| Autor: |
Brandts, B., Borchard, R., Macianskiene, R., Gendviliene, V., Dirkmann, D., Van Bracht, M., Prull, M., Meine, M., Wickenbrock, I., Mubagwa, K., Trappe, H.-J. |
| Zdroj: |
The Journal of Pharmacology and Experimental Therapeutics; January 2004, Vol. 308 Issue: 1 p134-142, 9p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
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