Slowing of the Inactivation of Cardiac Voltage-Dependent Sodium Channels by the Amiodarone Derivative 2-Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015)

Abstract

2-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°C using the whole-cell (with [Na⁺]_i = [Na⁺]_o = 10 mM) and cell-attached patch-clamp techniques. KB markedly slowedI_Na inactivation, due to the development of a slow-inactivating component (τ_slow ≈ 50 ms) at the expense of the normal, fast-inactivating component (τ_fast ≈ 2–3 ms). The effect was concentration-dependent, with a half-maximally effective concentration (K_0.5) of 2.1 μM. KB also slowed the recovery from inactivation and shifted the voltage-dependent inactivation (ΔV_0.5 = −15 mV;K_0.5 ≥ 6.9 μM) and activation to more negative potentials. Intracellular cell dialysis with 10 μM 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 μM) and 10 μM 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 μM it increasedI_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.