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.     

1,25-Dihydroxyvitamin D downregulation of TGFalpha/EGFR expression and growth signaling: a mechanism for the antiproliferative actions of the sterol in parathyroid hyperplasia of renal failure

Elevated serum levels of parathyroid hormone (PTH) contribute to the increased morbidity and mortality in renal failure patients. Parathyroid gland hyperplasia is a major cause of high serum PTH. The present studies used the rat model of renal failure to address the mechanisms underlying uremia-induced parathyroid hyperplasia and the antiproliferative properties of vitamin D therapy (1,25-dihydroxyvitamin D (1,25(OH)(2)D(3)) or its less calcemic analogs). Enhanced TGFalpha/EGFR co-expression is the major mitogenic signal in uremic parathyroid glands. At early stages of renal failure, vitamin D therapy efficiently counteracts uremia- and high phosphorus-induced hyperplasia by inhibiting the increases in parathyroid-TGFalpha/EGFR co-expression. In established hyperparathyroidism, characterized by highly enhanced-TGFalpha/EGFR co-expression, vitamin D therapy arrests growth by suppressing EGFR-growth signals from the plasma membrane and nuclear EGFR actions as a transactivator of the cyclin D1 gene, an important contributor to parathyroid hyperplasia in humans. In advanced renal failure, reduced-parathyroid vitamin D receptor levels limits the antiproliferative efficacy of vitamin D therapy. However, non-antiproliferative doses of 1,25-dihydroxyvitamin D enhance the anti-EGFR actions of EGFR-tyrosine kinase inhibitors (TKI). In fact, combined 1,25-dihydroxyvitamin D/TKI therapy inhibits parathyroid hyperplasia more efficiently than phosphorus restriction, the most powerful promoter of parathyroid growth arrest available at present.     

Morphological study of the parathyroid gland and thyroid C cell in senescence-accelerated mouse (SAMP6), a murine model for senile osteoporosis

SAMP6, a substrain of senescence-accelerated mouse, was developed as an animal model for senile osteoporosis. We investigated the morphology of the parathyroid gland and thyroid C cell, together with the serum parathyroid hormone (PTH) and calcitonin (CT) in SAMP6 and age-matched normal mice SAMR1. We did not find any significant differences between SAMR1 and SAMP6 at 1 month of age with regard to the serum PTH level and the morphology of the parathyroid glands. As compared with SAMR1, the serum PTH level was significantly higher in SAMP6 at 2, 5 and 12 months of age. In the parathyroid chief cells of SAMP6 at 2, 5 and 12 months of age, the Golgi complexes and the cisternae of the granular endoplasmic reticulum were well developed. Numerous secretory granules were located near the plasma membranes and mitoses were sometimes observed. There was no marked difference between SAMR1 and SAMP6 regarding the morphology of the thyroid C cells and the serum CT level. These findings suggest that the secretory activity of the parathyroid gland is stimulated in SAMP6 at 2, 5 and 12 months of age. The parathyroid follicle was sometimes found in SAMP6, and the significance of this structure was also discussed.     

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.     

Percutaneous ethanol injections in the treatment of secondary hyperparathyroidism

INTRODUCTION: Renal insufficiency is the most common etiology of secondary hyperparathyroidism. In case of resistance for conservative treatment, methods of choice are surgical intervention or percutaneous ethanol injections. AIM OF THE STUDY: The aim of the study was to evaluate usefulness of percutaneous ethanol injection therapy in the treatment of patients with secondary hyperparathyroidism. MATERIAL AND METHODS: We performed percutaneous 96% ethanol injections under USG guideance in 51 patients: 22 women (mean age 49.6 years) and 29 men (46.6 yrs). The base level of parathormone was 689.35 pg/ml. We managed to visualize one parathyroid gland in 34 patients, 2 in 12, 3 in 5 patients. The mean volume of a single gland was 0,8 cm3. All the injections were performed with the use of needle number 6. We repeated injections in case of no effects. One injection was performed in 18 patients, 2 in 18, 3 in 13, 5 in 1 and 6 in 1 patient. Before and after the treatment patients were examined with USG, scintigraphy and densitometry. Serum levels of calcium (Ca), phosphorus (P), parathormone (PTH) and alkaline phosphatase (FA) activity were also obtained. The main criteria for success was decrease in parathormone level of 50% or more in comparison with pre-injection level or to less than 200 pg/ml. RESULTS: In the whole group of patients after the first month, positive results were observed in 67%. There were no changes in 23%, and PTH level increased in 10%. After 6 months-positive results in 53%, no change in 35% and increase in 12%. We noted the best results in patients with PTH less than 800 pg/ml-72% of them had positive results after 1 as far as after the 6 month. CONCLUSIONS: Percutaneous ethanol injections are valuable method of treatment of secondary hyperparathyroidism. The best results can be obtained if PTH level is less than 800 pg/ml, one parathyroid gland dominating over the rest is visualised in USG, and if patient responds after 1 or at least 2 injections.     

L-amino acids regulate parathyroid hormone secretion

Parathyroid hormone (PTH) secretion is acutely regulated by the extracellular Ca(2+)-sensing receptor (CaR). Thus, Ca(2+) ions, and to a lesser extent Mg(2+) ions, have been viewed as the principal physiological regulators of PTH secretion. Herein we show that in physiological concentrations, l-amino acids acutely and reversibly activated the extracellular Ca(2+)-sensing receptor in normal human parathyroid cells and inhibited parathyroid hormone secretion. Individual l-amino acids, especially of the aromatic and aliphatic classes, as well as plasma-like amino acid mixtures, stereoselectively mobilized Ca(2+) ions in normal human parathyroid cells in the presence but not the absence of the CaR agonists, extracellular Ca(2+) (Ca(2+)(o)), or spermine. The order of potency was l-Trp = l-Phe > l-His > l-Ala > l-Glu > l-Arg = l-Leu. CaR-active amino acids also acutely and reversibly suppressed PTH secretion at physiological ionized Ca(2+) concentrations. At a Ca(2+)(o) of 1.1 mm and an amino acid concentration of 1 mm, CaR-active amino acids (l-Phe = l-Trp > l-His = l-Ala), but not CaR-inactive amino acids (l-Leu and l-Arg), stereoselectively suppressed PTH secretion by up to 40%, similar to the effect of raising Ca(2+)(o) to 1.2 mm. A physiologically relevant increase in the -fold concentration of the plasma-like amino acid mixture (from 1x to 2x) also reversibly suppressed PTH secretion in the Ca(2+)(o) concentration range 1.05-1.25 mm. In conclusion, l-amino acids acutely and reversibly activate endogenous CaRs and suppress PTH secretion at physiological concentrations. The results indicate that l-amino acids are physiological regulators of PTH secretion and thus whole body calcium metabolism.     

Parathyroid hormone controls the size of the intracellular Ca(2+) stores available to receptors linked to inositol trisphosphate formation

In HEK 293 cells stably expressing type 1 parathyroid (PTH) receptors, PTH stimulated release of intracellular Ca(2+) stores in only 27% of cells, whereas 96% of cells responded to carbachol. However, in almost all cells PTH potentiated the response to carbachol by about 3-fold. Responses to carbachol did not desensitize, but only the first challenge in Ca(2+)-free medium caused an increase in [Ca(2+)](i), indicating that the carbachol-sensitive Ca(2+) stores had been emptied. Subsequent addition of PTH also failed to increase [Ca(2+)](i), but when it was followed by carbachol there was a substantial increase in [Ca(2+)](i). A similar potentiation was observed between ATP and PTH but not between carbachol and ATP. Intracellular heparin inhibited responses to carbachol and PTH, and pretreatment with ATP and carbachol abolished responses to PTH, suggesting that the effects of PTH involve inositol trisphosphate (IP(3)) receptors. PTH neither stimulated detectable IP(3) formation nor affected the amount formed in response to ATP or carbachol. PTH stimulated cyclic AMP formation, but this was not the means whereby PTH potentiated Ca(2+) signals. We suggest that PTH may regulate Ca(2+) mobilization by facilitating translocation of Ca(2+) between discrete intracellular stores and that it thereby regulates the size of the Ca(2+) pool available to receptors linked to IP(3) formation.     

Normal responsiveness of serum parathyroid hormone to beta-adrenergic blockade in patients with secondary hyperparathyroidism

Infusion of calcium gluconate (15 mg Ca++/kg body weight in 4 h) to 6 patients with secondary hyperparathyroidism (due to mild renal insufficiency) decreased serum parathyroid hormone (PTH) levels to the same degree (on a percent basis) as in normal subjects. Serum PTH values at 4 h were 60 +/- 4.5 (SEM)% of baseline in the patients and 59 +/- 2.9% of baseline in the normal subjects. Infusion of propranolol (1 mg i.v. bolus followed by an infusion of 60 micrograms/min for 2 h) to 7 additional patients with secondary hyperparathyroidism also decreased serum PTH to the same degree as in normal subjects. Serum PTH values at 2 h were 68 +/- 10.4% of baseline in the patients and 68 +/- 3.3% of baseline in the normal subjects. The studies indicate normal responsiveness of serum PTH to calcium or beta-adrenergic blockade in secondary hyperparathyroidism due to mild renal insufficiency.     

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.     

Fate of parathyroid hormone during hemodialysis and ultrafiltration

In order to shed light on the discrepant changes in plasma immunoreactive parathyroid hormone (iPTH) during hemodialysis (HD) and ultrafiltration (UF) in end-stage renal failure, the influence of filtration of PTH fragments on the iPTH level in plasma was examined in 2 sets of experiments: in vitro dialysis of 125I-bPTH 1-84, 125I-hPTH 1-34 and 125I-hPTH 53-84 added to plasma was successively performed through a cuprophane membrane. Gel filtration on a Biogel P-100 column and subsequent counting of the eluate were performed with the plasma before and after dialysis, and with the dialysate fluid after dialysate fluid after dialysis. An ultrafiltrate obtained from a patient with renal failure was also analyzed for iPTH with a 'C-' and with an 'N-terminal' antiserum (GP 500 MA and AS 211/32), and so was his plasma before and after UF, and after a subsequent dialysis session. Fluid obtained by lavage of the filter with acetic acid after dialysis was also analyzed. Chromatography with measurements of iPTH in the eluate was performed in each case, and the procedure was repeated applying a different transmembrane pressure. Immunoreactive material found in the concentrated ultrafiltrate, but not in plasma, was characterized by means of dilution curves in different RIA performed with the C-terminal antiserum preincubated with various synthetic PTH fragments. Results showed that intact PTH does not cross the cuprophane membrane during both in vitro dialysis and in vivo UF. The 1-34 fragments are poorly dialyzed in vitro; either they stick to the membrane or they are disintegrated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increase of (Ca2++Mg2+)-ATPase activity of renal basolateral membrane by parathyroid hormone via cyclic AMP-dependent membrane phosphorylation

Studies were made on the mechanism of the effect of parathyroid hormone (PTH) on the activity of (Ca2++Mg2+)-ATPase, a membrane bound Ca2+-extrusion pump enzyme from the basolateral membranes (BLM) of canine kidney (Km for free Ca2+ = 1.3 X 10(-7) M, Vmax = 200 nmol Pi/mg/min). At 1 X 10(-7) M free Ca2+, both PTH (10(-7)-10(-6) M) and cAMP (10(-6)-10(-4) M) stimulated (Ca2++Mg2+)-ATPase activity dose-dependent and their stimulatory effects were inhibited completely by 5 microM H-8, an inhibitor of cAMP-dependent protein kinase. PTH (10(-7) M) also caused 40% increase in 32P incorporation into the BLM and 5 microM H-8 inhibited this increase too. PTH (10(-7) M) was found to stimulate phosphorylation of a protein of Mr 9000 by cAMP dependent protein kinase and 5 microM H-8 was found to block this stimulation also. From these results, it is proposed that PTH stimulates (Ca2++Mg2+)-ATPase activity by enhancing its affinity for free Ca2+ via cAMP-dependent phosphorylation of a BLM protein of Mr 9000.     

Extracellular calcium is a direct effecter of VDR levels in proximal tubule epithelial cells that counter-balances effects of PTH on renal Vitamin D metabolism

In renal proximal tubules, VDR is transiently decreased by parathyroid hormone (PTH) during times of hypocalcemia and returns to normal levels with the rise in serum calcium (Ca). In this study we tested the hypothesis that elevated extracellular Ca induces VDR in a human renal proximal cell line (HK-2G) stably expressing PTH receptor type I. Exposure of HK-2G cells to increasing Ca concentration, up to 3 mM, induced the expression of VDR. The increase in VDR occurred within 1 h and was sustained over 24 h. The increase in VDR was also dose-dependently increased using 20–100 nM gadolinium, suggesting the induction of VDR is regulated via the extracellular Ca sensing receptor (CaSR) with is naturally expressed in HK-2G cells. In conclusion, an extracellular Ca concentration in the physiological range is capable of direct increase of renal proximal VDR expression, and the induction mechanism represents a strategy the body may use to counterbalance effects of PTH on renal Vitamin D metabolism.     

Expression-level dependent activation of recombinant human parathyroid hormone/parathyroid hormone-related peptide receptor: effect of human parathyroid hormone (1-34), (1-31), and (28-48)

A stable recombinant chinese hamster ovary (CHO) cell model system expressing the human type-1 receptor for parathyroid hormone and parathyroid hormone-related peptide (hPTH-R) was established for the analysis of human PTH (hPTH) variants. The cell lines showed receptor expression in the range from 10(5) to I.9 x 10(6) receptors per cell. The affinity of the receptors for hPTH-(1-34) was independent of the receptor number per cell (Kd approximately = 8 nmol/1). The induction of cAMP by hPTH-(1-34) is maximal in clones expressing >2x10(5) receptors per cell and Ca++ signals were maximal in cell lines expressing >1.4x10(6) receptors per cell. Second messenger specific inhibitors demonstrated that PTH-induced increases in intracellular cAMP and Ca++ are independent and Ca++ ions are derived from intracellular stores. The cAMP-specific receptor activator hPTH-(1-31) showed also an increase in intracellular Ca++. Even in cell lines expressing more than 10(6) receptors per cell the Ca++/PKC specific activator hPTH-(28-48) did not activate hPTH-Rs. Based on these results, synthesis of further derivatives of PTH is required to identify pathway-specific ligands for the type-1 hPTH-R.     

Pathophysiology of primary hyperparathyroidism

Parathyroid gland is the overall regulatory organ within the systemic calcium homeostasis. Through cell surface bound calcium-sensing receptors external calcium inversely regulates release of parathyroid hormone (PTH). This mechanism, which is voltage independent and most sensitive around physiologic calcium concentrations, is regulated through a 120 kDa calcium sensing receptor, CaR. Inherited inactivation of this receptor is the cause for familial hypocalciuric hypercalcemia (FHH). Parallel research identified the 550 kDa glycoprotein megalin, which also is expressed on the parathyroid cell surface, as another potential calcium sensing protein. Although this protein expresses numerous calcium binding sites on its external domain, its main function may be calcium sensitive binding and uptake of steroid hormones, such as 25-OH-vitamin D3 (bound to vitamin D binding protein) and retinol. In hyperparathyroidism (HPT), excessive PTH is secreted and the calcium sensitivity of the cells reduced, i.e. the set-point, defined as the external calcium concentration at which half-maximal inhibition of PTH release occurs, shifted to the right. Pathological cells have reduced expression of both CaR and megalin, and reduced amount of intracellular lipids, possibly including stored steroid hormones. A number of possible genetic disturbances have been identified, indicating multifactorial reasons for the disease. In postmenopausal women, however, the individual group with highest incidence of disease, a causal relation to reduced effect of vitamin D is possible. An incipient renal insufficiency with age, lack of sunshine in the Northern Hemisphere, and an association to the baT haplotype of the vitamin D receptor supports this theory. This review summarizes data on regulation of PTH release, dysregulation in HPT, as well as proliferation of parathyroid cells.     

Age-related changes in renal and hepatic cellular mechanisms associated with variations in rat serum thyroid hormone levels

Aging is associated with changes in thyroid gland physiology. Age-related changes in the contribution of peripheral tissues to thyroid hormone serum levels have yet to be systematically assessed. Here, we investigated age-related alterations in the contributions of the liver and kidney to thyroid hormone homeostasis using 6-, 12-, and 24-mo-old male Wistar rats. A significant and progressive decline in plasma thyroxine occurred with age, but triiodothyronine (T(3)) was decreased only at 24 mo. This was associated with an unchanged protein level of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) in the kidney and with a decreased MCT8 level in the liver at 24 mo. Hepatic type I deiodinase (D1) protein level and activity declined progressively with age. Renal D1 levels were decreased at both 12 and 24 mo but D1 activity was decreased only at 24 mo. In the liver, no changes occurred in thyroid hormone receptor (TR) TRalpha(1), whereas a progressive increase in TRbeta(1) occurred at both mRNA and total protein levels. In the kidney, both TRalpha(1) and TRbeta(1) mRNA and total protein levels were unchanged between 6 and 12 mo but increased at 24 mo. Interestingly, nuclear TRbeta1 levels were decreased in both liver and kidney at 12 and 24 mo, whereas nuclear TRalpha(1) levels were unchanged. Collectively, our data show differential age-related changes among hepatic and renal MCT8 and D1 and TR expressions, and they suggest that renal D1 activity is maintained with age to compensate for the decrease in hepatic T(3) production.     

Direct inhibitory effect of amino-terminal parathyroid hormone fragment [PTH(1-34)] on PTH secretion from bovine parathyroid primary cultured cells in vitro

We have examined the possibility of direct inhibitory effect of PTH(1-34) on PTH secretion in bovine parathyroid cells. As low as 10(-12) M PTH(1-34) completely inhibited low calcium (0.5 mM Ca2+)-stimulated PTH secretion by these cells. In the presence of 1.25 mM Ca2+, 10(-12) M PTH(1-34) inhibited PTH secretion by about 14.3% of the basal value, while 10(-11) M or higher concentration of PTH(1-34) showed potent inhibitory effects equivalent to the inhibitory action of high calcium concentration (2.5 mM Ca2+) on PTH secretion. At 2.5 mM Ca2+, as much as 10(-9) M PTH(1-34) failed to inhibit PTH secretion further. These results suggest that PTH(1-34) might directly, not via calcium concentration, inhibit PTH secretion by parathyroid cells and that a cooperative mechanism could exist between calcium and PTH(1-34) to inhibit PTH secretion.     

Parathyroid Hormone Level Changes Following Radioiodine Therapy for Thyroid Cancer: A Prospective Observational Study

ObjectiveOur objective was to analyze the effect of radioiodine (RAI) therapy on parathyroid hormone (PTH) secretion.MethodsA total of 137 patients were included and divided into 2 groups based on pretherapy PTH levels. The residual thyroid tissue volume was classified into 4 grades (0-3), and a value of 0 indicated that there was no apparent residual tissue. We analyzed the PTH level changes among different time points in each group and the factors that could predict the PTH level changes.ResultsIn 113 patients with normal parathyroid gland function, the PTH level at baseline, 1 day, 7 days, 1 month, 3 months, and 6 months after RAI therapy did not show any significant difference; in 24 patients with decreased parathyroid gland function, the level of PTH immediately decreased after the implementation of RAI therapy but gradually returned to a pre-RAI therapy level within 6 months. On the seventh day after therapy, the mean value of PTH in patients with a residual thyroid tissue volume of extent of 0/1 was 8.0 ± 2.3 pg/mL, which was significantly higher than that in patients with a residual thyroid tissue volume of extent of 2/3 (P = .011). Similar phenomena were observed 1 month, 3 months, and 6 months after therapy.ConclusionRAI therapy had a significant transient adverse effect on parathyroid gland function in patients with decreased PTH secretion pretherapy, and the extent was associated with the amount of residual thyroid tissue.     

Effect of aging on the mechanisms of PTH-induced calcium influx in rat intestinal cells

We have investigated the effects of aging on parathyroid hormone (PTH) modulation of intracellular calcium homeostasis and their relationship to signal transduction pathways in isolated rat duodenal cells (enterocytes). PTH (10(-8)-10(-9) M) increased enterocyte (45)Ca(2+) influx and intracellular Ca(2+) concentration ([Ca(2+)](i)) to a greater extent (twofold and 50%, respectively) in aged (24 months) than in young (3 months) animals. The [Ca(2+)](i) response of old cells to the hormone was slower, lacking the early phase of changes in cytosolic Ca(2+). Ca(2+) influx induced by PTH was prevented by the protein kinase A antagonist Rp-cAMPS in both young and aged enterocytes, whereas neomycin and compound U73122, inhibitors of PLC-catalyzed phosphoinositide hydrolysis, abolished hormone-dependent Ca(2+) influx in young but had no effect on aged cells. Higher basal adenylyl cyclase (AC) activity and cAMP content were detected in old enterocytes. PTH increased the absolute levels of cAMP in aged cells and AC activity of microsomes isolated therefrom to a greater extent (>/= twofold) than in young enterocytes/membranes. In young cells, the hormone also induced a rapid and transient release of inositoltrisphosphate (IP(3)) and diacylglycerol (neomycin-sensitive) at 45 sec, and a delayed phase of DAG at 5 min (neomycin-insensitive). The early formation of IP(3) and DAG was blunted in aged animals. These results suggest that both the PLC and adenylyl cyclase cascades are involved in PTH stimulation of Ca(2+) influx in duodenal cells. During aging, however, only the cAMP pathway is operative, mediating a potentiation of the effects of the hormone. Additional studies are required to establish the relative role of PTH-dependent messenger systems in the regulation of intestinal calcium absorption and age-related abnormalities.     

Dimethyl sulfoxide increases cytoplasmic Ca2+ concentration and inhibits parathyroid hormone release in normal bovine and pathological human parathyroid cells

The acute effects of dimethyl sulfoxide (DMSO) on parathyroid hormone (PTH) release and the cytoplasmic Ca2+ concentration (Ca2+i) were studied in dispersed bovine cells and cells isolated from human parathyroid adenomas. At extracellular Ca2+ concentrations in the 0.5-3.0 mM range, but not at less than 25 nM, addition of 2% DMSO caused a rapid rise of Ca2+i. This effect corresponded to an inhibition of PTH release and there was a strong negative correlation between Ca2+i and secretion. The actions of DMSO on Ca2+i and PTH release were less pronounced in the pathological human cells. The data are consistent with a DMSO effect on the Ca2+-sensor function of the parathyroid cell, possibly mediated by an altered plasma membrane fluidity.