The Na+/Ca2+ exchanger inhibitor KB-R7943 activates large-conductance Ca2+-activated K+ channels in endothelial and vascular smooth muscle cells
The Na+/Ca2+ exchanger inhibitor KB-R7943 activates large-conductance Ca2+-activated K+ channels in endothelial and vascular smooth muscle cells
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DOI：
10.1016/j.ejphar.2007.12.021
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发表时间：
2008-03-17
影响因子：
5
通讯作者：
Suh, Suk Hyo
中科院分区：
文献类型：
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作者：
Liang, Guo Hua;Kim, Ji Aee;Suh, Suk Hyo
在培养的人脐静脉内皮细胞(HUVECs)和新鲜分离的小鼠主动脉平滑肌细胞(MASMCs)上，观察了Na+/Ca~(2+)交换选择性抑制剂KB-R7943对大电导钙激活钾通道(BKCa)的影响。在电压钳制细胞中，KB-R7943可逆地激活HUVECs和MASMCs的BKCa电流。KB-R7943对人脐静脉内皮细胞BKCa电流激活的EC50为6.78+/-0.7mM。在由内向外和由外向外的斑片上，KB-R7943显著增加BKC通道的活动，并使单通道电流幅度略有降低。在由内向外的斑块中，KB-R7943使[Ca~(2+)](I)与开放概率(P-o)的关系左移，引起半最大激活所需的[Ca~(2+)](I)从1220+/-68 nM(在没有KB-R7943的情况下)变为620+/-199 nM(在有10 mU的Kb-R7943存在的情况下)。此外，KB-R7943使膜电位与P-o的关系左移，膜电位从76.86+/-1.09 mV(无KB-R7943时)变为49.62+/-2.55 mV(10 mU KB-R7943存在时)。综上所述，KB-R7943是一种有效的BKCa通道激活剂，它能增加BKCa通道对胞浆内游离钙离子和膜电位的敏感性，从而增强BKCa通道的活性。当使用KB-R7943作为NCX阻滞剂时，应考虑这些结果。(C)2008爱思唯尔B.V.保留所有权利。
The effect of the selective inhibitor of Na+/Ca2+ exchanger (NCX), KB-R7943, on large-conductance Ca2+-activated K+ (BKCa) channels was examined in cultured human umbilical vein endothelial cells (HUVECs) and freshly isolated mouse aortic smooth muscle cells (MASMCs). In voltage-clamped cells, KB-R7943 reversibly activated BKCa currents in HUVECs and MASMCs. The EC50 of KB-R7943 for BKCa current activation in HUVECs was determined to be 6.78 +/- 0.7 mu M. In inside-out and outside-out patches, KB-R7943 markedly increased BKC channel activity and slightly decreased single channel current amplitudes. In inside-out patches, KB-R7943 shifted the relationship between [Ca2+](i) and open probability (P-o) to the left-, the [Ca2+](i) required to evoke half-maximal activation changed from 1220 +/- 68 nM (in the absence of KB-R7943) to 620 +/- 199 nM (in the presence of 10 mu M KB-R7943). In addition, KB-R7943 shifted the relationship between membrane potential and P-o, to the left; the membrane potential to evoke half-maximal activation changed from 76.86 +/- 1.09 mV (in the absence of KB-R7943) to 49.62 +/- 2.55 mv (in the presence of 10 mu M KB-R7943). In conclusion, KB-R7943 was found to act as a potent BKCa channel activator, which increases the sensitivity of BKCa channels to cytosolic free Ca2+ and membrane potential, and thereby BKCa channel activity. These results should be considered when KB-R7943 is used as NCX blocker. (c) 2008 Elsevier B.V. All rights reserved.