title: Class Ia anti-arrhythmic drug ajmaline blocks HERG potassium channels: mode of action.
abstract: Ajmaline is a class Ia anti-arrhythmic drug used in several European countries and Japan as first-line treatment for ventricular tachyarrhythmia. Ajmaline has been reported to induce cardiac output (QT) prolongation and to inhibit cardiac potassium currents in guinea pig cardiomyocytes. In order to elucidate the molecular basis of these effects, we examined effects of ajmaline on human ether a-go-go related gene HERG potassium channels. Electrophysiological experiments were performed with human embryonic kidney (HEK) cells (whole-cell patch clamp) and Xenopus oocytes (double-electrode voltage clamp) expressing wild-type and mutant HERG channels. Ajmaline blocked HERG currents with an IC(50) of 1.0 micromol/l in HEK cells and 42.3 micromol/l in Xenopus oocytes. The onset of block was fast and reached steady-state conditions after 180 s. The inhibitory effect was completely reversible upon wash-out. In HERG mutant channels Y652A and F656A lacking aromatic residues in the S6 domain, the inhibitory effect of ajmaline was completely abolished. Ajmaline induced a small shift in HERG current half-maximal activation voltage towards more negative potentials. Ajmaline did not markedly affect HERG inactivation. Inhibitory effects were not voltage-dependent. Ajmaline block exhibited positive frequency dependence. Ajmaline blocked HERG channels in the open, but not in the closed states. Binding of ajmaline to inactivated HERG channels may also be possible. In inactivation-deficient HERG S620T channels, the sensitivity to ajmaline was markedly reduced. The IC(50) of HERG channel blockade in HEK cells lies within the range of unbound therapeutic plasma concentrations of ajmaline. Therefore, inhibitory effects on HERG channels may contribute to both the high anti-arrhythmic efficacy of ajmaline and to its pro-arrhythmic potential.
authors.affiliation: Department of Cardiology, University of Heidelberg Medical School, Bergheimerstrasse 58, 69115 Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kiesecker
authors.forename: Edgar
authors.initials: E
authors.lastname: Zitron
authors.forename: Sonja
authors.initials: S
authors.lastname: Lück
authors.forename: Ramona
authors.initials: R
authors.lastname: Bloehs
authors.forename: Eberhard P
authors.initials: EP
authors.lastname: Scholz
authors.forename: Sven
authors.initials: S
authors.lastname: Kathöfer
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.forename: Volker A W
authors.initials: VA
authors.lastname: Kreye
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schoels
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Karle
authors.forename: Johann
authors.initials: J
authors.lastname: Kiehn
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000404:Ajmaline / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D006801:Humans; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000502:physiology; D014982:Xenopus laevis
chemical_list: D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated; D000404:Ajmaline