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 voltagedependent Na ϩ current (I Na ) were studied in pig single ventricular myocytes at 22°C using the whole-cell (with [Na ϩ ] i ϭ [Na ϩ ] o ϭ 10 mM) and cell-attached patch-clamp techniques. KB markedly slowed I Na inactivation, due to the development of a slow-inactivating component ( slow Ϸ 50 ms) at the expense of the normal, fast-inactivating component ( fast Ϸ 2-3 ms). The effect was concentration-dependent, with a half-maximally effective concentration (K 0.5 ) of 2.1 M. KB also slowed the recovery from inactivation and shifted the voltage-dependent inactivation (⌬V 0.5 ϭ Ϫ15 mV; K 0.5 Ն 6.9 M) and activation to more negative potentials. Intracellular cell dialysis with 10 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 ϩ channel opening. Amiodarone (10 M) and 10 M 3,5,-diiodo-L-thyropropionic acid had no effect on inactivation and did not prevent KB effects. 3,3Ј,5-Triodo-L-thyronine (T 3 ) also had no effect on inactivation, but at 10 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 T 3 on Na ϩ channels.Voltage-dependent Na ϩ channels play an important role in the initiation and conduction of electrical signals in excitable cells. A dysfunction of Na ϩ channels, as may occur after genetic mutation or as a consequence of drug action, is the basis for a variety of cardiac arrhythmias (e.g., those related to the long QT and the Brugada syndromes), skeletal muscle diseases, and epileptic seizures (for reviews, see Fozzard and

Inhibition of G Protein-Coupled and ATP-Sensitive Potassium Currents by 2-Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015), an Amiodarone Derivative

“…6). A similar failure of intracellular KB (in contrast to extracellular KB) to modify Na ϩ channels has been observed (Macianskiene et al, 2003b). For amiodarone, based on 1) the high lipophilicity, 2) the slow time course of its action, and 3) the ability of bathapplied molecules to block I K(ACh) in cell-attached patches, it has been proposed that its effect on I K(ACh) is caused by drug diffused into the intracellular medium (Altomare et al, 2000).…”

“…Hence, KB could be expected to exert similar effects. However, besides the recently described and unexpected effects of KB on voltagedependent Na ϩ and Ca 2ϩ channels (Macianskiene et al, 2003b), its effects on other ion channels are largely unknown.…”

“…KB has effects on Na ϩ and Ca 2ϩ channels (Macianskiene et al, 2003a). Other ion currents (e.g., the Na ϩ -K ϩ pump, the Na ϩ -Ca 2ϩ exchange, or the Na ϩ -activated K ϩ currents that are sensitive to intracellular Na ϩ concentrations) might also be indirectly affected by the expected increase in Na i due to prolonged Na ϩ channel opening (Macianskiene et al, 2003b). In addition, the contribution of I K(ACh) might be overwhelmed by a larger contribution of I K1 , especially at the resting potential.…”

“…However, no prediction can be made about which of the amiodarone effects are conserved, or about their magnitude. As an example is the unexpected effect of KB on Na ϩ channel inactivation, which is nonexistent with amiodarone (Macianskiene et al, 2003b). Other structural analogs of amiodarone such as dronaderone (SR33589) have been shown to exert chronic and acute effects on ion channels similar to those of the parent agent amiodarone.…”

The Amiodarone Derivative KB130015 [2-Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran] Induces an Na+-Dependent Increase of [Ca2+] in Ventricular Myocytes

“…Like amiodarone, it acts on many ion channels, including Ca 2ϩ , Na ϩ , and K ϩ channels (for review, see Mubagwa et al, 2003). Unlike amiodarone, KB slows the inactivation of voltage-dependent Na ϩ channels (Macianskiene et al, 2003b (Macianskiene et al, 2003a). The net effect of these opposite actions is yet unknown and is of considerable interest given the earlier experience of increased mortality during chronic treatment in patients with heart failure with agents that increased cellular Ca 2ϩ (Packer, 1993).…”