Sustained stimulation of rat adrenal chromaffin cell proliferation by reserpine

Chronic administration of reserpine is associated with the development of pheochromocytomas in rats. Short-term administration of reserpine to rats has been shown to stimulate chromaffin cell proliferation, leading to the hypothesis that reserpine causes pheochromocytomas indirectly by providing a proliferative backdrop on which genetic damage may occur. However, it is not known whether the proliferative effects of reserpine persist long enough for this model to be tenable. In the present investigation, the effects of reserpine on bromodeoxyuridine (BrdU) incorporation into epinephrine (E)- and norepinephrine (NE)-type chromaffin cells were studied after 1, 4, and 12 weeks of reserpine administration. Reserpine administered in the diet at 10 or 50 ppm was shown to result in a persistent mitogenic stimulation of the rat adrenal medulla. Cells that incorporated BrdU at all time points appeared to be typical E- and NE-type chromaffin cells, and the ratio of BrdU-labeled E cells to BrdU-labeled NE cells was not altered by reserpine. An additional observation was that the ratio of all E cells to all NE cells declined after Week 1 and that the decline could be accelerated by administration of reserpine. This finding suggests that neural stimulation of chromaffin cells might play a role in age-related functional changes of the adrenal medulla during early adult life. The present observations support the hypothesis that reserpine induces pheochromocytomas indirectly by increasing chromaffin cell proliferation. They also decrease the likelihood that rat pheochromocytomas arise from preferential stimulation of proliferation of a particular cell type.