Calcium Set Point Research Articles

The interaction of lithium and time-of-day on calcium, magnesium, parathyroid hormone, and calcitonin in rats

Effects of lithium on the concentrations and temporal patterns of serum and cerebellar calcium and magnesium, parathyroid hormone, and calcitonin were studied in 186 rats sacrificed around 24 hours of clock time. Serum calcium, serum and cerebellar magnesium, and parathyroid hormone were increased and calcitonin decreased in lithium-fed animals. Lithium-fed rats also showed different temporal patterns in serum calcium, parathyroid hormone, cerebellar magnesium, and calcitonin. Data support the hypothesis that lithium competes for calcium receptor sites, causing a compensatory increase in parathyroid hormone and decrease in calcitonin until a new, higher set-point for calcium is established. Lithium strongly affected biological rhythms, an effect which may account in part for the diverse literature on lithium's influence on calcium and magnesium regulation.

Abnormal Regulation of Parathyroid Hormone Release by Calcium in Secondary Hyperparathyroidism due to Chronic Renal Failure*

Dispersed parathyroid cells were employed to study calcium-regulated parathyroid hormone (PTH) release in severe secondary hyperparathyroidism due to chronic renal insufficiency. Cell preparations were obtained from 16 parathyroid glands of 6 patients undergoing subtotal parathyroidectomy for parathyroid bone disease and/or hypercalcemia. The effects of increasing ambient calcium concentration on immunoreactive PTH release in vitro were assessed and compared with results observed in cells prepared from 7 adenomas and 6 normal parathyroid glands. There was no difference in maximal PTH release for the 3 types of tissue (mean +/- SEM, 8.48 +/- 1.9 , 8.1 +/- 3, and 10.1 +/- 0.78 ng/10(5) cells. h respectively). In 14 of 16 hyperplastic glands, 6 of 7 adenomas, and all of the normal glands, PTH release was inhibited more than 50% by 2-3 mM calcium (suppressible glands). Of the normal glands, half of the maximal inhibition of PTH release (the set-point) occurred at less than 1.03 mM calcium in 5 of 6 cases. In 12 of 14 suppressible hyperplastic glands and all of the 6 suppressible adenomas, on the other hand, the set-point was 1.03 mM or higher (p less than 0.01 and P less than 0.002, respectively). Thus, in severe secondary parathyroid hyperplasia due to chronic renal insufficiency, there is frequently an increase in the set-point for calcium without a change in the maximal secretory rate per cell. Abnormal calcium-regulated PTH release at the cellular level, therefore, is not limited to parathyroid neoplasia (i.e. adenoma or primary hyperplasia), but may occur in secondary hyperplasia as well.

Calmodulin in dispersed human parathyroid cells.

We investigated the presence and several of the properties of calmodulin in human parathyroid cells. Boiled extracts of such cell preparations contained a heat-stable factor causing a 2- to 3-fold calcium-dependent stimulation of calmodulin-deficient phosphodiesterase activity, which was parallel to that due to pure porcine calmodulin. This activation could be totally blocked by 10(-4) M trifluoperazine, with half-maximal inhibition at 3 X 10(-5) M, similar to the effects of this phenothiazine on porcine calmodulin. These results suggested the presence of calmodulin in human parathyroid cells. By comparison with known quantities of porcine calmodulin, human parathyroid cells contained 9-208 ng calmodulin/10(6) cells. The content of calmodulin in 3 normal parathyroid glands [65 +/- 8 (+/- SEM) ng/10(6) cells] did not differ significantly from that of 12 adenomas (61 +/- 16 ng/10(6) cells). Cells from 7 glands showing secondary hyperplasia, however, had significantly greater levels of calmodulin (164 +/- 11 ng/10(6) cells) than either normal cells or adenomas (P less than 0.001 and P less than 0.005, respectively). Extracts of human parathyroid cells caused half-maximal stimulation of phosphodiesterase activity at 1.1-4.8 microM free calcium. The concentrations of calcium half-maximally activating phosphodiesterase (Ka) did not differ significantly for normal or abnormal cells (3.3 +/- 0.03 vs. 2.6 +/- 0.33; P greater than 0.3). Moreover, in 2 cases in which normal parathyroid tissue was obtained from patients with adenomas, the Ka values for calcium for the normal and abnormal cells were similar (3.3 vs. 2.5 and 3.4 vs. 2.5 microM, respectively). Finally, there was no significant correlation between either the content of calmodulin or the Ka for calcium and the set-point for calcium [the calcium concentration causing half-maximal inhibition of parathyroid hormone (PTH) release] or the maximal rate of PTH secretion for dispersed parathyroid cells. These results suggest that human parathyroid cells contain calmodulin, but provide no evidence for a role of this protein in the abnormal calcium-regulated PTH release in hyperparathyroidism.

Abnormal calcium-regulated PTH release in normal parathyroid tissue from patients with adenoma

The regulation of parathyroid hormone (PTH) secretion by calcium was studied in normal and abnormal parathyroid tissue from five patients with a parathyroid adenoma. Dispersed cells were prepared from the adenoma and from a portion of a normal parathyroid gland and were incubated for two hours with varying concentrations of calcium. PTH release as a function of the concentration of calcium was determined by radioimmunoassay (C-terminal). Cells from the normal glands showed a lower set-point for calcium (the concentration of calcium causing half of the maximal inhibition of PTH release) than those from the adenomas in four of five cases. Moreover, both set-point and maximal PTH release at low concentrations of calcium were significantly lower in normal glands from patients with an adenoma than in normal glands from patients with normal calcium homeostasis (0.77 ± 0.04 [SEM] versus 0.99 ± 0.03 mM calcium and 3.4 ± 0.43 versus 10.1 ± 0.78 ng/10 5 cells/hr, respectively). These observations may explain, in part, the transient hypocalcemia frequently seen in patients after removal of a parathyroid adenoma. In addition, they suggest that the set-point for calcium and maximal PTH release in normal parathyroid tissue may be altered by prior exposure to chronic hypercalcemia or other physiologic variables. Finally, the “normal” set-point that we have noted previously in parathyroid tissue from some patients with primary parathyroid hyperplasia may be inappropriately high for the hypercalcemia seen in those cases.