Effects of tetrandrine on growth factor-induced DNA synthesis and proliferative response of rat pulmonary artery smooth muscle cells.

The objective of the present study was to investigate the effect of tetrandrine (a plant alkaloid isolated from Stephenia tetrandra) on growth factor-induced DNA synthesis and proliferative responses of rat pulmonary artery smooth muscle cells. Male rat and bovine pulmonary artery smooth muscle cells (PASMC) were cultured in Medium 199 containing FBS (10%). DNA synthesis was monitored from [(3)H]-thymidine uptake and cell proliferation by direct cell counting. In the present study FBS (1% v/v) caused a small increase in DNA synthesis above basal levels in rat and bovine PASMC (6% and 11% respectively). Platelet-derived growth factor (PDGF, 50 ng/ml), fibroblast growth factor (FGF, 50 ng/ml) or interleukin-1alpha (IL-1alpha, 100 pg/ml) alone increased rat PASMC proliferation (69-85%) and DNA synthesis above basal levels (76-92%). The addition of these growth factors in combination with FBS (1%) resulted in higher increases in DNA synthesis above basal levels (rat PASMC:PDGF, 465%; FGF, 421%; IL-1alpha, 406%; bovine PASMC:PDGF, 279%). Tetrandrine (10(-5) M) inhibited FBS (10%)-induced rat PASMC proliferation (90.5%) and DNA synthesis (89.0%). Tetrandrine significantly inhibited cell proliferation (86.5-98.5%) and DNA synthesis (79.9-89.0%) induced by FBS (1%) in combination with one of the following mitogens; PDGF (50 ng/ml), FGF (50 ng/ml), IL-1alpha (100 pg/ml). The inhibitory effects of tetrandrine were observed between 10(-6) and 10(-5)M and PASMC viability was not affected by tetrandrine below 3x10(-5) m. In summary, these results suggest that tetrandrine can exert anti-proliferative effects against a range of mitogenic stimuli for vascular smooth muscle cells in vitro. Such effects may contribute to the inhibitory effect of tetrandrine on pulmonary vascular remodelling associated with pulmonary hypertension.