TY - JOUR 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 SP - 134 LP - 142 DO - 10.1124/jpet.103.057646 VL - 308 IS - 1 AU - B. Brandts AU - R. Borchard AU - R. Macianskiene AU - V. Gendviliene AU - D. Dirkmann AU - M. Van Bracht AU - M. Prull AU - M. Meine AU - I. Wickenbrock AU - K. Mubagwa AU - H.-J. Trappe Y1 - 2004/01/01 UR - http://jpet.aspetjournals.org/content/308/1/134.abstract N2 - 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 ER -