KB130015, A New Amiodarone Derivative with Multiple Effects on Cardiac Ion Channels

Abstract

KB130015 (KB015), a new drug structurally related to amiodarone, has been proposed to have antiarrhythmic properties. In contrast to amiodarone, KB015 markedly slows the kinetics of inactivation of Na + channels by enhancing concentration-dependently (K 0.5 » 2 ìM) a slow-inactivating I Na component (ô slow » 50 ms) at the expense of the normal, fast-inactivating component (ô fast » 2 to 3 ms). However, like amiodarone, KB015 slows the recovery from inactivation and causes a shift (K 0.5 » 6.9 ìM) of the steady-state voltage-dependent inactivation to more negative potentials. Despite prolonging the opening of Na + channels KB015 does not lengthen but often shortens the action potential duration (APD) in pig myocytes or in multicellular preparations. Only short APDs in mouse are markedly prolonged by KB015, which frequently induces early afterdepolarizations. KB015 has also an effect on other ion channels. It decreases the amplitude of the L-type Ca 2+ current (I Ca-L ) without changing its time course, and it inhibits G-protein gated and ATP-gated K + channels. Both the receptor-activated I K(ACh) (induced in atrial myocytes by either ACh, adenosine or sphingosylphosphorylcholine) and the receptorindependent (GTPãS-induced or background) I K(ACh) are concentration-dependently (K 0.5 » 0.6 -0.9 ìM) inhibited by KB015. I K(ATP) , induced in atrial myocytes during metabolic inhibition with 2,4-dinitrophenol (DNP), is equally suppressed. However, KB015 has no effect on I K1 or on I to . Consistent with the effects in K + currents, KB015 does not depolarize the resting potential but antagonizes the APD shortening by muscarinic re-216 ceptor activation or by DNP. Intracellular cell dialysis with KB015 has marginal or no effect on Na + or K + channels and does not prevent the effect of extracellularly applied drug, suggesting that KB015 interacts directly with channels at sites more easily accessible from the extracellular than the intracellular side of the membrane. At high concentrations KB015 exerts a positive inotropic action. It also interacts with thyroid hormone nuclear receptors. Its toxic effects remain largely unexplored, but it is well tolerated during chronic administration.

Dronedarone Modulates M₁ and M₃ Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence

“…While it did show fewer side effects, dronedarone also was found to be less effective than amiodarone in both human and animal studies and is specifically contraindicated in certain patient groups [27] . Like amiodarone, dronedarone is a multichannel blocker [28] .…”

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

“…The reduction of I CaL is one element that contributes, as discussed before (Mubagwa et al, 2003). In the present study, we identify another, namely the larger sodium/potassium pump current.…”

“…However, there are some unique properties that may help to explain the observed protection (Mubagwa et al, 2003). Triggered early and delayed afterdepolarizations are important mechanisms underlying ventricular arrhythmias in heart failure; KB may partially reduce the likelihood of both these mechanisms.…”

“…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). Preliminary data indicated that KB increased cell shortening, especially at high concentrations (Mubagwa et al, 2003). Therefore, in the present study, we examined the effect of KB on cellular Ca 2ϩ load and Na ϩ /Ca 2ϩ exchange function associated with alterations in increased Na ϩ influx.…”

“…In the same study in guinea pig papillary muscle, KB has been shown to prolong action potential duration suggesting a potential antiarrhythmic effect. 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).…”