Chan Yau-Chi, Leung Fung-Ping, Yao Xiaoqiang, Lau Chi-Wai, Vanhoutte Paul M, Huang Yu
Department of Physiology, Faculty of Medicine, Chinese University of Hong Kong, Shatin, NT, Hong Kong.
J Pharmacol Exp Ther. 2005 Mar;312(3):1266-71. doi: 10.1124/jpet.104.077990. Epub 2004 Nov 18.
Effects of raloxifene have been documented in the systemic circulation. However, its impact on the pulmonary circulation is unclear. The present study investigated the role of gender, endothelial modulation, and Ca(2+) channel in relaxations evoked by raloxifene in rat pulmonary arteries and veins. Vascular responses were studied on isolated pulmonary blood vessels mounted in a myograph and constricted by U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha)). Constrictions to CaCl(2) were studied in Ca(2+)-free, 60 mM K(+) solution. Changes in the intracellular calcium ion concentration (Ca(2+)) in vascular smooth muscle were measured using a calcium fluorescence imaging method. Raloxifene was more effective in relaxing U46619-constricted pulmonary arteries from male than female rats. Raloxifene-induced relaxation was unaffected by ICI 182,780 [7alpha-[9-[(4,4,5,5,5,-pentafluoropentyl)-sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17beta-diol], inhibition of the nitric oxide (NO) pathway, or removal of the endothelium. In arteries without endothelium, raloxifene attenuated CaCl(2)-induced constriction and CaCl(2)-stimulated increase in Ca(2+) with similar potencies. Raloxifene caused endothelium-independent relaxations in pulmonary veins, albeit to a lesser degree than in pulmonary arteries. The venous responses showed a gender difference because raloxifene was more potent in male veins. In summary, raloxifene relaxed rat pulmonary arteries, and this effect did not involve the endothelium/NO or ICI 182,780-sensitive estrogen receptors. Raloxifene, like nifedipine, reduced constriction and Ca(2+) increase in response to CaCl(2) in high K(+) solution. Raloxifene also relaxed high K(+)-constricted pulmonary veins. Our data indicate that raloxifene acutely relaxes rat pulmonary blood vessels primarily via inhibition of Ca(2+) influx through voltage-sensitive Ca(2+) channels. Finally, raloxifene induced more relaxation in blood vessels isolated from male than female rats.
雷洛昔芬在体循环中的作用已有文献记载。然而，其对肺循环的影响尚不清楚。本研究调查了性别、内皮调节和钙离子通道在雷洛昔芬引起的大鼠肺动脉和静脉舒张中的作用。在安装于肌张力测定仪中的离体肺血管上研究血管反应，血管预先用U46619（9,11-二脱氧-11α,9α-环氧甲撑前列腺素F2α）收缩。在无钙、60 mM钾溶液中研究对氯化钙的收缩反应。采用钙荧光成像法测量血管平滑肌细胞内钙离子浓度（[Ca2+]i）的变化。雷洛昔芬对U46619收缩的雄性大鼠肺动脉的舒张作用比对雌性大鼠更有效。雷洛昔芬诱导的舒张不受ICI 182,780 [7α-[9-[(4,4,5,5,5-五氟戊基)-亚磺酰基]壬基]-雌-1,3,5(10)-三烯-3,17β-二醇]、一氧化氮（NO）途径抑制或去除内皮的影响。在无内皮的动脉中，雷洛昔芬减弱氯化钙诱导的收缩和氯化钙刺激的[Ca2+]i升高，且效力相似。雷洛昔芬引起肺静脉的非内皮依赖性舒张，尽管程度小于肺动脉。静脉反应存在性别差异，因为雷洛昔芬对雄性静脉的作用更强。总之，雷洛昔芬使大鼠肺动脉舒张，且这种作用不涉及内皮/NO或ICI 182,780敏感的雌激素受体。雷洛昔芬与硝苯地平一样，在高钾溶液中可减轻对氯化钙的收缩反应和[Ca2+]i升高。雷洛昔芬还可使高钾收缩的肺静脉舒张。我们的数据表明，雷洛昔芬主要通过抑制电压敏感性钙离子通道的钙离子内流，急性舒张大鼠肺血管。最后，雷洛昔芬对雄性大鼠分离的血管的舒张作用比对雌性大鼠更强。
