Tamoxifen induces vasorelaxation via inhibition of mitogen-activated protein kinase in rat aortic smooth muscle.
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 microM) 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 microM ICI 182,780, a selective antagonist of estrogen receptors. In the Ca(2+) channel inhibitor verapamil (1 microM)-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 microM) 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 Ca(2+)-independent MAPK pathway.
Park
Sohyun
S
Department of Veterinary Physiology, College of Veterinary Medicine, Konkuk University, Seoul, Korea.
Kim
Bokyung
B
Kim
Junghwan
J
Won
Kyung-Jong
KJ
Lee
Sangmok
S
Kwon
Seongchun
S
Cho
SungIl
S
D000818:Animals; D001011:Aorta / Q000378:metabolism; D015153:Blotting, Western; D019332:Endothelin-1 / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism; D000077267:Fulvestrant; D007093:Imidazoles / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism; D051381:Rats; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D019332:Endothelin-1; D007093:Imidazoles; D011725:Pyridines; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; C093642:SB 203580