Paradoxical effects of K + and D-600 on parathyroid hormone secretion and cytoplasmic Ca 2+ in normal bovine and pathological human parathyroid cells

Abstract

The effects of K + and the Ca 2+ channel blocker D-600 on parathyroid hormone (PTH) release and cytoplasmic Ca 2+ activity (Ca 2+ i) were measured at different Ca 2+ concentrations in dispersed parathyroid cells from normal cattle and from patients with hyperparathyroidism. When the extracellular Ca 2+ concentration was raised within the 0.5–3.0 mM range Ca 2+ i increased and PTH secretion was inhibited. There was also a stimulatory effect of Ca 2+ on secretion as indicated by a parallel decrease of Ca 2+ i and PTH release when extracellular Ca 2+ was reduced to less than 25 nM. Addition of 30–50 mM K + stimulated PTH release and lowered Ca 2+ i. The effect of K + was less pronounced in the human cells with a decreased suppressability of PTH release. The Ca 2+ channel blocker D-600 had no effect on Ca 2+ i and PTH release in the absence of extracellular Ca 2+. However, at 0.5–1.0 mM Ca 2+, D-600 increased Ca 2+ i and inhibited PTH release, whereas the opposite effects were obtained at 3.0 mM Ca 2+. The transition from inhibition to stimulation occurred at a higher Ca 2+ concentration in the human cells and the right-shift in the dose-effect relationship for Ca 2+-inhibited PTH release tended to be normalized by D-600. It is suggested that K + stimulates PTH release by increasing the intracellular sequestration of Ca 2+ and that the reduced response in the parathyroid human cells is due to the fact that Ca 2+ i already is lowered. D-600 appears to have both Ca 2+ agonistic and antagonistic actions in facilitating and inhibiting Ca 2+ influx into the parathyroid cells at low and high concentrations of extracellular Ca 2+, respectively. D-600 and related drugs are considered potentially important for the treatment of hyperparathyroidism.