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.