Extracellular potassium dependency of block of HERG by quinidine and cisapride is primarily determined by the permeant ion and not by inactivation.

Abstract

Drug induced Long QT syndrome results primarily from block of the cardiac potassium channel heRG (human-ether-a-gogo 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.

Role of the activation gate in determining the extracellular potassium dependency of block of HERG by trapped drugs

“…A number of reports have suggested that block of HERG by some drugs is sensitive to extracellular potassium 8,10,11,20,27 whereas block of HERG by other drugs is not sensitive to extracellular potassium. 12,13,28 In particular block of HERG by dofetilide has been shown to be independent of extracellular potassium over a concentration range from 2 mM to 50 mM.…”

“…It has been shown that block of HERG by a number of different drugs, including quinidine and cisapride is reduced with an increase in extracellular potassium. 8,10,11 However additional studies have shown that block of by two other drugs, quinidine and cisapride, is reduced with an increase in extracellular potassium. 10 Both bepridil and terfenadine are trapped inside the channel after channel closure, whereas quinidine and cisapride cannot be trapped inside the channel after the channel closes.…”

“…8,10,11 However additional studies have shown that block of by two other drugs, quinidine and cisapride, is reduced with an increase in extracellular potassium. 10 Both bepridil and terfenadine are trapped inside the channel after channel closure, whereas quinidine and cisapride cannot be trapped inside the channel after the channel closes. 16,17 We show here that this trapping mechanism may be partly responsible for the lack of extracellular potassium dependency of block of HERG by bepridil and terfenadine.…”

“…quinidine and cisapride, two drugs that are not trapped inside the channel after channel closure, correlates with the permeant ion and not with inactivation, at least in the range of extracellular potassium from 0 to 20 mM. 10 If the potassium dependency of block of WT HERG by bepridil and terfenadine is related to the ability of these drugs to be trapped inside the channel, then block of D540K by these drugs should be dependent on the permeant ion in the same way that block of WT HERG by quinidine or cisapride is dependent on the permeant ion. To address this we measured block of D540K in the presence of different extracellular cations with different permeabilities through the HERG channel.…”

“…The voltage protocol shown in the figure was repeated every 6 sec and blockade assessed as described in the materials and methods section and in more detail previously. 10 Traces above histogram: the inset above each histogram shows a representative block experiment from one oocyte and shows the current assessed at the beginning of the pulse to −60 mV plotted as a function of time for each repetitive pulse. After a steady-state current level was reached in the absence of drug, either 1 μM bepridil or 1 μM terfenadine was perfused into the bath.…”