title: State dependent dissociation of HERG channel inhibitors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  HERG channels were expressed heterologously in Xenopus oocytes and currents were measured with the two-electrode voltage clamp technique.
  
  
  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 voltage-dependent). 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 -140 mV.
  
  
  CONCLUSIONS
  Drug molecules dissociate at different rates from open and closed HERG channels ('use-dependent' 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, Vienna 1090, Austria.
authors.forename: D
authors.initials: D
authors.lastname: Stork
authors.forename: E N
authors.initials: EN
authors.lastname: Timin
authors.forename: S
authors.initials: S
authors.lastname: Berjukow
authors.forename: C
authors.initials: C
authors.lastname: Huber
authors.forename: A
authors.initials: A
authors.lastname: Hohaus
authors.forename: M
authors.initials: M
authors.lastname: Auer
authors.forename: S
authors.initials: S
authors.lastname: Hering
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009154:Mutation; D009865:Oocytes; D018408:Patch-Clamp Techniques; D014981:Xenopus
chemical_list: D051638:Ether-A-Go-Go Potassium Channels