The hypercalcemic effect of parathyroid hormone and skeletal cyclic AMP.

The effects of parathyroid hormone (PTH) on bone mineral mobilization are thought to involve the second messenger cyclic AMP. Intravenous administration of 10 U PTH induced rapid and marked accumulation of cyclic AMP in calvaria and plasma of thyroparathyroidectomized rats. The changes in cyclic AMP concentrations were not sustained, but returned to near-baseline values before the rise in plasma calcium concentration was manifest. Changes in the plasma levels of calcium and cyclic AMP in response to PTH infusion were demonstrated in thyroparathyroidectomized rats who were nephrectomized as well. In a series of experiments to clarify the association of cyclic AMP accumulation and calcium mobilization, it was found that small doses of PTH induced significant elevation of plasma calcium without stimulating an accumulation of cyclic AMP in calvaria, or plasma. Furthermore, in intact rats plasma calcium levels were elevated by endogenous PTH, provoked by EGTA induced hypocalcemia, without any demonstrable change of cyclic AMP metabolism in the skeletal tissue. At a higher dose of PTH, the magnitude of the integrated change of cyclic AMP metabolism in the skeletal tissue was well correlated to the amount of calcium mobilized. These observations indicate a coupling between enhanced production of cyclic AMP and calcium mobilization in the action of PTH on bone. They also suggest that either a minute change in cyclic AMP accumulation, which can not be detected due to a high basal level of this nucleotide in the tissue, or a change in metabolism of cyclic AMP in some particular cell compartment is an early event in PTH-induced calcium mobilization.