Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Naunyn Schmiedebergs Arch Pharmacol
2004 Dec 01;3706:423-35. doi: 10.1007/s00210-004-0976-8.
Show Gene links
Show Anatomy links
Class Ia anti-arrhythmic drug ajmaline blocks HERG potassium channels: mode of action.
Kiesecker C, Zitron E, Lück S, Bloehs R, Scholz EP, Kathöfer S, Thomas D, Kreye VA, Katus HA, Schoels W, Karle CA, Kiehn J.
???displayArticle.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.
Arias,
Effects of propafenone and its main metabolite, 5-hydroxypropafenone, on HERG channels.
2003, Pubmed
Arias,
Effects of propafenone and its main metabolite, 5-hydroxypropafenone, on HERG channels.
2003,
Pubmed Bouffard,
[Acute ajmaline poisoning. Study of 7 cases].
1983,
Pubmed Brugada,
What to do in patients with no structural heart disease and sudden arrhythmic death?
1996,
Pubmed Brugada,
Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts.
2000,
Pubmed Bussmann,
Comparison of antiarrhythmic effects of oral prajmalium bitartrate and intravenous lidocaine in acute myocardial infarction.
1980,
Pubmed Chen,
Efficacy of ajmaline and propafenone in patients with accessory pathways: a prospective randomized study.
1994,
Pubmed Enomoto,
Effects of ajmaline on non-sodium ionic currents in guinea pig ventricular myocytes.
1995,
Pubmed Eshchar,
Comparison of exercise and ajmaline tests with electrophysiologic study in the Wolff-Parkinson-White syndrome.
1986,
Pubmed Fernandez,
Physicochemical features of the HERG channel drug binding site.
2004,
Pubmed
,
Xenbase Ficker,
Molecular determinants of dofetilide block of HERG K+ channels.
1998,
Pubmed
,
Xenbase Haverkamp,
Torsade de pointes induced by ajmaline.
2001,
Pubmed Kaul,
Ajmaline-induced torsade de pointes.
1985,
Pubmed Khalilullah,
Ajmaline in WPW syndrome: an electrophysiologic study.
1980,
Pubmed Kiehn,
Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels.
1999,
Pubmed
,
Xenbase Kiehn,
Pathways of HERG inactivation.
1999,
Pubmed
,
Xenbase Kolár,
[Torsade de pointes after mesocaine and ajmaline in a patient with intermittent atrioventricular block. Favorable therapeutic effect of high doses of isoprenaline].
1987,
Pubmed Köppel,
Pharmacokinetics and antiarrhythmic efficacy of intravenous ajmaline in ventricular arrhythmia of acute onset.
1989,
Pubmed Körper,
Differential effects of alkaloids on sodium currents of isolated single skeletal muscle fibers.
1998,
Pubmed
,
Xenbase Madeja,
Follicular tissues reduce drug effects on ion channels in oocytes of Xenopus laevis.
1997,
Pubmed
,
Xenbase Manz,
Electrophysiological and haemodynamic effects of lidocaine and ajmaline in the management of sustained ventricular tachycardia.
1992,
Pubmed Mergenthaler,
Blocking effects of the antiarrhythmic drug propafenone on the HERG potassium channel.
2001,
Pubmed
,
Xenbase Mitcheson,
A structural basis for drug-induced long QT syndrome.
2000,
Pubmed
,
Xenbase Mitcheson,
Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate.
2000,
Pubmed
,
Xenbase Padrini,
Pharmacokinetics and electrophysiological effects of intravenous ajmaline.
1993,
Pubmed Paul,
Inhibition of HERG potassium channel current by the class 1a antiarrhythmic agent disopyramide.
2001,
Pubmed Paul,
Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine.
2002,
Pubmed Pearlstein,
Characterization of HERG potassium channel inhibition using CoMSiA 3D QSAR and homology modeling approaches.
2003,
Pubmed Redfern,
Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development.
2003,
Pubmed Ridley,
Characterisation of recombinant HERG K+ channel blockade by the Class Ia antiarrhythmic drug procainamide.
2003,
Pubmed Roden,
Cardiac ion channels.
2002,
Pubmed Sánchez-Chapula,
Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block.
2002,
Pubmed
,
Xenbase Sănchez-Chapula,
Voltage-dependent profile of human ether-a-go-go-related gene channel block is influenced by a single residue in the S6 transmembrane domain.
2003,
Pubmed
,
Xenbase Schmitt,
[Proarrhythmic effect of ajmaline in idiopathic ventricular tachycardia].
1989,
Pubmed Scholz,
Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine.
2003,
Pubmed
,
Xenbase Spector,
Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides.
1996,
Pubmed
,
Xenbase Thomas,
High-affinity blockade of human ether-a-go-go-related gene human cardiac potassium channels by the novel antiarrhythmic drug BRL-32872.
2001,
Pubmed
,
Xenbase Thomas,
The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels.
2002,
Pubmed
,
Xenbase Wellens,
Effect of procaine amide, quinidine, and ajmaline in the Wolff-Parkinson-White syndrome.
1974,
Pubmed Wilde,
Proposed diagnostic criteria for the Brugada syndrome.
2002,
Pubmed Zitron,
Bertosamil blocks HERG potassium channels in their open and inactivated states.
2002,
Pubmed
,
Xenbase
