Reeve H L, Archer S L, Soper M, Weir E K
Department of Medicine, University of Minnesota, Minneapolis 55455, University of Alberta, Edmonton, Canada T6G 267.
Am J Physiol. 1999 Sep;277(3):L662-6. doi: 10.1152/ajplung.1999.277.3.L662.
The anorexic agent dexfenfluramine causes the development of primary pulmonary hypertension in susceptible patients by an unknown mechanism that may include changes in K+-channel activity and intracellular Ca2+ concentration ([Ca2+]i). We investigated the dose-dependent effects of dexfenfluramine on [Ca2+]i, K+ current, and membrane potential in freshly dispersed rat pulmonary artery smooth muscle cells. Dexfenfluramine caused a dose-dependent (1-1,000 microM) increase in [Ca2+]i, even at concentrations lower than those necessary to inhibit K+ currents (10 microM) and cause membrane depolarization (100 microM). The [Ca2+]i response to 1 and 10 microM dexfenfluramine was completely abolished by pretreatment of the cells with 0.1 microM thapsigargin, whereas the response to 100 microM dexfenfluramine was reduced. CoCl2 (1 mM), removal of extracellular Ca2+, and pretreatment with caffeine (1 mM) reduced but did not abolish the response to 100 microM dexfenfluramine. We conclude that dexfenfluramine increases [Ca2+]i in rat pulmonary artery smooth muscle cells by both release of Ca2+ from the sarcoplasmic reticulum and influx of extracellular Ca2+.
食欲抑制剂右芬氟拉明可使易感患者发生原发性肺动脉高压，其机制不明，可能包括钾离子通道活性及细胞内钙离子浓度（[Ca2+]i）的改变。我们研究了右芬氟拉明对新鲜分离的大鼠肺动脉平滑肌细胞的[Ca2+]i、钾电流及膜电位的剂量依赖性效应。右芬氟拉明可使[Ca2+]i呈剂量依赖性（1 - 1000 μM）升高，即使在低于抑制钾电流（10 μM）及引起膜去极化（100 μM）所需的浓度时也是如此。用0.1 μM毒胡萝卜素预处理细胞后，对1 μM和10 μM右芬氟拉明的[Ca2+]i反应完全消失，而对100 μM右芬氟拉明的反应有所降低。1 mM氯化钴、去除细胞外钙离子及用1 mM咖啡因预处理可使对100 μM右芬氟拉明的反应降低，但未完全消除。我们得出结论，右芬氟拉明可通过从肌浆网释放钙离子及细胞外钙离子内流两种方式使大鼠肺动脉平滑肌细胞内的[Ca2+]i升高。
