The human ether-a-go-go-related gene (HERG) encodes a voltage-gated potassium channel involved in terminating the ventricular action potential. Block of HERG can result in the lethal arrhythmia torsade de pointes, characterized by severely compromised cardiac output. A large number of pharmaceutical compounds still in use have been shown to block HERG. However, the mechanisms by which drugs block HERG are still poorly understood. Previously published data have shown that HERG block by quinidine and cisapride is reduced with elevated extracellular potassium. This reduction in block could be explained by two general mechanisms: a “knockoff” effect of the permeant ion or an indirect effect in which extracellular potassium slows HERG inactivation and the drugs preferentially block the inactivated state. To pursue these two mechanisms, block of HERG by quinidine and cisapride was tested using two electrode voltage clamping of Xenopus oocytes in extracellular solutions of rubidium (Rb), cesium (Cs), and tetraethylammonium (TEA). The permeability of HERG follows the sequence PK = PRb > PCs >>> PTEA. Extracellular K, Rb, Cs, and TEA all slow HERG inactivation. Changing the extracellular solution from 0 to 20 mM potassium reduced HERG block of cisapride 8-fold and HERG block of quinidine 10-fold. A similar reduction was also seen when changing the extracellular solution from 0 mM potassium to 0 mM potassium with 20 mM rubidium. Changing the extracellular solution from 0 mM potassium to 0 mM potassium with 20 mM cesium only reduced HERG block by cisapride 2-fold and HERG block by quinidine 2.5-fold. Changing the extracellular solution from 0 mM potassium to 0 mM potassium with 40 mM TEA did not alter HERG block by cisapride or quinidine. Since 20 mM potassium, 20 mM rubidium, 20 mM cesium, and 40 mM TEA slow HERG inactivation by approximately equal amounts and the rank order of HERG permeability is PK = PRb > PCs >>> PTEA, these results suggest that cisapride and quinidine do not preferentially block inactivated HERG channels but that permeation through HERG channels is the major determinant of HERG block by quinidine and cisapride.
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