Abstract

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.