[Inhibition of the muscarinic potassium current by KB130015, a new antiarrhythmic agent to treat atrial fibrillation].
OBJECTIVE
Vagus-induced atrial fibrillation is of particular clinical interest. The muscarinic potassium current I(K(ACh)) mediates the induction of vagus-induced atrial fibrillation. Selective inhibition of I(K(ACh)) seems to be an option to treat atrial fibrillation. The application of amiodarone, presently one of the most important antiarrhythmic agents in the parmacological treatment of atrial fibrillation, is limited by its adverse effects. KB130015, a new amiodarone derivative, and ibutilide are new class III antiarrhythmic agents.


METHODS
In guinea-pig atrial myocytes the muscarinic potassium current (I(K(ACh))) was activated by acetylcholine and adenosine. The effect of KB130015 on I(K(ACh)) was measured using the whole-cell voltage-clamp method.


RESULTS
KB130015 and ibutilide in a concentration of 50 microM effectively inhibited the muscarinic potassium current. The effect was concentrationdependent and reversible. The half-maximum effective concentration was 0.8 microM (KB130015) and 2.8 microM (ibutilide). The inhibition of I(K(ACh)) was independent of the mode of its activation. The adenosine-induced ion current was as well inhibited by both drugs as the acetylcholine-induced ion current. Via GTP-gamma-S irreversibly activated I(K(ACh)) was also inhibited by KB130015 and ibutilide, whereas intracellular application showed no effect on I(K(ACh)).


CONCLUSIONS
KB130015 and ibutilide are potent inhibitors of IK(ACh). Their effect is most likely mediated by direct interaction with the extracellular part of the ion channel. Acute effects of KB130015 on ventricular myocardium are not known so far. Ibutilide on the other hand is known to inhibit I(kr). KB130015 is a promising antiarrhythmic agent for the pharmacotherapy of vagus-induced atrial fibrillation.
Borchard
Rolf
R
Medizinische Klinik II (Schwerpunkte Kardiologie und Angiologie), Ruhr-Universität, Bochum. rolf.borchard@ruhr-uni-bochum.de
van Bracht
Marc
M
Wickenbrock
Ingo
I
Prull
Magnus Wilhelm
MW
Pott
Lutz
L
Trappe
Hans-Joachim
HJ
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy*; D001572:Benzofurans / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D006168:Guinea Pigs; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D000889:Anti-Arrhythmia Agents; D001572:Benzofurans; C446946:KB 130015; D015221:Potassium Channels; D011976:Receptors, Muscarinic; D013449:Sulfonamides; C067192:ibutilide