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

2003; American Society for Pharmacology and Experimental Therapeutics; Volume: 308; Issue: 1 Linguagem: Inglês

10.1124/jpet.103.057646

1521-0103

Bodo Brandts, Rolf Borchard, Regina Mačianskienė, Vida Gendvilienė, Daniel Dirkmann, M. van Bracht, M. Prull, Mathias Meine, Ingo Wickenbrock, Kanigula Mubagwa, Hans‐Joachim Trappe,

Neuroscience and Neuropharmacology Research

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 (IC 50 value 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 (IC 50 value 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 K1 measured 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.