels were 8.6mg/dl, vitamin D 25-hydroxy levels were 32ng/dl and maintenance dose of vitamin D3 2000 IU daily also continued. Nucific-bio-x4 pill was discontinued. Conclusion: In conclusion, severe life threatening hypocalcemia can occur with unsupervised weight lossmedications due to malabsorption of magnesium in patient with likely mutation in magnesium receptors causing PTH resistance. Vitamin D deficiency worsens hypocalcemia resulting into secondary hyperparathyroidism.

Clinical Issues Regarding Cinacalcet Hydrochloride in Japan

Currently available cinacalcet hydrochloride has a greater advantage over conventional vitamin D therapy, although the ability of cinacalcet to suppress parathyroid hormone (PTH) varies among individuals. This article deals with the clinical issues of cinacalcet. Studies examining the impact of cinacalcet on parathyroid gland cells showed that cinacalcet may cause changes in PTH secretion, reduce the parathyroid gland size, and alter parathyroid gland function, suggesting the possibility that use of cinacalcet can eventually be stopped. Combined cinacalcet and vitamin D can reportedly increase vitamin D receptor expression. In a double-blind, placebo-controlled randomized study involving 1184 previously untreated secondary hyperparathyroidism (SHPT) patients, cinacalcet significantly reduced the likelihood of hospitalization for parathyroidectomy, fractures, and cardiovascular disease. Fibrous osteitis was suppressed in the rat model of renal failure treated with cinacalcet. Considering that the drug price of cinacalcet is lower in Japan than in the USA and Europe, it is highly likely that cinacalcet will be used to suppress PTH in Japan.

Calcium-phosphorus homeostasis and changes in parathyroid hormone secretion in cats with various stages of spontaneous chronic renal failure

Feline chronic renal failure was recognized with increased frequency in Maine coon, Abyssinian, Siamese, Russian blue, and Burmese cats. The objective of this study was to investigate the relationship between parathyroid hormone (PTH) level, calcium, and phosphorus homeostasis and the development of various stages of the naturally occurring chronic renal failure (CRF) in cats. Thirty-two CRF cats without history of receiving special diet for renal diseases that were presented to the Small Animal Hospital, Faculty of Veterinary Science, Chulalongkorn University were studied. Nineteen CRF cats were followed prospectively for 60 days and divided into two groups: uremic group (11 cats) and end-stage group (eight cats). The control group (13 cats) were normal cats, which were brought for vaccination at the same hospital within the same period. CRF cats with blood urea nitrogen concentrations of more than 50 mg/dl, serum creatinine level of more than 2.1 mg/dl, and urine specific gravity of between 1.008 and 1.014 were included into the study. Completed blood count, blood chemistry, electrolytes, including sodium, potassium, total calcium, and phosphorus, and PTH levels were measured on days 0, 14, 30, and 60 after the first diagnosis. The results showed that cats with CRF had significantly lower red blood cells, hemoglobin, and pack cell volume than control cats (p < 0.01) on days 0, 14, 30, and 60. PTH levels on first day of diagnosis were 50.51 ± 19.65, 79.41 ± 28.12, and 183.37 ± 50.12 pg/ml in controls, uremic, and end-stage groups, respectively. Cats in end-stage group had significantly increased levels of PTH when compared to control (p < 0.01) and uremic groups (p < 0.05) on days 0, 14, and 30. Serum phosphorus levels also increased significantly in end-stage group (p < 0.001), indicating the presence of renal secondary hyperparathyroidism. This study reveals that PTH level is significantly increased in end-stage CRF cats who did not received special diet for renal diseases. The development of renal secondary hyperparathyroidism in end-stage CRF cats significantly decreased its survival rate.

Rescue of Calcium-sensing Receptor Mutants by Allosteric Modulators Reveals a Conformational Checkpoint in Receptor Biogenesis

The calcium-sensing receptor (CaR), a member of G protein-coupled receptor family C, regulates systemic calcium homeostasis by activating G(q)- and G(i)-linked signaling in the parathyroid, kidney, and intestine. CaR is ubiquitinated by the E3 ligase dorfin and degraded via the endoplasmic reticulum-associated degradation pathway (Huang, Y., Niwa, J., Sobue, G., and Breitwieser, G. E. (2006) J. Biol. Chem. 281, 11610-11617). Here we provide evidence for a conformational or functional checkpoint in CaR biogenesis using two complementary approaches. First we characterized the sensitivity of loss- or gain-of-function CaR mutants to proteasome inhibition by MG132. The stabilization of loss-of-function mutants and insensitivity of gain-of-function mutants to MG132 suggests that receptor sensitivity to calcium influences susceptibility to proteasomal degradation. Second, we used the allosteric activator NPS R-568 and antagonist NPS 2143 to promote the active and inactive conformations of wild type CaR, respectively. Overnight culture in NPS R-568 increased expression of CaR, whereas NPS 2143 had the opposite effect. NPS R-568 and NPS 2143 differentially regulated maturation and cell surface expression of wild type CaR, directly affecting maximal signaling responses. NPS R-568 rescued expression of loss-of-function CaR mutants, increasing plasma membrane expression and ERK1/2 phosphorylation in response to 5 mM Ca(2+). Disorders of calcium homeostasis caused by CaR mutations may therefore result from altered receptor biogenesis independent of receptor function, i.e. a protein folding disorder. The allosteric modulators NPS R-568 and NPS 2143 not only alter CaR sensitivity to calcium and hence signaling but also modulate receptor expression.

Functional Desensitization of the Extracellular Calcium-Sensing Receptor Is Regulated via Distinct Mechanisms: Role of G Protein-Coupled Receptor Kinases, Protein Kinase C and β-Arrestins

The extracellular calcium-sensing receptor (CaR) senses small fluctuations of the extracellular calcium (Ca(2+)(e)) concentration and translates them into potent changes in parathyroid hormone secretion. Dissecting the regulatory mechanisms of CaR-mediated signal transduction may provide insights into the physiology of the receptor and identify new molecules as potential drug targets for the treatment of osteoporosis and/or hyperparathyroidism. CaR can be phosphorylated by protein kinase C (PKC) and G protein-coupled receptor kinases (GRKs), and has been shown to bind to beta-arrestins, potentially contributing to desensitization of CaR, although the mechanisms by which CaR-mediated signal transduction is terminated are not known. We used a PKC phosphorylation site-deficient CaR, GRK and beta-arrestin overexpression or down-regulation to delineate CaR-mediated desensitization. Fluorescence-activated cell sorting was used to determine whether receptor internalization contributed to desensitization. Overexpression of GRK 2 or 3 reduced Ca(2+)(e)-dependent inositol phosphate accumulation by more than 70%, whereas a GRK 2 mutant deficient in G alpha(q) binding (D110A) was without major effect. Overexpression of GRK 4-6 did not reduce Ca(2+)(e)-dependent inositol phosphate accumulation. Overexpression of beta-arrestin 1 or 2 revealed a modest inhibitory effect on Ca(2+)(e)-dependent inositol phosphate production (20-30%), which was not observed for the PKC phosphorylation site-deficient CaR. Agonist-dependent receptor internalization (10-15%) did not account for the described effects. Thus, we conclude that PKC phosphorylation of CaR contributes to beta-arrestin-dependent desensitization of CaR coupling to G proteins. In contrast, GRK 2 predominantly interferes with G protein-mediated inositol-1,4,5-trisphosphate formation by binding to G alpha(q).

The extracellular Ca2+-sensing receptor: central mediator of systemic calcium homeostasis.

The cloning of the G protein-coupled, extracellular calcium (Ca(2+)o)-sensing receptor (CaR) has identified a central mediator of the mechanism governing systemic Ca(2+)o homeostasis. This system enables organisms to adapt successfully to wide variations in dietary Ca(2+)o intake while maintaining near constancy of Ca(2+)o. Whereas discussions of Ca(2+)o homeostasis have generally focused on the key role of Ca(2+)o-elicited changes in parathyroid hormone secretion, the presence of the CaRs in effector tissues of this system enables direct regulation of processes (e.g. renal tubular Ca(2+) reabsorption and possibly bone formation and resorption) that add additional layers of homeostatic control. As we understand more about how the CaR regulates these tissues, we may find that it participates in other processes relevant to mineral ion homeostasis, including the control of the 1-hydroxylation and activation of vitamin D3 or reabsorption of phosphate in the renal proximal tubule. Regardless, the remarkable sensitivity of the CaR to small changes in Ca(2+)o allows adjustments in the response of the Ca(2+)o homeostatic system to increases or decreases in the intake of dietary Ca(2+), for instance, that cause barely detectable alterations in Ca(2+)o. Furthermore, the CaR likely participates in coordinating interactions among several different homeostatic control systems (including those for water, Mg(2+)o, Na(+), extracellular volume, and/or blood pressure), despite the fact that these systems are often considered to function largely independently of mineral ion metabolism.

Parvalbumin is expressed in normal and pathological human parathyroid glands.

The parathyroid glands are of major importance in calcium homeostasis. Small changes in the plasma calcium (Ca2+) concentration induce rapid changes in parathyroid hormone (PTH) secretion to maintain the extracellular Ca2+ levels within the physiological range. Extracellular Ca2+ concentration is continuously measured by a G-protein-coupled Ca2+-sensing receptor, which influences the expression and secretion of PTH. The mechanism of signal transduction from receptor sensing to PTH secretion is not well understood, but changes in PTH secretion are tightly linked to changes in the cytosolic Ca2+ concentration. Using immunohistochemistry and Western blot analysis, we detected the EF Ca2+ binding protein parvalbumin (PV) in normal and in hyperplastic and adenomatous human parathyroid glands. The strongest PV signal was present in chief cells and water clear cells, whereas in oxyphilic cells only a weak signal was observed. Immunohistochemistry and in situ hybridization of the PTH indicated a co-localization of PV and PTH in the same cell types. Because changes in the cytosolic Ca2+ concentration are believed to influence the process of PTH secretion, a possible role of PV as a modulator of this Ca2+ signaling is envisaged.

Ca2+-Induced Increases in Steady-State Concentrations of Intracellular Calcium Are Not Required for Inhibition of Parathyroid Hormone Secretion

It has been well established that increases in extracellular calcium concentration ([Ca2+]) inhibit parathyroid hormone (PTH) secretion. The effects of [Ca2+] are mediated through a G-protein-coupled receptor that has been cloned and characterized. Additionally, it has been demonstrated in parathyroid cells that an increase in [Ca2+] results in an increase in steady-state levels of intracellular calcium ([Ca2+]i). At present, it has not been fully resolved whether changes in [Ca2+]i are related to changes in PTH secretion. In the current study, the effect of increased [Ca2+] on PTH secretion and the connection regarding changes in concentrations of intracellular calcium [Ca2+]i have been examined in primary cultures of bovine parathyroid cells. PTH secretion was measured by radioimmunoassay and intracellular calcium was determined by single cell calcium imaging. Bovine parathyroid cells pre-incubated with either 0.5 or 1 mM calcium responded to rapid increases in [Ca2+] (≥0.5 mM) with an immediate and sustained increase in steady-state levels of [Ca2+]i that persisted for time intervals greater than 15 minutes. Although the magnitude of the sustained increase in [Ca2+]i varied among individual cells (∼40% to >300%), the overall pattern and course of time were similar in all cells examined (n = 142). In all trials, [Ca2+]i immediately returned to baseline levels following the addition of the calcium chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA). Additional control studies, however, suggest that sustained increases in [Ca2+]i do not correlate with regulation of parathyroid hormone secretion. Sustained elevations of [Ca2+]i were not observed when [Ca2+] was gradually increased by the addition of 0.1 mM increments at 1 minute intervals. Furthermore, the effect on inhibition of PTH secretion was the same regardless of whether [Ca2+] was increased by gradual or rapid addition.

Hypocalcemia, but not PTH or hypophosphatemia, induces a rapid increase in 1,25(OH)2D3 levels in rats.

This study determined whether acute decreases in plasma ionized calcium (Ca2+) levels regulate plasma 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels independent of changes in parathyroid hormone (PTH) secretion and plasma phosphate levels. Chronically catheterized rats were subjected to a hypocalcemic clamp (mean decrement of Ca2+ levels 0.38 +/- 0.04 mM), a rat PTH-(1-34) infusion, and a PTH vehicle infusion for 2 h. Plasma NH2-terminal immunoreactive PTH levels were elevated 3.2- and 8.7-fold during hypocalcemia and PTH infusion, respectively. Plasma phosphate decreased by 23 +/- 4 and 42 +/- 3% during hypocalcemia and PTH infusion, respectively. In response to hypocalcemia, plasma 1,25(OH)2D3 levels increased promptly, were significantly elevated by 15 min (56 +/- 23% increase), and continued to increase until the end of the experiment at 5 h (350 +/- 30% increase). In contrast, no changes in plasma 1,25(OH)2D3 levels occurred during the PTH infusion, but levels were elevated by 5 h, i.e., 3 h after the end of the infusion (360 +/- 20% increase). No significant changes in 25(OH)D3 or 24,25(OH)2D3 levels occurred in any protocol. Thus hypocalcemia rapidly elevates 1,25(OH)2D3 levels in rats, but the increase is not caused by elevated PTH secretion, hypophosphatemia, or elevated 25(OH)D3 levels. Furthermore, the increase in 1,25(OH)2D3 levels by hypophosphatemia does not occur rapidly. These studies show that there is a calcium-dependent mechanism that is independent of changes in PTH secretion and that results in the rapid elevation of plasma 1,25(OH)2D3 levels to counteract hypocalcemia.

Parathyroid Hormone Secretion and Target Organ Response in Experimental Acute Pancreatitis

To determine changes in parathyroid hormone secretion and target organ response caused by acute pancreatitis before the development of systemic toxic conditions, experimental acute pancreatitis was induced in rats with a choline-deficient, ethionine-supplemented diet. After 7 days, the rats were weighed and bled, and one kidney was assayed for 25-hydroxyvitamin D1 hydroxylase activity. Several manifestations of pancreatitis were observed in rats given the diet: weight loss (from 29.6 to 26.3 g vs that for control rats, from 29 to 52.8 g) and lower dietary intake (15.5 vs 47 g per rat per 7 days). Serum amylase levels fell from 1794 to 350 U/L in rats given the choline-deficient, ethionine-supplemented diet compared with levels of 1800 to 2100 U/L in control rats. The pancreases of rats given the choline-deficient, ethionine-supplemented diet showed degeneration, necrosis, and hemorrhaging. Serum levels of calcium, phosphorus, chloride, and parathyroid hormone did not change significantly throughout the experiment. Renal 25-hydroxyvitamin D1 hydroxylase activity was higher than in control rats (8.9 +/- 0.8 vs 7.6 +/- 0.6 fmol/mg of kidney per minute). Acute pancreatitis in this experimental animal model does not alter serum levels of calcium and parathyroid hormone or reduce target organ responsiveness to the hormone.

Diagnostic applicability of intact and midregion/C‐terminal parathyroid hormone assays in calcium metabolic disorders

We compared measurements of parathyroid hormone (PTH) using two assays, in order to detect intact PTH and midregion/C-terminal PTH (M/C-PTH) in a variety of calcium metabolic disorders. The series consisted of a total of 101 patients, including subjects with primary hyperparathyroidism (n = 24), hypoparathyroidism (n = 18), hypercalcaemia of malignancy (n = 10), moderate chronic renal failure (n = 14), chronic renal failure undergoing haemodialysis (n = 19), and small bowel disorders (n = 16). The intact PTH assay was superior to the M/C-PTH assay in reflecting parathyroid function in primary hyperparathyroidism, hypoparathyroidism and hypercalcaemia of malignancy. In patients with chronic renal failure, both assays were indicators of a comparable number of patients with elevated PTH levels. Intact PTH proved most reliable in detecting changes in parathyroid hormone secretion in response to variations in ionized calcium induced by haemodialysis. In patients with extensive intestinal resection, both assays showed increased levels of PTH. It is concluded that measurement of intact PTH is a more reliable index of parathyroid function than measurement of midregion/C-terminal PTH. Thus such an approach should be the one of choice for clinical evaluation of calcium homeostasis.

Measurement of circulating parathyroid hormone.

The measurement of parathyroid hormone (PTH) is important in the investigation of disorders of mineral metabolism. Though the first immunoassay for PTH was described more than 25 years ago, it is only recently that methods have been developed which provide the required sensitivity and specificity to detect small changes in hormone secretion in normal subjects. These new methods take advantage of modern labelled antibody technology and have already been shown capable of yielding improvements in the diagnosis and monitoring of disorders which involve changes in PTH secretion. In addition, they are now providing fresh insight into the basic physiology of PTH secretion.

Effects of metabolic acidosis on PTH and 1,25(OH)2D3 response to low calcium diet.

To study the effects of chronic metabolic acidosis on the metabolism of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] rats were given either a low calcium diet (LCD) (0.002% calcium) or chow (1.2% calcium); ammonium chloride (NH4Cl) was added (1 or 1.5%) to the drinking water of some rats eating LCD or chow while others served as nonacidotic controls. LCD increased circulating 1,25(OH)2D3 levels from 46 +/- 14 to 204 +/- 24 pg/ml (P less than 0.001) in the absence of NH4Cl; 1.5% NH4Cl prevented the increase in 1,25(OH)2D3 (25 +/- 6 vs. 27 +/- 8 pg/ml (P, NS) but 1% NH4Cl did not (50 +/- 12 vs. 161 +/- 23 pg/ml; P less than 0.001). Acidosis suppressed neither serum immunoreactive parathyroid hormone (PTH) nor urine cAMP response to LCD. Although total serum calcium and phosphorus showed no regular changes with NH4Cl, acidosis raised blood ionized calcium in rats fed either chow or LCD, and serum 1,25(OH)2D3 levels were inversely correlated with ionized calcium (r = 0.714; P less than 0.001) during LCD. Chronic NH4Cl acidosis prevented serum 1,25(OH)2D3 from rising during LCD, independent of changes in PTH secretion, cAMP generation, or serum phosphorus. The absence of a 1,25(OH)2D3 response may be due to increased ionized calcium produced by acidosis.

Idiopathic hypercalciuria: hydrochlorothiazide decrease urinary calcium without altered renal response to parathyroid hormone.

Hydrochlorothiazide (HTZ) therapy reduces the urinary excretion of calcium (UCa V) in patients with idiopathic hypercalciuria (IH). To test the role of parathyroid hormone (PTH), namely the possibility that HTZ sensitizes the kidney to PTH as the sole or contributory cause of decreased UCa V associated with HTZ therapy, we measured urinary excretion of calcium (UCa V) and cAMP (UcAMP V), the tubular reabsorption of phosphate (TRP), plasma immunoreactive PTH, and the renal response to infused PTH (change in UcAMP V and TRP) in 10 patients with IH. Patients were studied before (control) and after 4 weeks of treatment with HTZ (100 mg/day). HTZ therapy significantly reduced UCa V (mean change, -122 +/- 19 mg/24 h). The UcAMP V, TRP, and plasma levels of calcium, phosphorus, and immunoreactive PTH were initially within the normal range and did not change significantly during HTZ therapy. PTH infusion resulted in a significant increase in the UcAMP V and a significant decrease in TRP during both control and HTZ therapy studies. There was, however, no significant difference in the degree of these renal responses to PTH infusion during the control vs. HTZ therapy studies. We conclude that the hypocalciuric effect of HTZ in patients with IH is independent of changes in PTH secretion, and that HTZ does not cause general sensitization of the nephron, namely proximal tubules, to PTH, as assessed by an increase in UcAMP V and a decrease in TRP.

A permanent preparation allowing measurements of secretion of parathyroid hormone in conscious goats.

A preparation for estimations of rates of secretion of parathyroid hormone (PTH) in conscious goats is described. The procedure involved surgical isolation of a thyroid with its indwelling parathyroid gland, leaving the blood supply intact. Permanent access to the arterial and venous supplies of the preparation was secured by exteriorization of the jugular vein and carotid artery in skin-covered loops. The remaining parathyroids were removed leaving the isolated parathyroid gland as the only source of the hormone. For the seven goats operated on, the preparation has worked satisfactorily from the start in five and also in the remaining two after a reoperation to cut an accessory venous drainage. The loops have been catheterized repeatedly for extended periods of time and the preparation has proved useful for periods of up to 3 years. Secretion of PTH was measured in one goat at two consecutive parturitions. In late pregnancy, secretion rates of 0.7-0.9 ng/kg per min were observed when the dietary calcium intake was adequate. In the first weeks of lactation, secretion increased to 1.2-1.5 ng/kg per min when the intake of calcium was adequate and to 2.0-2.2 ng/kg per min when calcium intake was inadequate. Reductions in calcium intake led to increased rates of secretion of PTH both during pregnancy and during lactation. The results indicate that the preparation may be useful in the study of changes in PTH secretion both acutely and in connection with long-term studies of dietary adaptations of the calcium metabolism.

Renal transport of phosphate: role of alkaline phosphatase.

A new aspect in the study of mechanisms involved in the renal transport of phosphate, the role of alkaline phosphatase (ALP), was introduced by this laboratory in 1977. The present experiments were designed to examine the effects of levamisole, a known inhibitor of ALP, first on in vitro phosphotransferase activity of rat brush border ALP and second on in vivo transport of phosphate and other ionic species, using both clearance and micropuncture techniques.The results indicate that levamisole inhibits in vitro ALP of brush borders obtained from kidney cortex of dogs and rats by reducing the turnover of orthophosphate on the enzyme. When administered in vivo this drug inhibits the net reabsorption of phosphate in these two different mammalian species. Tubular reabsorption of phosphate falls from 87.0 ± 2.9 to 72.1 ± 3.5% when levamisole is administered in the dog femoral vein (25 mM) and from 85.1 ± 3.4 to 71.3 ± 3.2% when levamisole is infused in the dog renal artery (2.5 mM). In the intact rat this parameter falls from 96.7 ± 1.4 to 46.8 ± 9.8% during levamisole and it also decreases from 98.9 ± 0.8 to 67.4 ± 6.7% in the thyroparathyroidectomized animal. The effect of levamisole on the net tubular transport of phosphate is closely related (r = 0.967) to the amount of the drug reaching the tubular lumen from glomerular filtration: that fraction of administered levamisole which first reaches the early segments of the proximal tubule, where the bulk of filtered phosphate is normally reabsorbed.The effect of levamisole appears to be specific for phosphate as no change in the net transport of other ionic species could be documented in the dog experiments. Levamisole produces a significant decrement in renal plasma flow. The mechanism of this effect is not yet determined but certainly created a situation leading to underestimation of the levamisole effect on the net tubular transport of phosphate.Microinjections of 32P either diluted in isotonic saline or administered with flavone phosphate (0.2 mM), a substrate of ALP, were performed in early segments of superficial proximal tubules of the rat. Urinary 32 P recovery averaged 14 ± 4% and 34 ± 8% following saline and flavone phosphate, respectively.The effect of levamisole does not appear to be mediated by changes in parathyroid hormone secretion or other extrarenal humoral substances as a depression of phosphate reabsorption is seen when the drug is administered in the renal artery. The rapid and reversible effect of flavone phosphate suggests that this compound specifically interacts with ALP of brush border membranes.

Assessment of Acute and Chronic Changes in Parathyroid Hormone Secretion by a Radioimmunoassay with Predominant Specificity for the Carboxy-Terminal Region of the Molecule*

A sensitive RIA for parathyroid hormone (PTH) with specificity for the carboxy-terminal region of the hormone was developed and applied to clinical studies. The assay was useful in identifying patients with chronic hyperparathyroid states, such as primary and secondary hyperparathyroidism. In addition, the assay could detect acute changes in PTH seen during calcium, pentagastrin, and EDTA infusions and after parathyroidectomy. These studies demonstrated that an immunoassay with predominant specificity for the carboxy-terminal fragment of PTH can be used to evaluate acute as well as chronic changes in hormone secretion.

The effect of cellulose phosphate on plasma and urinary magnesium at different levels of parathyroid function in man.

1. Previously published data obtained by magnesium infusion in man were found to conform to a Tm/glomerular filtration rate (GFR) model on the assumption of 80% diffusibility of plasma magnesium. The lower limit of Tm,Mg/GFR was 625 mumol/l. 2. Previously published data concerning the effect of cellulose phosphate on magnesium metabolism in normal subjects, patients with latent hypoparathyroidism and patients with primary hyperparathyroidism were found to conform to the same model, with the same limit for Tm,Mg/GFR for all three levels of parathyroid function. 3. The threshold for magnesium excretion is sharper with less 'splay' than for phosphate, but as for phosophate it is close to the normal blood concentration. 4. Because of the geometrical relationship between different methods of presentation of data, at a constant value for Tm,Mg/GFR changes in magnesium load or in GFR automatically produce changes in fractional magnesium clearance. This is the explanation for the increase in fractional magnesium clearance which occurs which with diminishing renal function. 5. Renal conservation of magnesium is a passive consequence of the fall in plasma magnesium. There was no evidence of augmented tubular reabsorption of magnesium in response to magnesium deprivation in any of the three groups of subjects. 6. The tubular reabsorption of magnesium was not altered detectably by a moderate deficiency or excess of parathyroid hormore. Changes in parathyroid hormone secretion are probably not concerned in normal magnesium homeostasis.

Effects of 1α-hydroxy-vitamin D 3 and 1,25-dihydroxy-vitamin D 3 on calcium and phosphorus metabolism in hypoparathyroidism

The effects of 1α-OH D 3 or 1,25-(OH) 2D 3 on calcium and phosphorus metabolism have been evaluated in five hypoparathyroid patients to establish the direct effects of these compounds in adult humans, uncomplicated by compensatory changes in parathyroid hormone secretion. Doses of 1–2.5 μg/day in four patients (5 μg/day in a fifth patient on diphenyl-hydantoin and phenobarbital) caused a marked increase in serum calcium concentration and urinary calcium excretion, without significant changes in renal calcium clearance or urinary hydroxyproline excretion. These results suggest that the correction of hypocalcemia involved primarily a stimulation of intestinal calcium absorption rather than a stimulation of skeletal calcium resorption. Simultaneously, there were increases in urinary phosphorus excretion and variable changes in serum inorganic phosphate concentration. These effects were produced by doses of 1α-OH D 3 and 1,25-(OH) 2D 3 which approach the dose needed to prevent rickets, in contrast to the very large doses of vitamin D or 25-OH D 3 required for comparable effects in hypoparathyroid patients. The increased relative effectiveness of these one-hydroxylated forms of vitamin D reveals a deficiency of vitamin D one-hydroxylation in hypoparathyroidism. The rapidity of action of 1α-OH D 3 and 1,25-(OH) 2D 3 was also striking. Apart from its physiologic implications, the potency of the one-hydroxylated forms of vitamin D offers significant therapeutic advantages in some patients whose hypoparathyroidism is difficult to control with vitamin D itself.

The effect of calcium infusions on renal handling of amino acids in hypophosphatemic vitamin D resistant rickets.

Amino acid clearances were studied in four patients with hypophosphatemic vitamin D resistant rickets. T,e clearances of the single amino acids in the patients did not differ from that of control individuals for all amino acids tested. The reabsorption of amino acids and phosphate was further investigated with the use of calcium infusions. Under these conditions there was a significant decrease in the filtered fraction of phosphate and amino acid excreted in the vitamin D resistant group suggesting a depression of parathyroid hormone secretion. It seems likely, as demonstrated in the vitamin D resistant group, that in this disorder the renal tubule is particularly sensitive to changes in parathyroid hormone secretion in respect to amino acid reabsorption.