Background and purpose: Inhibition of HERG channels prolongs the ventricular action potential and the QT interval with the risk of torsade de pointes arrhythmias and sudden cardiac death. Many drugs induce greater inhibition of HERG channels when the cell membrane is depolarized frequently. The dependence of inhibition on the pulsing rate may yield different IC 50 values at different frequencies and thus affect the quantification of HERG channel block. We systematically compared the kinetics of HERG channel inhibition and recovery from block by 8 blockers at different frequencies. Experimental approach: HERG channels were expressed heterologously in Xenopus oocytes and currents were measured with the two-electrode voltage clamp technique. Key results: Frequency-dependent block was observed for amiodarone, cisapride, droperidol and haloperidol (group 1) whereas bepridil, domperidone, E-4031 and terfenadine (group 2) induced similar pulse-dependent block at all frequencies. With the group 1 compounds, HERG channels recovered from block in the presence of drug (recovery being voltagedependent). No substantial recovery from block was observed with the second group of compounds. Washing out of bepridil, domperidone, E-4031 and terfenadine was substantially augmented by frequent pulsing. Mutation D540K in the HERG channel (which exhibits reopening at negative voltages) facilitated recovery from block by these compounds at À140 mV. Conclusion and implications: Drug molecules dissociate at different rates from open and closed HERG channels ('usedependent' dissociation). Our data suggest that apparently 'trapped' drugs (group 2) dissociated from the open channel state whereas group 1 compounds dissociated from open and resting states.
The inner cavity of the hERG potassium ion channel can accommodate large, structurally diverse compounds that can be trapped in the channel by closure of the activation gate. A small set of propafenone derivatives was synthesized, and both use-dependency and recovery from block were tested in order to gain insight into the behavior of these compounds with respect to trapping and non-trapping. Ligand-protein docking into homology models of the closed and open state of the hERG channel provides the first evidence for the molecular basis of drug trapping.
Inhibition of HERG channels prolongs the ventricular action potential and correspondingly the QT-interval with the risk of torsade de pointes arrhythmias and sudden cardiac death. Many drugs induce stronger HERG channel inhibition when the cell membrane is depolarised frequently. The dependence of inhibition on the pulsing rate may yield different IC 50 values at different frequencies and thus affect the quantification of HERG channel block. We compared the kinetics of HERG channel inhibition and recovery from block by 9 known blockers and several new propafenone derivatives at different frequencies. HERG channels were expressed heterologously in Xenopus oocytes and currents were measured with the two-electrode voltage-clamp technique. Frequency-dependent block was observed for amiodarone, cisapride, droperidol, haloperidol and the propafenone derivative GPV-0576 (group 1) whereas bepridil, domperidone, E-4031, terfenadine and propafenone (group 2) induced similar pulse-dependent block at all frequencies. With the group 1 compounds, HERG channels recovered from block in the presence of drug. No substantial recovery from block was observed with the second group of compounds. Washing out of bepridil, domperidone, E-4031 and terfenadine was substantially augmented by frequent pulsing. Our data suggest that apparently "trapped" drugs (group 2) dissociate from the open channel state whereas group 1 compounds dissociate from open and resting states.
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