RT Journal Article SR Electronic T1 Inhibition of G Protein-Coupled and ATP-Sensitive Potassium Currents by 2-Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015), an Amiodarone Derivative JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 134 OP 142 DO 10.1124/jpet.103.057646 VO 308 IS 1 A1 B. Brandts A1 R. Borchard A1 R. Macianskiene A1 V. Gendviliene A1 D. Dirkmann A1 M. Van Bracht A1 M. Prull A1 M. Meine A1 I. Wickenbrock A1 K. Mubagwa A1 H.-J. Trappe YR 2004 UL http://jpet.aspetjournals.org/content/308/1/134.abstract AB 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 [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 wholecell voltage-clamp technique. Receptor-activated IK(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 IK(ACh), which contributes to the resting conductance of atrial myocytes, were equally sensitive to KB (IC50value of ≈0.9 μM). IK(ATP)induced in atrial myocytes during metabolic inhibition with 2,4-dinitrophenol (DNP) was also suppressed by KB, whereas IK1measured 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 IK(ACh) nor IK(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 IK(ACh)and IK(ATP)by direct drug-channel interaction at a site more easily accessible from extracellular side of the membrane. The American Society for Pharmacology and Experimental Therapeutics