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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 20, 2003; DOI: 10.1124/jpet.103.057646

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Received for publication August 6, 2003.
Revised August 27, 2003.
Accepted for publication September 29, 2003.

INHIBITION OF G PROTEIN COUPLED AND ATP SENSITIVE POTASSIUM CURRENTS BY KB130015, AN AMIODARONE DERIVATIVE

Bodo Brandts 1*, Borchard Rolf 1, Regina Macianskiene 2, Victoria Gendviliene 3, Daniel Dirkmann 1, Marc Van Bracht 1, Magnus Wilhelm Prull 1, Mathias Meine 1, Ingo Wickenbrock 1, Kani Mubagwa 2, Hans-Joachim Trappe 1

1 Department of Cardiology, Marienhospital Herne, University of Bochum, Herne, Germany 2 Centre for Experimental Surgery and Anaesthesiology, University of Leuven, Leuven, Belgium 3 Laboratory of Membrane Biophysics, Institute of Cardiology, Kaunas, Lithuania

* Address correspondence to: E-mail: bodo.brandts{at}ruhr-uni-bochum.de

Abstract

KB130015 (KB), a novel compound derived from amiodarone, has been proposed to have antiarrhythmic properties. Its effect on the G protein-coupled inward rectifying K+ current (IK(ACh) or IK(Ado) ), ATP sensitive K+ current (IK(ATP) ), and background inward rectifying current (IK1) were studied in guinea-pig atrial and ventricular myocytes by the whole-cell voltage clamp technique. Receptor-activated IK(ACh/Ado), induced in atrial myocytes by the stimulation of either muscarinic or Ado receptors was concentration-dependently (IC50 {approx} 0.6-0.8 µM) inhibited by KB. Receptor-independent, GTP-{gamma}-S-induced and background IK(ACh), which contributes to the resting conductance of atrial myocytes, were equally sensitive to KB (IC50 {approx} 0.9 µM). IK(ATP) induced in atrial myocytes during metabolic inhibition with 2,4-dinitrophenol (DNP) was also suppressed by KB, whereas IK1 measured in ventricular myocytes was insensitive to the drug (KB <= 50 µM). While being effective when applied from the outside, intracellular application of KB via the patch pipette affected neither IK(ACh) nor IK(ATP). T3, which shares structural groups with KB, did not have an effect on the K+ currents. Consistent with the effects on single myocytes, KB did not depolarize the resting potential but antagonized the shortening of action potential duration by CCh or by DNP in multicellular preparations and antagonized the shortening of action potential duration by ACh in single myocytes. It is concluded that KB inhibits IK(ACh) and IK (ATP) by direct drug-channel interaction at a site more easily accessible from extracellular side of the membrane.


Key words: KB130015, action potential duration, antiarrhythmic drug, atp sensitive potassium current, cardiac myocyte, muscarinic potassium current




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