Barrows Brad, Cheung Krystin, Bialobrzeski Tim, Foster Jamison, Schulze John, Miller Alan
Touro University College of Osteopathic Medicine, Vallejo, CA, USA.
Channels (Austin). 2009 Jul-Aug;3(4):239-48. Epub 2009 Jul 15.
Drug induced Long QT syndrome results primarily from block of the cardiac potassium channel HERG (human-ether-a-go-go related gene). In some cases prolongation of the QT interval can result in the lethal arrhythmia torsade de pointes, an arrhythmia characterized by a rapid heart rate and severely compromised cardiac output. Many patients requiring medication present with abnormal serum electrolyte levels due to a variety of conditions including gastrointestinal dysfunction, renal and endocrine disorders, diuretic use, alcoholism and aging. Extracellular cations have significant influence on HERG channel gating and in some instances they have been shown to alter drug block of HERG. However, the mechanisms by which drug block is altered in different extracellular cation solutions are not well understood. In this study, HERG block by quinidine and cisapride was assessed in extracellular solutions of calcium, potassium, rubidium, cesium and tetraethylammonium (TEA) using two-electrode voltage clamping of Xenopus oocytes. Consistent with previous reports we show that increases in extracellular potassium reduce HERG block by quinidine and cisapride. We also show that increasing extracellular rubidium and cesium reduced HERG block by quinidine and cisapride whereas increasing extracellular calcium and extracellular TEA did not alter HERG block by quinidine and cisapride. These results demonstrate that at lower extracellular potassium concentrations, the permeant ion is almost exclusively responsible for the reduction in quinidine and cisapride block of HERG due to increases in extracellular potassium.
药物诱导的长QT综合征主要源于心脏钾通道HERG（人醚-a-去相关基因）的阻断。在某些情况下，QT间期延长可导致致命性心律失常尖端扭转型室速，这是一种以心率加快和心输出量严重受损为特征的心律失常。许多需要用药的患者由于各种情况，包括胃肠功能障碍、肾脏和内分泌疾病、使用利尿剂、酗酒和衰老等，会出现血清电解质水平异常。细胞外阳离子对HERG通道门控有显著影响，在某些情况下，它们已被证明会改变HERG的药物阻断作用。然而，在不同细胞外阳离子溶液中药物阻断作用改变的机制尚不清楚。在本研究中，使用非洲爪蟾卵母细胞的双电极电压钳技术，在钙、钾、铷、铯和四乙铵（TEA）的细胞外溶液中评估了奎尼丁和西沙必利对HERG的阻断作用。与先前的报道一致，我们发现细胞外钾离子浓度升高会降低奎尼丁和西沙必利对HERG的阻断作用。我们还发现，增加细胞外铷离子和铯离子浓度会降低奎尼丁和西沙必利对HERG的阻断作用，而增加细胞外钙离子和细胞外TEA浓度则不会改变奎尼丁和西沙必利对HERG的阻断作用。这些结果表明，在较低的细胞外钾离子浓度下，由于细胞外钾离子浓度升高，通透离子几乎完全是导致奎尼丁和西沙必利对HERG阻断作用降低的原因。
