SUSTAINED STIMULATION OF RAT ADRENAL CHROMAFFIN CELL-PROLIFERATION BYRESERPINE

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, lea ding to the hypothesis that reserpine causes pheochromocytomas indirec tly by providing a proliferative backdrop on which genetic damage may occur. However, it is not known whether the proliferative effects of r eserpine persist long enough for this model to be tenable. In the pres ent investigation, the effects of reserpine on bromodeoxyuridine (BrdU ) incorporation into epinephrine (E)- and norepinephrine (NE)-type chr omaffin cells were studied after 1, 4, and 12 weeks of reserpine admin istration. Reserpine administered in the diet at 10 or 50 ppm was show n to result in a persistent mitogenic stimulation of the rat adrenal m edulla. Cells that incorporated BrdU at all time points appeared to be typical E- and NE-type chromaffin cells, and the ratio of BrdU-labele d E cells to BrdU-labeled NE cells was not altered by reserpine. An ad ditional 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 ad ministration of reserpine. This finding suggests that neural stimulati on of chromaffin cells might play a role in age-related functional cha nges of the adrenal medulla during early adult life. The present obser vations support the hypothesis that reserpine induces pheochromocytoma s indirectly by increasing chromaffin cell proliferation. They also de crease the likelihood that rat pheochromocytomas arise from preferenti al stimulation of proliferation of a particular cell type. (C) 1995 Ac ademic Press, Inc.