Stimulation of Adrenal Chromaffin Cell Proliferation by Hypercalcemia Induced by Intravenous Infusion of Calcium Gluconate in Rats

Increased incidence of adrenal pheochromocytoma is frequently encountered in ratcarcinogenicity studies. In some of the studies, the finding is judged to be due to arat-specific mechanism of carcinogenesis caused by a disturbance of calcium homeostasis.However, direct evidence that the proliferation of chromaffin cells in the adrenal medulla isinduced solely by hypercalcemia is not available. In this study, calcium gluconate wasintravenously infused for 7 days to rat chromaffin cells by a tail cuff method, and cumulativelabeling with bromodeoxyuridine (BrdU) was carried out to evaluate the proliferative activity.The serum calcium concentration was dose-dependently increased, and a high calciumconcentration was stably sustained from day 2 to 7. In the adrenal medulla, BrdU-positivechromaffin cells increased in the calcium gluconate-treated animals, and the BrdU-labelingindex increased in a dose-dependent manner. In addition, an increased BrdU-labeling index ofchromaffin cells was shown to correlate with the serum calcium concentration. Our resultsdemonstrate that hypercalcemia directly enhances the proliferative activity of chromaffin cellsand that the proliferative activity is correlated with the serum calcium concentration.