Vol. 304, Issue 1, 130-138, January 2003

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

R. Macianskiene, S. Viappiani, K. R. Sipido and K. Mubagwa

Centre for Experimental Surgery and Anaesthesiology (R.M., S.V., K.M.) and Laboratory of Experimental Cardiology (K.R.S.), University of Leuven, Leuven, Belgium

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 slowed I_Na inactivation, due to the development of a slow-inactivating component (_slow  50 ms) at the expense of the normal, fast-inactivating component (_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 (V_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 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.