DIPYRIDAMOLE INHIBITS PDGF-INDUCED AND BFGF-INDUCED VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION

Dipyridamole is the only pharmacologic agent demonstrated to reduce po lytetrafluoroethylene (PTFE) graft occlusion in hemodialysis patients. However, the mechanism of action of dipyridamole in preventing graft occlusion is unknown. The purpose of this study was to examine the dir ect effects of dipyridamole on both platelet-derived growth factor (PD GF) and basic fibroblast growth factor (bFGF)-induced vascular smooth muscle cell (VSMC) proliferation. Human aortic smooth muscle cells wer e grown to confluence in 96 well plates. A total of 5 x 10(-6) molar d ipyridamole, PDGF 10 ng/ml, or bFGF 10 ng/ml were added to appropriate wells at the start of each experiment. Cell proliferation at 48 hours was determined using tritiated thymidine uptake. Intracellular cyclic AMP (cAMP) was measured using a competitive enzyme immunoassay. Treat ment of VSMC with 5 mu M dipyridamole dramatically reduced basal proli feration rates compared to controls [5229 +/- 1131 counts per minute ( CPM) versus 387 +/- 68 CPM, P < 0.001]. Treatment with dipyridamole al so reduced PDGF-stimulated VSMC proliferation (7311 +/- 1655 CPM vs. 5 93 +/- 110 CPM, P < 0.001) as well as the response to bFGF (5632 +/- 1 270 CPM vs. 310 +/- 31 CPM, P < 0.001). Treatment of VSMC with either 5 or 20 mu M dipyridamole did not change intracellular cAMP levels. Fu rthermore, the addition of dibutyryl cAMP to VSMC demonstrated only a modest inhibitory effect on proliferation. We conclude that dipyridamo le inhibits both PDGF- and bFGF-stimulated VSMC proliferation. The eff ects of dipyridamole on VSMC proliferation do not appear to be entirel y mediated by changes in intracellular cAMP concentrations. The direct effect of dipyridamole on VSMC proliferation may account for its effi cacy in reducing PTFE graft thrombosis in hemodialysis patients.