Abstract
The contribution of the mitogen-activated protein kinase (MAPK) pathway to the relaxation induced by tamoxifen, a synthetic non-steroidal anti-estrogen, was examined in rat vascular smooth muscle. Tamoxifen (0.1-300 μM) inhibited the contraction induced by endothelin-1 (ET-1, 3 nM) in aortic smooth muscle in a concentration-dependent manner. The inhibitory effect of tamoxifen was not attenuated by 10 μM ICI 182,780, a selective antagonist of estrogen receptors. In the Ca2+ channel inhibitor verapamil (1 μM)-pretreated strips, tamoxifen also inhibited the contraction induced by ET-1. Both PD098059 and SB203580, inhibitors of MAPK/extracellular signal-regulated kinase (ERK) kinase and p38 MAPK, respectively, inhibited ET-1-induced contraction in aortic smooth muscle. In Western blot analysis with anti-phosphorylated MAPK antibodies, ET-1 (3 nM) enhanced activities of both ERK1/2 and p38 MAPK in aortic muscle strips, which were not attenuated by the treatment with 4 mM EGTA. Tamoxifen (100 μM) inhibited the activities of ERK1/2 and p38 MAPK induced by ET-1 without significant changes in the expression of these kinases. These results suggest that tamoxifen induces relaxation of rat vascular smooth muscle, and that this is, at least in part, mediated by the inhibition of the Ca2+-independent MAPK pathway.
