title: Inhibition of cardiac Kv1.5 and Kv4.3 potassium channels by the class Ia anti-arrhythmic ajmaline: mode of action.
abstract: Ajmaline is a class Ia anti-arrhythmic compound that is widely used for the diagnosis of Brugada syndrome and the acute treatment of atrial or ventricular tachycardia. For ajmaline, inhibitory effects on a variety of cardiac K(+) channels have been observed, including cardiac Kv1 and Kv4 channels. However, the exact pharmacological properties of channel blockade have not yet been addressed adequately. Using two different expression systems, we analysed pharmacological effects of ajmaline on the potassium channels Kv1.5 and Kv4.3 underlying cardiac I Kur and I to current, respectively. When expressed in a mammalian cell line, we find that ajmaline inhibits Kv1.5 and Kv4.3 with an IC50 of 1.70 and 2.66 μM, respectively. Pharmacological properties were further analysed using the Xenopus expression system. We find that ajmaline is an open channel inhibitor of cardiac Kv1.5 and Kv4.3 channels. Whereas ajmaline results in a mild leftward shift of Kv1.5 activation curve, no significant effect on Kv4.3 channel activation could be observed. Ajmaline did not significantly affect channel inactivation kinetics. Onset of block was fast. For Kv4.3 channels, no significant effect on recovery from inactivation or channel deactivation could be observed. Furthermore, there was no use-dependence of block. Taken together, we show that ajmaline inhibits cardiac Kv1.5 and Kv4.3 channels at therapeutic concentrations. These data add to the current understanding of the electrophysiological basis of anti-arrhythmic action of ajmaline.
authors.affiliation: Department of Internal Medicine III (Cardiology), University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Fischer
authors.forename: N
authors.initials: N
authors.lastname: Vonderlin
authors.forename: E
authors.initials: E
authors.lastname: Zitron
authors.forename: C
authors.initials: C
authors.lastname: Seyler
authors.forename: D
authors.initials: D
authors.lastname: Scherer
authors.forename: R
authors.initials: R
authors.lastname: Becker
authors.forename: H A
authors.initials: HA
authors.lastname: Katus
authors.forename: E P
authors.initials: EP
authors.lastname: Scholz
mesh_terms: D000404:Ajmaline / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D016466:CHO Cells; D003412:Cricetulus; D066298:In Vitro Techniques; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors* / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051672:Shal Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D014981:Xenopus
chemical_list: D000889:Anti-Arrhythmia Agents; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D051672:Shal Potassium Channels; D000404:Ajmaline