Urinary Cyclic AMP Research Articles

The effects of muscle-building exercise on bone mineral density of the radius, spine, and hip in young men

We previously demonstrated that muscle-building exercise is associated with increases in serum Gla-protein, serum 1,25(OH)2D, and urinary cyclic AMP. These studies were interpreted to mean that this form of exercise increases bone formation and modifies the vitamin D-endocrine system to provide more calcium for bone. The present investigation was carried out in normal young adult white men to determine the effects of exercise on bone mineral density at weight-bearing and nonweight-bearing sites. Twelve men who had regularly engaged in muscle-building exercises (use of weights, exercise machines, or both) for at least 1 year and 50 age-matched controls (aged 19-40 years) were studied. The body weights of the two groups were not different from each other (78 +/- 2 vs. 74 +/- 1 kg, NS). Bone mineral density (BMD) of the lumbar spine, trochanter, and femoral neck was measured by dual-photon absorptiometry, and BMD of the midradius was measured by single photon absorptiometry. It was found that muscle-building exercise was associated with increased BMD at the lumbar spine (1.35 +/- 0.03 vs. 1.22 +/- 0.02 g/cm2, P less than 0.01), trochanter (0.99 +/- 0.04 vs. 0.86 +/- 0.02 g/cm2, P less than 0.01), and femoral neck (1.18 +/- 0.03 vs. 1.02 +/- 0.02 g/cm2, P less than 0.001) but not at the midradius (0.77 +/- 0.02 vs. 0.77 +/- 0.01 g/cm2, NS). These studies provide additional evidence that muscle-building exercise is associated with increases in BMD at weight-bearing sites but not at nonweight-bearing sites.

上部尿路結石症に対する食事性蛋白質の影響についての実験的・臨床的研究

The effect of dietary protein load on the incidence of nephrolithiasis was studied in rats and men. Three groups of adult male Wister rats were fed with a standard protein diet, a high protein diet, or a low protein diet for 4 weeks. In the high protein group, calcium excretion was significantly increased and citrate excretion was remarkably decreased. This group also exhibited low grade metabolic acidosis due to catabolism of excess amino acids, and increases in urinary cyclic AMP excretion and bone resorption. These findings indicate that protein-induced hypercalciuria is due to low grade metabolic acidosis, which directly affects renal handling of calcium. Long-term calcium loss in the urine may lead to negative calcium balance and hyperfunction of the parathyroid gland may induce bone resorption. The influence of 40 g animal protein load on urinary risk factors of calcium stone formation was investigated in 23 healthy males and 26 patients with nephrolithiasis. All subjects were given control diets each day containing 60 g protein for a week and during the next week each received an additional 40 g animal protein. In the controls, added dietary protein resulted in decreased urinary citrate and increased urinary uric acid, with no change in urinary calcium or cyclic AMP excretion. In contrast, the patients showed increased urinary calcium and cyclic AMP as well as decreased urinary citrate. Further examination of the patients revealed that the significant increases of calcium and cyclic AMP excretion occurred only in hypercalciuric patients, who seemed to be classified into renal hypercalciuria.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetate and hypercalciuria during total parenteral nutrition.

Hypercalciuria and negative calcium balance are complications of total parenteral nutrition (TPN). Because metabolism of the TPN formula generates an acid load that can induce hypercalciuria, we evaluated the effect of supplementing the formula with acetate. In a randomized crossover study six patients on continuous and six on cyclic TPN received no added acetate or 160 mmol acetate/d replacing 160 mmol chloride/d for 3 d each. Blood and urine measurements were obtained on day 3 of each formula. Acetate, which is metabolized to bicarbonate, increased blood pH and decreased renal acid excretion. Urinary Ca decreased in every patient from 422 +/- 63 to 240 +/- 46 mg/d (10.5 +/- 1.6 to 6.0 +/- 1.4 mmol/d) and from 468 +/- 68 to 285 +/- 54 mg/d (11.7 +/- 1.7 to 7.1 +/- 1.3 mmol/d) during continuous and cyclic TPN, respectively. Filtered Ca load decreased slightly whereas renal tubular Ca reabsorption increased significantly with acetate. Serum parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and urinary cyclic AMP were not different.

Evidence of a probable role for 25-hydroxyvitamin D in the regulation of human calcium metabolism.

1,25-Dihydroxyvitamin D [1,25-(OH)2D] is the principal mediator of the biologic effects of vitamin D. We showed previously that obese white subjects have low serum vitamin D and 25-hydroxyvitamin D (25-OHD) with increased serum-immunoreactive parathyroid hormone (PTH) and 1,25-(OH)2D, low urinary calcium, and increased urinary cyclic adenosine 3',5'-monophosphate (cyclic AMP) compared with nonobese white individuals. To determine whether 25-OHD modulates calcium metabolism, the effects of 25-OHD3, 40-100 micrograms/day for 9 days, were compared in seven obese and seven nonobese white subjects who were between the ages of 20 and 34 years. Each of them was hospitalized on a metabolic ward and given a constant daily diet that contained 400 mg calcium, 900 mg phosphate, and 18 mEq magnesium. Whereas 25-OHD3 increased mean serum 25-OHD from 7 +/- 1 to 37 +/- 5 ng/ml (P less than 0.01) and urinary calcium from 102 +/- 18 to 146 +/- 17 mg/day (P less than 0.001) and decreased mean serum 1,25-(OH)2D from 40 +/- 2 to 28 +/- 2 pg/ml (P less than 0.01) and urinary cyclic AMP from 3.23 +/- 0.57 to 2.00 +/- 0.17 nM/dl GF (P less than 0.05), it did not change mean serum calcium, ionized calcium, phosphate, magnesium, immunoreactive PTH or urinary phosphate, or creatinine clearance in the obese subjects. In contrast, 25-OHD3 increased mean serum 25-OHD from 16 +/- 1 to 46 +/- 4 pg/ml (P less than 0.001) but did not alter mean serum 1,25-(OH)2D or urinary calcium or cyclic AMP in the nonobese subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of phosphorus on endogenous calcium losses during total parenteral nutrition

Intravenous phosphorus can reduce urinary calcium losses in patients receiving total parenteral nutrition (TPN). We investigated the effect of intravenous P on urinary and fecal Ca loss in intravenously fed normal and thyroparathyroidectomized (TPTX) rats to assess the role of parathyroid hormone (PTH) and endogenous fecal Ca losses. Doubling the intravenous P load during TPN decreased urinary Ca losses by 54% (0.299 vs 0.137 mmol/d) in intact rats and by 43% (0.514 vs 0.294 mmol/d) in TPTX rats. Increased P load in normal rats had no effect on urinary cyclic AMP excretion, serum Ca, serum P, serum 1,25-dihydroxycholecalciferol, or endogenous fecal Ca losses. These observations suggest that the hypocalciuric effect of P during TPN is independent of PTH and is not caused by a repartitioning of obligatory Ca losses from the renal to the intestinal route.

A hypercalcemic nude rat model that completely mimics human syndrome of humoral hypercalcemia of malignancy.

Tumors causing humoral hypercalcemia of malignancy (HHM) were implanted to athymic nude rats. In one of these rat models transplanted with uterine cancer (UCC), a complete reproduction of human HHM syndrome was achieved: hypercalcemia, hypophosphatemia with increased urinary phosphate and cyclic AMP excretion, and suppressed serum 1,25-dihydroxy-vitamin D (1,25(OH)2D) level. In another hypercalcemic nude rat model implanted with oral cavity cancer (OCC), all the features were similar except for markedly elevated serum 1,25(OH)2D. Hypercalcemia disappeared by surgical removal of the tumors in both models, confirming the humoral mechanisms for causing these features. Furthermore, in UCC tumor-bearing rats, hypophosphatemia, increased renal phosphate excretion, and reduced serum 1,25(OH)2D concentration were already present when these rats were only marginally hypercalcemic. These results raise the possibility that the changes in renal tubular phosphate handling and vitamin D metabolism in HHM are not secondary to hypercalcemia but are due to direct effects of the humoral factor(s) that cause this syndrome. Extracts of both tumors exhibited stimulation of cyclic AMP production in osteoblastlike cells, UMR 106, which could be almost completely inhibited by parathyroid hormone (PTH) antagonist, human PTH(3-34). By comparing the nature and characteristics of humoral factor(s) from UCC and OCC models, mechanisms responsible for causing these abnormalities can be explored. Thus, these nude rat models can be useful for elucidating the underlying mechanism of the development of HHM.

The effect of intravenous magnesium sulphate on parathyroid function in primary hyperparathyroidism.

AbstractTen patients with primary hyperparathyroidism caused by enlargement of a single parathyroid gland were studied preoperatively. An intravenous bolus of 4 g magnesium sulphate followed by a continuous infusion of 2 g per hour for 3 hours increased serum magnesium from 0.76 to 2.12 mmol/l (median values,p <0.005). Serum C‐terminal parathyroid hormone (PTH) decreased from 94 to 78 pmol/l (p <0.005), and serum intact PTH from 7.0 to 4.8 pmol/l (p <0.008). The PTH changes preceded decreases in serum total calcium from 2.79 to 2.55 mmol/1 (p <0.01), and serum ionized calcium from 1.52 to 1.45 mol/1 (p <0.007). Urinary calcium excretion increased and urinary phosphate excretion decreased. Serum phosphorus, pH, albumin, creatinine, alkaline phosphatase, and urinary cyclic AMP showed no significant changes. The study showed that an intravenous magnesium sulphate infusion which at least doubled the normal serum magnesium concentration significantly suppressed PTH secretion in patients with primary hyperparathyroidism and subsequently reduced the serum calcium concentration.

Diagnosis and treatment of Zollinger-Ellison syndrome

A diagnostic and therapeutic strategy for the management of patients with Zollinger-Ellison syndrome has been developed, based on the review of a large personal experience and the most recent literature. The mainstay of a modern ZES management is the eradication of tumoral processes whenever feasible. Diagnosis is centred upon gastric acid and gastrin secretion measurements both in basal conditions and on secretin stimulation. Recognition of other endocrine involvement and familial inheritance is of the utmost importance in distinguishing sporadic ZES patients from those who have the condition known as multiple endocrine neoplasia type I. Blood calcium and phosphorus levels, parathyroid hormone concentration, combined if necessary with urinary cyclic AMP excretion measurement, should be performed routinely once ZES diagnosis is established or highly suspected. Localization of the tumour is the next essential step, and this has been considerably facilitated by the recent development in imaging techniques: it involves computerized axial tomography and selective abdominal angiography, a combination of which allows tumour detection in 60-70% of sporadic gastrinoma patients, with a maximal sensitivity for well-developed hepatic metastases. In sporadic ZES exploratory laparotomy is legitimate when preoperative localization of the tumour has failed; this laparotomy will allow further detection and then eradication of gastrinomas in a significant number of patients. Control of gastric acid secretion is mandatory throughout the work-up period; modern antisecretory agents are efficacious in most cases; total gastrectomy, when control of acid hypersecretion has failed, is now exceptional. Eradication of the tumour should be attempted in cases of sporadic ZES in the absence of recognizable liver involvement. The chance of a definite cure provided by surgery when performed by an experienced surgeon varies from 20% to 60% in pancreatic and ectopic gastrinomas respectively. In ZES patients with MEN I, exploratory laparotomy is seldom indicated (other than for symptomatic associated endocrine secretion), as the chance of a definite cure by surgery is very rare. Parathyroid surgery is often indicated and should take place before any form of abdominal surgery. In cases of hepatic metastases, chemotherapy with streptozocin and fluorouracil is indicated and soon, perhaps, chemo-embolization.

Acute effects of oral phosphate-salt ingestion on serum phosphorus, serum ionized calcium, and parathyroid hormone in young adults

We studied the effect of acute oral phosphate loading on parathyroid hormone (PTH) secretion and action. Eighteen adults were studied before and after ingestion of 1 g elemental phosphorus as neutral sodium-potassium phosphate in grape juice or in water and 1.7 g NaCl in juice was used as a control. Five subjects were studied after ingesting 1.5 g P in juice. Blood was drawn every 15 min from -45 to +300 min for measurement of serum ionized calcium (Ca++), P, total Ca, creatinine, and immunoreactive PTH (iPTH); urine was collected hourly. Serum P declined after NaCl ingestion but rose significantly after ingestion of 1 g P in juice or in water. There were no significant changes in serum Ca++, iPTH, or urinary cyclic AMP excretion. Acute ingestion of 1-1.5 g P, which exceeds the P content of a normal meal, does not decrease serum Ca++ or increase iPTH secretion or renal action in normal adults.

Effect of 24,25-dihydroxyvitamin D3 on 1,25-dihydroxyvitamin D3 metabolism in calcium-deficient rats

The effect of 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] on 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] metabolism was examined in rats fed on a low-calcium diet. These rats exhibit hypocalcaemia, high urinary cyclic AMP excretion, a markedly elevated serum 1,25(OH)2D concentration and low serum concentrations of both 24,25(OH)2D and 25(OH)D. When the rats are treated orally with 1, 5 or 10 micrograms of 24,25(OH)2D3/100 g every day, there is a dramatic decrease in serum 1,25(OH)2D concentration in a dose-dependent manner concomitant with an increase in serum 24,25(OH)2D concentration. Serum calcium concentration and urinary cyclic AMP excretion are not significantly affected by the 24,25(OH)2D3 treatment, which suggests that parathyroid function is not affected by the 24,25(OH)2D3 treatment. The 25(OH)D3 1 alpha-hydroxylase activity measured in kidney homogenates is markedly elevated in rats on a low-calcium diet but is not affected by any doses of 24,25(OH)2D3. In contrast, recovery of intravenously injected [3H]1,25(OH)2D3 in the serum is decreased in 24,25(OH)2D3-treated rats. Furthermore, when [3H]1,25(OH)2D3 is incubated in vitro with kidney or intestinal homogenates of 24,25(OH)2D3-treated rats there is a decrease in the recovery of radioactivity in the total lipid extract as well as in the 1,25(OH)2D3 fraction along with an increase in the recovery of radioactivity in the water-soluble phase. These results are consistent with the possibility that 24,25(OH)2D3 has an effect on 1,25(OH)2D3 metabolism, namely that of enhancing the degradation of 1,25(OH)2D3. However, because a considerable proportion of the injected 24,25(OH)2D3 is expected to be converted into 1,24,25(OH)3D3 by renal 1 alpha-hydroxylase in 24,25(OH)2D3-treated rats, at least a part of the decrease in serum 1,25(OH)2D concentration may be due to a competitive inhibition by 24,25(OH)2D3 of the synthesis of 1,25(OH)2D3 from 25(OH)D3. Thus the physiological importance of the role of 24,25(OH)2D3 in regulating the serum 1,25(OH)2D concentration as well as the mechanism and metabolic pathway of degradation of 1,25(OH)2D3 remain to be clarified.

Effect of age on renal responsiveness to parathyroid hormone and calcitonin in rats.

The purpose of these studies was to determine whether the responsiveness of the kidney to parathyroid hormone (PTH) and calcitonin changed with age. Experiments were performed in young (3 months old), adult (12-14 months old) and old (22-24 months old) male Fischer 344 rats fed normal diets and thyroparathyroidectomized. Parathyroid hormone was administered i.p. at 24, 12 and 2 h before death and calcitonin was given i.p. at 12 and 2 h before death. Parathyroid hormone significantly increased the conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) by renal slices from young but not adult or old animals. A similar age-related decline in the capacity of PTH to raise serum 1,25-dihydroxyvitamin D (1,25-(OH)2D) levels was also seen. Parathyroid hormone significantly decreased tubular reabsorption of phosphorus, increased concentrations of urinary cyclic AMP (cAMP) and increased serum concentrations of calcium in all age groups. In contrast, calcitonin significantly increased 1,25-(OH)2D3 production by renal slices from both young and adult animals. Calcitonin decreased serum concentrations of calcium in young but not in adult rats. These results suggest that there are maturational changes in the PTH- and cAMP-dependent pathways in the kidney but not in the calcitonin- and cAMP-independent pathways. The changes in the PTH- and cAMP-dependent pathways affect the stimulation of 1,25-(OH)2D production but not the inhibition of phosphate transport.

Urinary cyclic AMP response to bovine parathyroid hormone during treatment with neuroleptics

AbstractThe urinary cyclic AMP response to bovine parathyroid hormone and urinary concentrating ability (max Uosm) after des‐amino‐D‐arginine vasopressin were studies in nine volunteers and seven patients receiving long‐term neuroleptic treatment. Max Uosm was lower in the patient group (770 ± 70 mosmol/kg) compared with the controls (948 ± 152 mosmol/kg) but the trend to a lower cAMP response to bovine PTH was not statistically significant. These results suggest that, although adenylate cyclase inhibition may contribute, other mechanisms are also important in the genesis of reduced uring concentrating ability in patients treated with psychotropic drugs.

Renal handling of calcium in the early newborn period

Urinary calcium excretion was studied in two matched groups of 28 clinically-well preterm and fullterm infants between 24 and 48 hours of life. In the developmental period from 28 to 40 weeks gestation, urinary calcium excretion was positively correlated to the gestational age (r = 0.583, P less than 0.01), serum calcium levels (r = 0.512, P less than 0.01), the rate of glomerular filtration (r = 0.715, P less than 0.001), and urinary cyclic AMP excretion (r = 0.717, P less than 0.001). Urinary calcium excretion was independent of sodium and calcium intake, and urinary sodium and phosphate excretion. The mean fractional total calcium excretion and fractional ionized calcium excretion in babies less than or equal to 32 weeks was less than 1.0%, compared to greater than 2.5% for sodium. Serum calcium levels were positively correlated with gestational age (r = 0.803, P less than 0.001), and serum phosphate levels (r = 0.85, P less than 0.001). Whole blood ionized calcium levels were positively correlated to gestational age (r = 0.625, P less than 0.001), and serum total calcium levels (r = 0.440, P less than 0.05). The newborn kidney in babies less than or equal to 32 weeks gestation, did not have impaired conservation of calcium as for sodium; and neither sodium nor calcium intake appeared to affect urinary calcium excretion in the well newborn infant. Probably neither excess excretion of calcium nor serum phosphate levels contribute to early neonatal hypocalcemia.

Prevention of parathyroid hormone-dependent nephrocalcinosis by chronic administration of the organic phosphorothioate WR-2721.

Pharmacological inhibition of parathyroid hormone (PTH) secretion has been the object of several experimental and clinical trials in the past. It is only recently that a drug, WR-2721 [S-,2-(3-aminopropylamino)-,ethylphosphorothioic acid], has been shown to effectively inhibit PTH secretion in euparathyroid subjects and in parathyroid cancer patients within a few hours after its administration. In the present study we tested its long term efficacy as a PTH inhibitor in a model of nephrocalcinosis resulting from secondary hyperparathyroidism. Intact and thyroparathyroidectomized (TPTX) rats were pair-fed on a low Ca (0.2%)-high phosphorus (1.6%) diet (nephrocalcinotic diet) or on a normal Ca (1.1%)-normal phosphorus (0.8%) diet for 7 days. Simultaneously, either 0.2 mmol/kg of WR-2721 or its solvent was injected subcutaneously twice daily. The intact animals on the nephrocalcinotic diet had an increased urinary cyclic AMP excretion and important renal Ca accumulation. This nephrocalcinosis was markedly reduced by WR-2721 treatment. The kidney Ca content of the WR-2721-treated rats was 58 +/- 6% lower than that of the nontreated animals. The low Ca-high phosphorus diet did not cause nephrocalcinosis in the TPTX rats. WR-2721 failed to reduce the nephrocalcinosis induced by 1,25 dihydroxyvitamin D3 intoxication in TPTX rats fed the normal Ca-normal phosphorus diet. In conclusion, the present study suggests that chronic treatment with WR-2721, a potent inhibitor of PTH secretion, may be effective for preventing the deleterious consequences of hyperparathyroidism, such as nephrocalcinosis.

The effects of aluminum loading on the renal response to parathyroid hormone in the vitamin D-replete rat

Aluminum (Al) may cause vitamin D-resistant osteomalacia and depress the serum levels of immunoreactive parathyroid hormone (iPTH) in patients treated with maintenance dialysis and those on total parental nutrition (TPN). Both conditions have been associated with low serum levels of 1,25(OH)2-vitamin D (1,25(OH)2D). Al may inhibit PTH secretion in vitro; however, induction of hypocalcemia can enhance endogenous PTH secretion in Al-loaded dogs and TPN patients. Despite hypocalcemia and/or increased endogenous iPTH levels, Al-loaded TPN patients fail to show the expected rise in serum 1,25(OH)2D levels. Such observations suggest that Al may impair the renal response to PTH. We studied vitamin D-replete rats given Al or saline vehicle IP for 5 days. Al and control rats then received a saline infusion with an IV bolus of PTH 1-34. Urinary cyclic AMP and P excretion rose in Al and control rats by 1 hr post-PTH, without differences between the groups. Serum P and ionized Ca levels were not different between Al and control rats. In other Al and control rats, serum 1,25(OH)2D levels were measured after saline without PTH. Serum 1,25(OH)2D levels were higher in controls given PTH than in those without, but 1,25(OH)2D levels were not different between Al rats given PTH and those with none. Thus, aluminum does not affect cyclic AMP or P excretion but may impair 25(OH)D-1 alpha-hydroxylase activity in response to PTH.

High doses of fluoride do not affect cyclic AMP levels in human and rat plasma or urine.

The effect of fluoride ingestion on plasma and urinary cyclic AMP levels was studied in healthy volunteers, children undergoing prophylactic fluoride treatment and in rats. In the first series of experiments fluoride ingestion led to a 20-fold increase in plasma fluoride concentration, which was unrelated to changes in plasma cyclic AMP. The only significant effect on plasma cyclic AMP occurred prior to fluoride, an effect attributed to stress. In the second series performed in children increases in urinary F- of up to 200-fold were associated with slight but nonsignificant changes in cyclic AMP excretion. In rat experiments the blood sampling procedure was associated with a rise in plasma cyclic AMP. When this was prevented by pretreatment with propranolol (3 mg/kg), the effect of fluoride (50 ppm in the drinking water) was tested. A fall in urine production was not associated with any change in cyclic AMP excretion or in nephrogenic cyclic AMP. It is concluded that if fluoride alters cyclic AMP in rats and man the effect is small and easily masked by other factors such as catecholamine release following stress.

The renal sensitivity for endogenous parathormone in patients with primary hyperparathyroidism, vitamin D deficiency and renal stones.

Baseline levels and increases in urinary cyclic AMP excretion (UcAMP) and immunoreactive parathormone (iPTH) were studied before and during infusion of EDTA in euparathyroid patients with renal stones (n=11), patients with primary hyperparathyroidism (PHP; n=14) and patients with vitamin D deficiency (n = 12). In all three groups, EDTA evoked a significant rise in iPTH and UcAMP. In patients with PHP and in those with vitamin D deficiency, there was a sufficiently close relationship between increments in iPTH (delta iPTH) and in UcAMP (delta UcAMP) (r = 0.90, P less than 0.001 and r = 0.67, P less than 0.02, respectively) to use this model to assess renal sensitivity for changes to endogenous PTH levels. We quantified sensitivity of the kidney for PTH, by calculating the ratio delta UcAMP/delta TPTH for the three studied groups. The ratio was comparable in patients with renal stones (16.7 +/- 10.3) and PHP (13.8 +/- 4.9, P greater than 0.10), but was significantly increased in patients with vitamin D deficiency (33.2 +/- 17.9; P less than 0.01 versus patients with renal stones and P less than 0.01 versus patients with PHP). Within the group of patients with PHP there was no correlation between baseline serum calcium concentrations and the ratio delta UcAMP/delta TPTH. It is concluded that in patients with vitamin D deficiency, renal sensitivity to PTH is increased compared with patients with PHP and euparathyroid patients with renal stones, perhaps an expression of a teleological useful adaptation of end organ sensitivity.

Normalization of hypercalcemia associated with a decrease in renal calcium reabsorption in Leydig cell tumor-bearing rats treated with WR-2721.

The Rice-500 Leydig cell tumor (LCT) in Fischer rats is a model of humoral hypercalcemia of malignancy (HHM). In this model, the elevation of plasma calcium (Ca) does not result merely from an increased bone resorption, but also from an enhanced tubular Ca reabsorption (TRCa). We investigated the hypocalcemic response to WR-2721 [S-2,2-(3-aminopropylamino)-, ethylphosphorothioic acid] in LCT-bearing Fischer rats. WR-2721 is a potent inhibitor of normal and aberrant parathyroid hormone (PTH) secretion. Moreover, it exerts a PTH-independent inhibitory effect on TRCa. In hypercalcemic LCT-bearing rats WR-2721 induced a fall in plasma Ca from 3.24 +/- 0.12 to 2.66 +/- 0.23 mmol/liter within 2 h after one single injection of 0.7 mmol/kg body wt. The decrement in plasma Ca was associated with a marked increase in urinary Ca excretion, indicating an inhibition of TRCa. The elevated urine cyclic AMP of LCT-bearing rats, however, was not altered by WR-2721 treatment. These results suggest that in this HHM model, WR-2721 can normalize calcemia through its PTH-independent inhibitory effect on TRCa. WR-2721 could therefore be an effective drug to treat human hypercalcemia of malignancy, particularly in those tumors wherein a markedly enhanced renal Ca reabsorption contributes to the elevation of the plasma Ca level.

Divalent ion handling in human kidney donors with increased blood pressure after uninephrectomy

In a prospective study of 21 normal human kidney donors, increases in blood pressure were found in seven of 12 males and in three of nine females within the first year after uninephrectomy. Donors with blood pressure increases were characterized by greater weight and body mass indexes. In addition, urinary phosphate excretion was positively correlated (r = 0.73, p <0.001) and tubular reabsorption of phosphate negatively correlated (r = −0.61, p <0.01) with blood pressure at the follow-up periods in which increases were observed. All donors experienced an increase in parathyroid hormone levels and urinary cyclic AMP excretion. These changes were accompanied by decreases in urinary calcium and serum phosphate values. Thus, the increase in blood pressure took place in a milieu similar to that of “normocalcemic” hyperparathyroidism. The correlation of phosphate excretion and blood pressure in normal donors suggests an important role for phosphate metabolism in the genesis of hypertension associated with loss of renal mass.

Effects of NaCl on Calcium Balance, Parathyroid Function and Hydroxyproline Excretion in Prednisolone-Treated Rats Consuming Low Calcium Diet

The short-term effects of dietary sodium chloride supplementation on calcium balance were examined in an animal model of corticosteroid-mediated osteoporosis. Changes in calcium and phosphate balance, parathyroid function and bone resorption elicited by salt supplements alone (8 g/100 g diet), prednisolone alone (2.2 mg/kg body wt per day) and both salt and prednisolone in combination were measured in rats consuming a low calcium diet (0.1% calcium) for 10 d. Parathyroid function was monitored by measuring urinary cyclic AMP excretion. Bone resorption was monitored by measuring urinary hydroxyproline excretion. Salt alone raised urinary calcium, cyclic AMP and hydroxyproline; prednisolone alone depressed net calcium absorption and urinary hydroxyproline but had no effect on urinary calcium. Salt and prednisolone each depressed calcium retention independently and together produced an additive adverse effect on calcium balance. Thus high dietary salt intakes augment urinary calcium loss, raise parathyroid activity, increase bone resorption and adversely affect calcium balance in prednisolone-treated growing rats with a restricted dietary calcium intake. These findings support the view that high salt intakes may exaggerate bone loss during chronic glucocorticoid therapy. Because people also develop osteoporosis during glucocorticoid therapy and respond to dietary salt supplements by increasing urinary calcium excretion and parathyroid hormone, high salt intakes may accelerate bone loss in patients receiving chronic glucocorticoid therapy. The beneficial effects of dietary salt restriction on the conservation of bone mass warrant investigation in these patients.