Slowing of the inactivation of cardiac voltage-dependent sodium channels by the amiodarone derivative 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015).
-Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015 or KB) is a new drug, structurally related to amiodarone and to thyroid hormones. Its effects on cardiac voltage-dependent Na+ current (I Na) were studied in pig single ventricular myocytes at 22 degrees C using the whole-cell (with [Na+]i = [Na+]o = 10 mM) and cell-attached patch-clamp techniques. KB markedly slowed I Na inactivation, due to the development of a slow-inactivating component (tau slow approximately equal 50 ms) at the expense of the normal, fast-inactivating component (tau fast approximately equal 2-3 ms). The effect was concentration-dependent, with a half-maximally effective concentration (K0.5) of 2.1 micro M. KB also slowed the recovery from inactivation and shifted the voltage-dependent inactivation (DeltaV(0.5) = -15 mV; K0.5 > or = 6.9 micro M) and activation to more negative potentials. Intracellular cell dialysis with 10 micro M KB had marginal or no effect on inactivation and did not prevent the effect of extracellularly applied drug. In cell-attached patches, extracellular KB prolonged Na+ channel opening. Amiodarone (10 micro M) and 10 micro M 3,5,-diiodo-L-thyropropionic acid had no effect on inactivation and did not prevent KB effects. 3,3',5-Triodo-L-thyronine (T3) also had no effect on inactivation, but at 10 micro M it increased I Na amplitude and partially prevented the slowing of inactivation by KB. These data suggest the existence of a binding site for KB and T3 on Na+ channels.
Macianskiene
R
R
Centre for Experimental Surgery and Anaesthesiology, University of Leuven, Leuven, Belgium.
Viappiani
S
S
Sipido
K R
KR
Mubagwa
K
K
D000465:Algorithms; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D002462:Cell Membrane / Q000502:physiology; D004594:Electrophysiology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D007700:Kinetics; D008564:Membrane Potentials / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013552:Swine; D014284:Triiodothyronine / Q000494:pharmacology
D001572:Benzofurans; C446946:KB 130015; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014284:Triiodothyronine