Song J, Standley P R, Zhang F, Joshi D, Gappy S, Sowers J R, Ram J L
Department of Physiology, Wayne State University, Detroit, Michigan, USA.
J Pharmacol Exp Ther. 1996 Jun;277(3):1444-53.
Tamoxifen (Tx) has been used in breast cancer treatment and prophylaxis because of its antiestrogenic activity; however, Tx may also have beneficial cardiovascular effects and other actions mediated by mechanisms other than estrogen receptors. Previous studies showing interactions of Tx with Ca+(+)-channel blockers suggested that Tx may affect Ca++ channels, an hypothesis that was investigated using whole cell patch clamp techniques in vascular smooth muscle cells (cell line A7r5 and freshly dissociated cells) and by determining effects on contractions of isolated blood vessels. Tx reduced current through L-type Ca+2 channels, with an ID50 of 2 x 10(-6) M when applied by cumulative addition to A7r5 cells. With acute application, 10(-6) M Tx significantly reduced L-type current in A7r5 cells within 2 min to 88% of control (vehicle, 0.1% ethanol) in A7r5 cells, 67% of control in aortic vascular smooth muscle cells, and 60% of control in tail artery vascular smooth muscle cells. Tx also decreased the rate of inactivation of L-type current. Inhibition of T-type current by Tx was less than for L-type current but was significant at 10(-5) M Tx. Treatment of tail artery rings with Tx (10(-5) M, 15 min; 10(-6) M, 4 hr) reduced K+-elicited contractions. Since therapeutic concentrations of Tx during treatment may exceed 10(-6) M, these effects of Tx on vascular smooth muscle Ca++ channels and vessel contractions may have a role in the efficacy and side-effects of Tx treatment.
他莫昔芬（Tx）因其抗雌激素活性已被用于乳腺癌治疗和预防；然而，Tx也可能具有有益的心血管效应以及由雌激素受体以外的机制介导的其他作用。先前的研究表明Tx与钙通道阻滞剂存在相互作用，提示Tx可能影响钙通道，这一假说通过在血管平滑肌细胞（A7r5细胞系和新鲜分离的细胞）中使用全细胞膜片钳技术并通过测定对离体血管收缩的影响进行了研究。Tx减少通过L型钙通道的电流，当以累积添加方式应用于A7r5细胞时，其半数抑制浓度（ID50）为2×10⁻⁶ M。急性应用时，10⁻⁶ M Tx在2分钟内使A7r5细胞中的L型电流显著降低至对照（溶媒，0.1%乙醇）的88%，在主动脉血管平滑肌细胞中为对照的67%，在尾动脉血管平滑肌细胞中为对照的60%。Tx还降低了L型电流的失活速率。Tx对T型电流的抑制作用小于对L型电流，但在10⁻⁵ M Tx时具有显著作用。用Tx（10⁻⁵ M，15分钟；10⁻⁶ M，4小时）处理尾动脉环可减少钾离子引发的收缩。由于治疗期间Tx的治疗浓度可能超过10⁻⁶ M，Tx对血管平滑肌钙通道和血管收缩的这些作用可能在Tx治疗的疗效和副作用中起作用。
