Plasma Parathyroid Hormone Levels Research Articles

Parathyroid hormone-related protein, parathyroid hormone, and vitamin D in hypercalcemia of malignancy

The pathogenesis of cancer-associated hypercalcemia is not yet completely understood. In the majority of cancer patients, hypercalcemia appears to be a consequence of the tumor production of parathyroid hormone (PTH)-related protein (PTHrP). However, patients with humoral hypercalcemia of malignancy, in contrast to those with primary hyperparathyroidism, have an uncoupled bone turnover, and they usually have low circulating levels of 1,25(OH)2D3. We performed a case-control study to assess the relationship of plasma PTHrP, PTH and 1,25(OH)2D3 with hypercalcemia in cancer patients with a variety of tumors. Sixty of these patients had hypercalcemia, and 45 were normocalcemic. We measured PTHrP and PTH by immunoradiometric assay (Nichols), and 1,25(OH)2D3 by radioreceptor assay (Nichols), in plasma in both groups of cancer patients. Using a logistic regression analysis, we found that the higher PTHrP in plasma, the higher association with hypercalcemia occurred in these patients. In addition, the decreased plasma levels of PTH and 1,25(OH)2D3 in the majority of cancer patients were found to be significantly associated with hypercalcemia. Our results indicate that the combined determination of PTH, PTHrP and 1,25(OH)2D3 in plasma represents a more comprehensive approach to the investigation of hypercalcemia in cancer patients. Our data also support the role of PTHrP as a humoral factor responsible for hypercalcemia in these patients.

Evidence for the impairment of the vitamin D activation pathway by cyclosporine A

Cyclosporine A (CsA) is a potent immunosuppressant with the drawback of renal side effects. We reported that CsA markedly decreases calcium-binding protein calbindin-D28k mRNA levels in rat kidneys, and showed that this decrease is associated with its adverse renal effects. The transcription of the calbindin-D28k gene is activated via the vitamin D pathway. In this work, the potential CsA-mediated impairment of the vitamin D pathway was investigated. Wistar rats were treated for 12 days with 50 mg/kg/day CsA or for 20 days with 50 mg/kg/day of the non-immunosuppressant and non-nephrotoxic SDZ PSC 833, which had been previously shown not to affect calbindin-D28k mRNA levels. The expression of the three vitamin D-regulated genes calbindin-D28k, 1,25-dihydroxyvitamin D 3-24-hydroxylase (24-OHase), and vitamin D receptor (VDR) were quantified in rat kidney homogenates by real-time reverse transcription–polymerase chain reaction. Plasma parathyroid hormone (PTH) as well as plasma and kidney 1,25 dihydroxyvitamin D 3 (calcitriol) levels were monitored in all animals. CsA induced a 85% decrease in calbindin-D28k mRNA levels as well as a 40% and 69% decrease in VDR and 24-OHase mRNA levels, respectively. Plasma and kidney 1,25 dihydroxyvitamin D 3 as well as plasma PTH levels were increased by CsA, but not by SDZ PSC 833. The treatment with SDZ PSC 833 did not affect calbindin-D28k or VDR expression, but did cause a 73% decrease in 24-OHase mRNA levels. Taken together, these results indicate an association between CsA-mediated down-regulation of rat renal calbindin-D28k mRNA and the decrease in other 1,25 dihydroxyvitamin D 3-regulated genes, suggesting an impairment of the vitamin D pathway by CsA which may be related to its adverse renal side effects and its immunosuppressive activity.

Impaired Parathyroid Hormone Action on Urinary Phosphorus Excretion in Isolated Perfused Kidney of Streptozotocin-Induced Diabetic Rats

To study the effects of diabetes on the renal actions of parathyroid hormone (PTH), we observed urinary excretion of cyclic adenosine monophosphate (cAMP) and phosphorus in isolated perfused rat kidney. Diabetic rats were kept for 7 days after an intraperitoneal injection of 70 mg/kg streptozotocin (STZ). STZ-induced diabetic rats were treated with a daily injection of 20 U/kg lente-type insulin for 7 days. Plasma albumin, calcium, phosphorus, and PTH levels were not different among normal control, diabetic and insulin-treated diabetic groups. In the control rat kidney, the addition of PTH increased urinary cAMP excretion from 8 +/- 3 to 190 +/- 49 pmol/5 min and urinary phosphorus excretion from 11.3 +/- 4.4 to 33.6 +/- 10.8 microg/5 min. In the STZ-diabetic rat kidney, basal urinary cAMP was impaired, and PTH altered neither urinary cAMP nor phosphorus excretion (from below 0.7 to below 0.7 pmol/5 min, and from 15.5 +/-4.5 to 13.6 +/- 8.1 microg/5 min, respectively). Insulin treatment completely recovered the PTH actions. These results show that insulinopenic diabetes induces PTH resistance in the kidney.

Calcitonin is a major regulator for the expression of renal 25-hydroxyvitamin D 3 -1α-hydroxylase gene in normocalcemic rats

Regulation of vitamin D metabolism has long been examined by using vitamin D-deficient hypocalcemic animals. We previously reported that, in a rat model of chronic hyperparathyroidism, expression of 25-hydroxyvitamin D3-1alpha-hydroxylase (CYP27B1) mRNA was markedly increased in renal proximal convoluted tubules. It is believed that the major regulator for the expression of renal CYP27B1 is parathyroid hormone (PTH). However, in the normocalcemic state, the mechanism to regulate the renal CYP27B1 gene could be different, since plasma levels of PTH are very low. In the present study, the effect of PTH and calcitonin (CT) on the expression of renal CYP27B1 mRNA was investigated in normocalcemic sham-operated rats and normocalcemic thyroparathyroidectomized (TPTX) rats generated by either PTH or CaCl2 infusion. A single injection of CT dose-dependently decreased the expression of vitamin D receptor mRNA in the kidney of normocalcemic sham-TPTX rats. Concomitantly, CT greatly increased the expression of CYP27B1 mRNA in the kidney of normocalcemic sham-TPTX rats. CT also increased the expression of CYP27B1 mRNA in the kidney of normocalcemic TPTX rats. Conversion of serum [3H]1alpha,25(OH)2D3 from 25-hydroxy[3H]vitamin D3 in vivo was also greatly increased by the injection of CT into sham-TPTX rats and normocalcemic TPTX rats, but not into hypocalcemic TPTX rats. In contrast, administration of PTH did not induce the expression of CYP27B1 mRNA in the kidney of vitamin D-replete sham-TPTX rats and hypocalcemic TPTX rats. PTH increased the expression of renal CYP27B1 mRNA only in vitamin D-deficient hypocalcemic TPTX rats. These results suggest that CT plays an important role in the maintenance of serum 1alpha,25(OH)2D3 under normocalcemic physiological conditions, at least in rats.

Erythrocyte voltage-dependent calcium influx is reduced in hemodialyzed patients

Uremia displays increased cytosolic free calcium ([Ca2+]i) in many different cell types, supporting the hypothesis of an altered Ca2+ transport modifying the functional activity of calcium signaling pathway. Thirty-five hemodialyzed patients and 20 age-matched subjects were studied. Erythrocyte resting [Ca2+]i and Ca2+ influx were measured by the fluorescent Ca2+-sensitive dye fura-2. We found an increase of resting [Ca2+]i in erythrocytes from uremic hemodialyzed patients compared with matched healthy controls (103 +/- 2.5 nM, N = 20, vs. 90 +/- 4, N = 20, P < 0.01). Moreover, we found an altered voltage-dependent Ca2+ influx showing a reduced transport rate (0.42 +/- 0.03 nM/second vs. 0.74 +/- 0.08, P < 0.01). High levels of plasma parathyroid hormone (PTH) were related to augmented Ca2+ entry (r = 0.511, P < 0.05), contributing to maintain a high level of [Ca2+]i. Hemodialysis had no effect on cell calcium level and Ca2+ influx indices. The therapy with Ca2+ antagonists did not modify the values of resting [Ca2+]i or Ca2+ influx indices, but the correlation between PTH and influx indices was lost. In conclusion, we found evidence for an alteration of erythrocyte Ca2+ influx caused by uremic toxicity that could be related to some organ disorders in uremia. The chronic increase of cellular calcium may contribute to influx derangement.

Capacity of a Low Calcium Diet to Induce the Renal Vitamin D 1a-Hydroxylase Is Decreased in Adult Rats

Young animals adapt to a low calcium diet by increasing renal production of 1,25-dihydroxyvitamin D [1,25(OH)2D], the active metabolite of vitamin D. However, the capacity of adult animals to adapt is markedly diminished. With the recent cloning of the cytochrome P450 component (CYP1a) of the renal 1-hydroxylase enzyme complex, it is now possible to determine directly the effect of dietary calcium and maturation on the expression of renal 1-hydroxylase. Using a ribonuclease protection assay, it was found that feeding a low Ca diet markedly increased renal CYP1a mRNA levels in young rats. However, feeding this diet to adult rats produced an increase in CYP1a mRNA that was only 10% that of the young rats. These studies demonstrate that a low calcium diet increases renal 1,25-dihydroxyvitamin D production in young animals but not in adult animals by increasing CYP1a expression. Since the low calcium diet increased plasma parathyroid hormone levels to similar levels in both age groups, this suggests that in the adult there is a renal refractoriness to parathyroid hormone.

The calcimimetic NPS R-568 decreases plasma PTH in rats with mild and severe renal or dietary secondary hyperparathyroidism.

NPS R-568 is a Ca2+ receptor agonist ("calcimimetic") compound that reduces circulating parathyroid hormone (PTH) levels in rats and humans with mild secondary hyperparathyroidism (secondary HPT) resulting from chronic renal insufficiency (CRI). These studies extend those observations to show that NPS R-568 is equally effective in decreasing plasma PTH and Ca2+ levels in rats with mild or severe secondary HPT, resulting either from CRI or from dietary calcium deficiency. Male rats were 5/6 nephrectomized and fed either normal chow or a high-phosphorus diet; other normal rats were fed a low-calcium diet. When secondary HPT had developed, NPS R-568 was administered and blood samples were collected for up to 6 h. PTH levels decreased to a minimum level within 30 min in both CRI and calcium deficiency models of secondary HPT. PTH and Ca2+ levels remained significantly depressed for >3 h after dosing. The percentage decrease in PTH levels was unaffected by the severity of secondary HPT or the basal plasma Ca2+ or phosphate levels. In rats with severe secondary HPT, the minimum plasma PTH level after NPS R-568 was greater than the basal level in mild secondary HPT. Thus, NPS R-568 is equally effective in suppressing plasma PTH and Ca2+ levels in rats with mild or severe renal or nutritional secondary HPT.

Calcimimetics with potent and selective activity on the parathyroid calcium receptor.

Parathyroid hormone (PTH) secretion is regulated by a cell surface Ca2+ receptor that detects small changes in the level of plasma Ca2+. Because this G protein-coupled receptor conceivably provides a distinct molecular target for drugs useful in treating bone and mineral-related disorders, we sought to design small organic molecules that act on the Ca2+ receptor. We discovered that certain phenylalkylamine compounds, typified by NPS R-568 and its deschloro derivative NPS R-467, increased the concentration of cytoplasmic Ca2+ ([Ca2+]i) in bovine parathyroid cells and inhibited PTH secretion at nanomolar concentrations. These effects were stereoselective and the R enantiomers were 10- to 100-fold more potent than the S enantiomers. NPS R-568 potentiated the effects of extracellular Ca2+ on [Ca2+]i and PTH secretion but was without effect in the absence of extracellular Ca2+. Both compounds shifted the concentration-response curves for extracellular Ca2+ to the left. Presumably, these compounds act as positive allosteric modulators to increase the sensitivity of the Ca2+ receptor to activation by extracellular Ca2+. Both NPS R-467 and NPS R-568 increased [Ca2+]i in HEK 293 cells expressing the human parathyroid Ca2+ receptor but were without effect in wild-type HEK 293 cells. Neither compound affected the cytoplasmic Ca2+ responses elicited by several other G protein-coupled receptors in HEK 293 cells or in bovine parathyroid cells. Significantly, these compounds did not affect responses elicited by the homologous metabotropic glutamate receptors, mGluR1a, mGluR2, or mGluR8. These compounds therefore act selectively on the Ca2+ receptor. Compounds that mimic or potentiate the effects of extracellular Ca2+ at the Ca2+ receptor are termed calcimimetics. The discovery of calcimimetic compounds with potent and selective activity enables a pharmacological approach to regulating plasma levels of PTH. Calcimimetic compounds could conceivably provide a specific medical therapy for primary hyperparathyroidism.

Randomized crossover study comparing the phosphate-binding efficacy of calcium ketoglutarate versus calcium carbonate in patients on chronic hemodialysis

The objective of the study was to evaluate the phosphate-binding efficacy, side effects, and cost of therapy of calcium ketoglutarate granulate as compared with calcium carbonate tablets in patients on chronic hemodialysis. The study design used was a randomized, crossover open trial, and the main outcome measurements were plasma ionized calcium levels, plasma phosphate levels, plasma intact parathyroid hormone (PTH) levels, requirements for supplemental aluminum- aminoacetate therapy, patient tolerance, and cost of therapy. Nineteen patients on chronic hemodialysis were treated with a dialysate calcium concentration of 1.25 mmol/L and a fixed alfacalcidol dose for at least 2 months. All had previously tolerated therapy with calcium carbonate. Of the 19 patients included, 10 completed both treatment arms. After 12 weeks of therapy, the mean (+/-SEM) plasma ionized calcium level was significantly lower in the ketoglutarate arm compared with the calcium carbonate arm (4.8+/-0.1 mg/dL v 5.2+/-0.1 mg/dL; P = 0.004), whereas the mean plasma phosphate (4.5+/-0.3 mg/dL v 5.1+/-0.1 mg/dL) and PTH levels (266+/-125 pg/mL v 301+/-148 pg/mL) did not differ significantly between the two treatment arms. Supplemental aluminum-aminoacetate was not required during calcium ketoglutarate treatment, while two patients needed this supplement when treated with calcium carbonate. Five of 17 (29%) patients were withdrawn from calcium ketoglutarate therapy within 1 to 2 weeks due to intolerance (anorexia, vomiting, diarrhea, general uneasiness), whereas the remaining 12 patients did not experience any side effects at all. The five patients with calcium ketoglutarate intolerance all had pre-existing gastrointestinal symptoms; four of them had received treatment with cimetidine or omeprazol before inclusion into the study. Calculations based on median doses after 12 weeks showed that the cost of the therapy in Denmark was 10 times higher for calcium ketoglutarate compared with calcium carbonate (US$6.00/d v US$0.65/d). Calcium ketoglutarate may be an effective and safe alternative to treatment with aluminum-containing phosphate binders in patients on hemodialysis who are intolerant of calcium carbonate or acetate because of hypercalcemia. However, care must be exercised when dealing with patients with pre-existing gastrointestinal discomfort. Due to the high cost of the therapy, calcium ketoglutarate should be used only for selected patients. (Am J Kidney Dis 1998 Feb;31(2):257-62)

Renal function in hyperbaric environment.

During mixed gas saturation diving (to 3-49.5 ATA) daily urine flow increases by about 500 ml/day, with no changes in fluid intake and glomerular filtration rate. The diuresis is accompanied by a significant decrease in urine osmolality and increase in excretion of such solutes as urea, K+, Na+, Ca2+ and inorganic phosphate (Pi). The fall in urine osmolality is mainly due to a reduction of free water reabsorption which is associated with a suppression of insensible water loss and the attendant inhibition of antidiuretic hormone (ADH) system. The increase in urea excretion may be associated with a reduction of urea reabsorption at the collecting duct as a consequence of ADH suppression. The rise in K+ excretion is due to a facilitated K+ secretion at the distal tubule as a result of increased aldosterone, urine flow and excretion of impermeable anions such as Pi. The activation of aldosterone system is partly attributed to a transient dehydration induced by early hyperbaric diuresis. The increase in Na+ excretion in the face of enhanced aldosterone secretion indicates that the Na+ transport in the proximal tubule is markedly inhibited (by unknown mechanism). The Pi excretion increases with no changes in plasma level of parathyroid hormone (PTH), thus it may be due to an inhibition of Na(+)-Pi cotransport in the proximal tubule. The increase in Ca2+ excretion may be secondary to the inhibition of Na+ transport at the proximal tubule. Precise information on the proximal tubular Na+ transport is important to understand the mechanisms of impaired solute transport under hyperbaric conditions.

Interleukin-1 beta, -6 and interferon-gamma productions in patients undergoing continuous ambulatory peritoneal dialysis.

In order to investigate cytokine productions in patients undergoing continuous ambulatory peritoneal dialysis (CAPD), we studied the production of interleukin (IL)-1 beta, -6 and interferon (IFN)-gamma by cultured peripheral blood mononuclear cells (PBMC) in peritonitis-free CAPD patients. The correlation of cytokine production with plasma parathyroid hormone (PTH) and albumin levels was also evaluated. While the release of IL-1 beta was not markedly different from controls release of IL-6 from 24-hour cultured PBMCs was significantly greater than that of controls, (Mean +/- S.D., IL-6: 2186.8 +/- 1217.9 pg/ml, vs 1516.3 +/- 767.9, p < 0.05). The addition of lipopolysaccharide (LPS, 10 micrograms/ml, significantly stimulated IL-1 beta and -6 production of PBMCs in CAPD patients and controls, compared to an unstimulated condition. The LPS-induced IL-1 beta production was also not markedly different from controls, whereas LPS-induced IL-6 production was significantly higher than controls (IL-6: 13,220.7 +/- 7177.4 vs 7411.4 +/- 1236.9, p < 0.05). However, the percentage increases of IL-6 production stimulated with LPS in CAPD patients were not significantly different from controls (p > 0.05). No difference of baseline IFN-gamma was detected between CAPD patients controls, but phytohemagglutinin (PHA, 10 micrograms/ml)-stimulated IFN-gamma release was significantly higher in CAPD patients than controls (2425.9 +/- 1565.0 pg/ml vs 1364.0 +/- 755.1, p < 0.05). There was no significant correlation between PTH and, IL-1 beta, serum albumin level and LPS-stimulated IL-6 production (r = 0.54, p < 0.05). In conclusion, CAPD seems to partly induce activation of PBMCs with an enhanced release of IL-6 and IFN-gamma, and CAPD patients with higher serum albumin levels tend to show higher IL-6 production in immune response.

Cardiovascular actions of parathyroid hormone and parathyroid hormone-related peptide.

Cardiovascular cells (cardiomyocytes and smooth muscle cells) are target cells for parathyroid hormone (PTH) and the structurally related peptide parathyroid hormone-related peptide (PTH-rP). PTH activates protein kinase C (PKC) of cardiomyocytes via a PKC activating domain previously identified on chondrocytes. Activation of PKC leads to hypertrophic growth and re-expression of fetal type proteins in cardiomyocytes. This hypertrophic effect of PTH might contribute to left ventricular hypertrophy in hemodialysis patients with secondary hyperparathyroidism. PTH-rP is expressed in cardiovascular cells (endothelial cells and smooth muscle cells). It does not mimic the above described actions of PTH but exerts effects of its own on cardiomyocytes. These effects involve activation of protein kinase A, via a N-terminal domain distinct from that identified on PTH, and activation of PKC, via a C-terminally located domain distinct from that found on PTH. On smooth muscle cells PTH and PTH-rP reduce the influence of extracellular calcium, through cAMP-dependent mechanisms. These inhibitory effects on voltage-dependent L-type calcium channels of smooth muscle cells cause vasorelaxation. Present studies concerning cardiovascular actions of either PTH and PTH-rP suggest that increased plasma levels of PTH and PTH-rP influence cardiomyocyte and smooth muscle cell physiology. It can be assumed that PTH-rP acts as a paracrine or autocrine modulator in heart and vessels.

A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure: Rapid Communication

The control of hyperparathyroidism in patients with chronic renal failure continues to be a problem, particularly when parathyroid hormone (PTH) suppression becomes refractory to calcitriol activation of parathyroid cell 1,25-dihydroxyvitamin D receptors. To evaluate whether parathyroid cell calcium receptor activation may be useful in suppressing PTH levels, we tested the safety and effectiveness of a novel calcimimetic agent in dialysis patients with hyperparathyroidism. In a prospective, dose finding study, the calcimimetic agent, NPS R-568, was administered orally to seven patients at the start of a hemodialysis session and again 24 hours later. Plasma PTH, calcitonin and ionized calcium levels were measured over a 48 hour period and patients were observed for adverse events. Plasma PTH levels fell abruptly in all patients after a single dose of the compound, with the maximum suppression occurring within one to two hours after its administration. Following the administration of low doses (40 or 80 mg), the suppressed PTH levels rose to baseline values over 48 hours, whereas in patients who received high doses (120 or 200 mg) the mean PTH level remained 51% below baseline. Plasma calcitonin increased after the administration of both low and high doses (peak effect within 4 to 6 hr), with levels always returning to baseline by 48 hours. There were no episodes of hypocalcemia and no adverse effects were reported. We conclude that the activation of parathyroid cell calcium receptors by a novel calcimimetic compound is safe and effective in acutely suppressing PTH secretion in dialysis patients with hyperparathyroidism. Whether concomitant stimulation of calcitonin secretion will provide added beneficial effects on bone remodeling remains to be determined in long-term studies.

Calcium Concentration in the Capd Dialysate: What is Optimal and is There a Need to Individualize?

To evaluate risk/benefit of various continuous ambulatory peritoneal dialysis (CAPD) dialysate calcium concentrations. A review of the literature on the effects of various CAPD dialysate Ca concentrations on plasma Ca, plasma phosphate, plasma parathyroid hormone (PTH), doses of calcium carbonate, doses of vitamin D analogs, and requirements of aluminum-containing phosphate binders. Eleven studies of nonselected CAPD patients, and 13 studies of CAPD patients with hypercalcemia were reviewed. In nonselected CAPD patients, treatment with a reduced dialysate Ca concentration (1.00, 1.25, or 1.35 mmol/L) improved the tolerance to calcium carbonate and/or vitamin D metabolites and reduced the need for Al-containing phosphate binders. When using dialysate Ca 1.25 or 1.35 mmol/L, the initial decrease of plasma Ca and increase of PTH could easily be reversed with an immediate adjustment of the treatment. After 3 months, stable plasma Ca and PTH levels could be maintained using only monthly investigations. In patients with hypercalcemia and elevated PTH levels, treatment with dialysate Ca concentrations below 1.25 mmol/L implied a considerable risk for the progression of secondary hyperparathyroidism. When hypercalcemia was present in combination with suppressed PTH levels, a controlled increase of PTH could be obtained with a temporary discontinuation of vitamin D and/or a reduction of calcium carbonate treatment in combination with a dialysate Ca concentration of 1.25 or 1.35 mmol/L. Most CAPD patients can be treated effectively and safely with a reduced dialysate Ca concentration of 1.35 or 1.25 mmol/L. Treatment with dialysate Ca concentrations below 1.25 mmol/L should not be used. A small fraction of patients with persistent hypocalcemia need treatment with high dialysate Ca, such as 1.75 mmol/L.

Spinal Cord Compression by Heterotopic Ossification Associated with Pseudohypoparathyroidism

This report describes a 37-year-old man presenting with a gait disturbance due to spastic paraparesis. Physical findings showed typical features of Albright's hereditary osteodystrophy, including short stature, obesity, brachydactyly and dental hypoplasia. He was diagnosed as having pseudohypoparathyroidism type Ia, on the basis of his hypocalcaemia, hyperphosphataemia, increased plasma level of parathyroid hormone (PTH), and the unresponsiveness to exogenous PTH loading of his urinary excretion of both nephrogenous cyclic adenosine monophosphate and phosphate. Magnetic resonance imaging and myelographic computed tomographic scans clearly demonstrated severe compression of the spinal cord at T 9/10 by tumour-like ossifications of the paravertebral ligaments. Neurosurgical decompression therapy was, therefore, performed to alleviate his spastic paraparesis. This was a rare case of pseudohypoparathyroidism complicated with spinal cord compression caused by ectopic ossification of the ligaments.

Abnormal sulfate metabolism in vitamin D-deficient rats.

To explore the possibility that vitamin D status regulates sulfate homeostasis, plasma sulfate levels, renal sulfate excretion, and the expression of the renal Na-SO4 cotransporter were evaluated in vitamin D-deficient (D-D-) rats and in D-D- rats rendered normocalcemic by either vitamin D or calcium/lactose supplementation. D-D- rats had significantly lower plasma sulfate levels than control animals (0.93+/-0.01 and 1.15+/-0.05 mM, respectively, P < 0.05), and fractional sulfate renal excretion was approximately threefold higher comparing D-D- and control rats. A decrease in renal cortical brush border membrane Na-SO4 cotransport activity, associated with a parallel decrease in both renal Na-SO4 cotransport protein and mRNA content (78+/-3 and 73+/-3% decreases, respectively, compared with control values), was also observed in D-D- rats. Vitamin D supplementation resulted in a return to normal of plasma sulfate, fractional sulfate excretion, and both renal Na-SO4 cotransport mRNA and protein. In contrast, renal sulfate excretion and renal Na-SO4 cotransport activity, protein abundance, and mRNA remained decreased in vitamin D-depleted rats fed a diet supplemented with lactose and calcium, despite that these rats were normocalcemic, and had significantly lower levels of parathyroid hormone and 25(OH)- and 1,25(OH)2-vitamin D levels than the vitamin D-supplemented groups. These results demonstrate that vitamin D modulates renal Na-SO4 sulfate cotransport and sulfate homeostasis. The ability of vitamin D status to regulate Na-SO4 cotransport appears to be a direct effect, and is not mediated by the effects of vitamin D on plasma calcium or parathyroid hormone levels. Because sulfate is required for synthesis of essential matrix components, abnormal sulfate metabolism in vitamin D-deficient animals may contribute to producing some of the abnormalities observed in rickets and osteomalacia.

Plasma levels of parathyroid hormone that induce anabolic effects in bone of ovariectomized rats can be achieved by stimulation of endogenous hormone secretion

Parathyroid hormone (PTH) administration increases bone mass in normal and osteopenic animals. However, this treatment currently requires the daily injection of large amounts of PTH, and the relationship of these doses to plasma levels of PTH that are achievable physiologically is unknown. We determined in ovariectomized (ovx) rats: 1) the plasma PTH levels that occur after the subcutaneous injection of graded doses of rat PTH, 2) whether similar PTH levels can be achieved by stimulation of endogenous PTH secretion, and 3) whether a plasma PTH profile that is achievable physiologically is anabolic on bone. Injection of 1, 5, or 25 μg/kg rat PTH-(1–34) increased plasma PTH by 46, 164, or 520 pg/mL, respectively, above basal levels within 60 min. Infusion of ethylene glycol- bis(β-aminoethyl ether)- N,N,N′,N′-tetraacetic acid for 2 h reduced plasma Ca 2+ by 0.36 mmol/L and produced a total plasma PTH response (area under the plasma PTH curve) similar to that with the 5 μg/kg rat PTH injection. Then, 1, 5, or 25 μg/kg doses or rat PTH-(1–34) were injected subcutaneously daily for 28 days in 19-week-old rats that were ovx 7 weeks earlier. The 5 and 25 μg/kg doses significantly increased bone mineral density in the distal femur and trabecular bone area and average trabecular thickness in the proximal tibia. All doses of PTH significantly increased indices of trabecular connectivity and cancellous bone formation, including double-labeled surface, mineralizing surface, and surface-referent bone formation rate. In conclusion, anabolic effects on bone can be achieved with a plasma PTH profile similar to that attained following stimulation of the parathyroid gland by induced hypocalcemia. These data suggest that agents that transiently increase endogenous PTH secretion may represent a novel means to promote anabolic effects in skeletal tissues.

Phosphate and cyclic AMP excretion decreases during less than 12 hours of hypoxia in conscious rats.

Hypocapnia is known to have an antiphosphaturic effect that overcomes the phosphaturic effect of hypoxia. The objective of this study was to examine whether conscious rats exposed to acute hypoxia show a decrease in phosphate excretion due to the concomitant hypocapnia. Wistar rats weighing 200 g were exposed to hypoxia (inspired oxygen fraction = 0.10) or normoxia (inspired oxygen fraction = 0.21) for 6 h; and rats were alternately exposed to hypoxia or normoxia every 12 h for a total 36 h. Renal clearance and hormone studies were performed. Rats exposed to 6 h of hypoxia (n = 11) showed significant hypophosphaturia and decreases in absolute and fractional excretion of phosphate (0.38 +/- 0.10 microgram min-1, mean +/- SE, P < 0.0001 and 0.59 +/- 0.15%, P < 0.0001) as compared with normoxic rats (n = 11, 3.91 +/- 0.68 micrograms min-1 and 5.62 +/- 0.85%). In addition, nephrogenous adenosine 3',5'-cyclic monophosphate level per glomerular filtrate was significantly decreased (-0.87 +/- 0.64 nmol dL GF-1, P < 0.05) and plasma parathyroid hormone level was unchanged (45.2 +/- 9.5 pg mL-1) after 6 h of hypoxia as compared with normoxic rats (4.03 +/- 1.83 nmol dL GF-1 and 54.3 +/- 10.4 pg mL-1). A parallel increase in urinary noradrenaline and a decrease in dopamine excretion was observed in rats after 6 h of hypoxia. The decreased phosphate and adenosine 3',5'-cyclic monophosphate excretion during acute hypoxia were restored to normoxic levels by reoxygenation with 21% oxygen in the study of 12-h intermittent hypoxia. In summary, (1) hypoxia produced by inhalation of 10% oxygen for 12 h or less causes reduced phosphate and adenosine 3',5'-cyclic monophosphate (cAMP) excretion by spontaneously breathing rats; (2) these effects are reversed by reoxygenation and (3) hypoxia elicits a parallel increase in noradrenaline excretion and a decrease in dopamine excretion. These data suggest that renal adrenergic and dopaminergic systems play important roles in hypophosphaturia during acute hypoxia in conscious rats.

Early increase in plama parathyroid hormone levels following liver transplantation

Background/Aims: The pathogenesis of post-transplantation bone loss is poorly understood, although glucocorticoid therapy is believed to play an important role. In the present study we have measured plasma parathyroid hormone concentrations in the first few months after orthotopic liver transplantation, in order to examine the potential contribution of hyperparathyroidism to bone disease. Patients and Methods: Twenty-seven patients aged 32–54 years, 12 male, undergoing liver transplantation were studied prospectively before and for 3 months after operation. Plasma parathyroid hormone and serum 25-hydroxyvitamin D concentrations were measured by radioimmunoassay. Results: Plasma parathyroid hormone levels were normal in all but two patients prior to transplantation. There was a highly significant increase in plasma parathyroid hormone concentrations at 1 and 2 months ( p<0.0005 and 0.001, respectively, versus baseline); by 3 months, values were close to those obtained preoperatively. Serum 25-hydroxyvitamin D concentrtions showed no significant change over the study period. However, 74% of the patients had subnormal values at baseline. Conclusions: An early and transient increase in plasma parathyroid hormone after liver transplantation may be responsible for the high rates of bone loss which occur during the first few post-operative months. Prevention of post-transplantation bone disease is most likely to be achieved by peri-operative intervention with an anti-resorptive agent.

Effects of new vitamin D analogues on parathyroid function in chronically uraemic rats with secondary hyperparathyroidism

Treatment with calcitriol or its analogue, alfacalcidol often leads to hypercalcaemia, hyperphosphataemia or both in patients which chronic renal failure and advanced secondary hyperparathyroidism. We tested three new vitamin D analogues (CB 1093, EB 1213, GS 1725) in an attempt to identify potentially non hypercalcaemic compounds, capable of decreasing plasma parathyroid hormone (PTH) concentration. Male Wistar AF rats aged 12-14 weeks were fed a synthetic, phosphate-rich diet and underwent either sham surgery (control) or a standard two-step 5/6th nephrectomy. Four weeks later, renal function was mildly decreased in the latter. Chronic renal failure rats were then divided into six groups, with 8-10 rats in each group. They received daily 1.p. injections, from days 0 to 4, of either placebo, calcitriol, or one of the following three active vitamin D analogues: CB1093, 0.25 micrograms; EB1213, 0.25 or 1.25 micrograms; and GS1725, 0.025 micrograms/kg body weight per day, respectively. Sham-operated rats received no drug. On day 5, arterial blood was sampled and rats were sacrificed. At predefined dosage schedules, all three compounds significantly decreased plasma immunoreactive PTH levels (except EB1213 at low dose). The decrement was somewhat less marked than that obtained with calcitriol, at the dose of 0.25 micrograms/kg b.w. per day. However, calcitriol induced a marked increase in plasma calcium and phosphate concentrations at that dose, whereas vitamin D analogues led to a more modest increase in plasma calcium level, and none to a worsening of hyperphosphataemia. CB1093 treatment was even associated with a significant decrease in plasma phosphate level. All three calcitriol analogues tested are promising as non-hypercalcaemic agents in the treatment of uraemic secondary hyperparathyroidism. However, more prolonged administration to uraemic rats of calcitriol analogues with slightly modified dosage schedules and of calcitriol with lower non-hypercalcaemic dose is required for an optimal comparison before considering clinical trials.