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CARDIOVASCULAR

Inhibition of G Protein-Coupled and ATP-Sensitive Potassium Currents by 2-Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015), an Amiodarone Derivative

Department of Cardiology, Marienhospital Herne, University of Bochum, Herne, Germany (B.B., R.B., D.D., M.V.B., M.M., M.P., I.W., H.J.T.); Centre for Experimental Surgery and Anaesthesiology, University of Leuven, Leuven, Belgium (R.M., K.M.); and Laboratory of Membrane Biophysics, Institute of Cardiology, Kaunas, Lithuania (R.M., V.G.).

2-Methyl-3- (3,5-diiodo-4-carboxymethoxybenzyl) benzofuran (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 [I_K(ACh)or I_K(Ado)], ATP-sensitive K⁺current [I_K(ATP)], and background inward rectifying current (I_K1) were studied in guinea pig atrial and ventricular myocytes by the wholecell voltage-clamp technique. Receptor-activated I_K(ACh/Ado), induced in atrial myocytes by the stimulation of either muscarinic or Ado receptors was concentration dependently (IC₅₀value of 0.6-0.8 µM) inhibited by KB. Receptor-independent guanosine 5'-O-(3-thio)triphosphate-induced and background I_K(ACh), which contributes to the resting conductance of atrial myocytes, were equally sensitive to KB (IC₅₀value of 0.9 µM). I_K(ATP)induced in atrial myocytes during metabolic inhibition with 2,4-dinitrophenol (DNP) was also suppressed by KB, whereas I_K1measured in ventricular myocytes was insensitive to the drug (KB 50 µM). Although being effective when applied from the outside, intracellular application of KB via the patch pipette affected neither I_K(ACh) nor I_K(ATP). 3,3',5-triodo-L-thyronin, 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 carbamylcholine-chloride or by DNP in multicellular preparations and antagonized the shortening of action potential duration by acetylcholine in single myocytes. It is concluded that KB inhibits I_K(ACh)and I_K(ATP)by direct drug-channel interaction at a site more easily accessible from extracellular side of the membrane.

Address correspondence to: Dr. Bodo Brandts, Medizinische Klinik II/Universitätsklinik Marienhospital Herne, Ruhr-Universität Bochum, Hölkeskampring 40, D-44625 Herne, Germany. E-mail: bodo.brandts{at}ruhr-uni-bochum.de