Inhibitory effects of tetrandrine on the serum- and platelet-derived growth factor-BB-induced proliferation of rat aortic smooth muscle cells through inhibition of cell cycle progression, DNA synthesis, ERK1/2 activation and c-fos expression

Tetrandrine (TET) is a well known naturally occurred nonspecific Ca2+ channel blocker. It has long been used for the treatment of arrhythmia, hypertension, and occlusive cardiovascular disorders. The objective of the present study was to investigate the effect of TET on the proliferation of primary cultured rat aortic smooth muscle cells (RASMCs). TET significantly inhibited both 10% fetal bovine serum (FBS) and 50 ng/ml platelet-derived growth factor (PDGF)-BB-induced proliferation, [H-3]thymidine incorporation into DNA, and p42/p44 mitogen-activated protein kinase (ERK1/2) phosphorylation at the concentration of 1.0 and 5.0 muM. Flow cytometry analysis of DNA content in synchronized cells revealed blocking of the FBS-inducible cell cycle progression by TET. In accordance with these findings, TET 5 muM caused a 48% decrease in the early elevation of c-fos expression induced after 10% FBS addition. Furthermore, in contrast to its distinguishable higher potency of Ca2+ antagonistic activity, verapamil showed lower potent antiproliferative activities than TET. These results suggest that TET can exert antiproliferative effects against mitogenic stimuli for RASMCs in vitro by a mechanism that involves the MAPK pathway, altering cell cycle progression, and the inhibitory action cannot be limited to its Ca2+ modulation. (C) 2004 Elsevier Ireland Ltd. All rights reserved.