title: Comparison of kinetic properties of quinidine and dofetilide block of HERG channels.
abstract: Many drugs inhibit human ether-a-go-go related gene (HERG) current and prolong cardiac action potential duration. We examined the kinetic properties of quinidine block of HERG channels expressed in Xenopus oocytes in comparison with those of the block by a class III antiarrhythmic dofetilide. Both of the drugs inhibited HERG currents in a use-dependent and frequency-independent manner. However, the underlying mechanisms were different. Under the steady state, quinidine block was voltage- and time-dependent. At positive membrane potentials, the onset of block was very fast. Thus, quinidine caused frequency-independent block mainly through this fast blocking kinetic. In contrast, dofetilide blocked HERG currents in a voltage- and time-independent manner under the steady state because of very slow unblocking at negative potentials, which also caused frequency-independent block. Therefore, quinidine and dofetilide might cause the reverse frequency-dependent prolongation of action potential duration through distinct mechanisms with regard to blocking and unblocking kinetics.
authors.affiliation: Department of Pharmacology II, Graduate School of Medicine, A7, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0874, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsujimae
authors.forename: Shingo
authors.initials: S
authors.lastname: Suzuki
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Yamada
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kurachi
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D015870:Gene Expression; D006801:Humans; D007564:Japan; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D010627:Phenethylamines / Q000493:pharmacokinetics*; D024642:Potassium Channels, Voltage-Gated / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000235:genetics; D011719:Pyrazines; D011802:Quinidine / Q000493:pharmacokinetics*; D011804:Quinolines / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000493:pharmacokinetics*; D013997:Time Factors; D014982:Xenopus laevis / Q000235:genetics
chemical_list: D010627:Phenethylamines; D024642:Potassium Channels, Voltage-Gated; D011719:Pyrazines; D011804:Quinolines; D013449:Sulfonamides; C041667:vesnarinone; D011802:Quinidine; C063533:dofetilide