Human mesangial cells in culture proliferate in response to platelet-derived growth factor (PDGF) and thrombin. Both of these agents also induce changes in cytosolic calcium that are dependent on both mobilization of intracellular calcium and influx of extracellular calcium. We hypothesized that calcium channel blockers, by preventing influx of extracellular calcium, may inhibit proliferation induced by these mitogens. We found that three different calcium channel blockers, diltiazem,

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... , and verapamil, were able to significantly inhibit [ 3 H]thymidine incorporation into human mesangial cells induced by either PDGF or thrombin. The inhibitory effect of these agents was significant at 1 0 s M. The calcium channel blockers also attenuated the increases in cell number and percentage of labeled nuclei induced by these mitogens. In contrast, dantrolene, an inhibitor of intracellular calcium mobilization, had no significant effect on [ 3 H]thymidine incorporation by PDGF or thrombin. Finally, the calcium channel agonist, Bay K 8644 was found to stimulate [ 3 H]thymidine incorporation into mesangial cells. Although the mechanisms for these effects of calcium channel blockers are not proven, these studies suggest that influx of extracellular calcium is an important signal in mitogen-induced mesangial proliferation and that these agents can be beneficial in preventing or attenuating renal diseases characterized by proliferation of these cells. (Hypertension 1990;15(suppl I):I-76-I-80) P roliferation of mesangial cells is observed in a variety of immune-and nonimmune-mediated glomerular diseases including hypertensive renal injury. 1 The factors responsible for stimulating this proliferation in vivo are unknown. In vitro studies using mesangial cells in culture, however, have shown that platelet-derived growth factor (PDGF) as well as the coagulation factor, thrombin, are both capable of stimulating DNA synthesis and cell division within these cells. 2 ' 3 PDGF and thrombin also stimulate increases in phosphoinositide turnover and cytosolic free Ca 2+ ([Ca 2+ ]|), which are thought to be critical intracellular signals for their mitogenic effects. 3 -4 The changes in [Ca 2+ ], for both of these mitogens show a similar pattern characterized by a rapid increase (as early as 5-10 seconds), a transient peak (at 30-50 seconds), and then a sustained elevation for 10-15 minutes. When extracellular calcium is removed from the media, the rapid transient [Ca 2+ ]j peak is reduced slightly, but more impressively, the sustained elevation in [Ca 2+ ] f is obliterated. 3 -4 The importance of these [Ca 2+ ]j signals in the mitogenic response is unclear, but if influx of extracellular