The amiodarone derivative KB130015 [2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl) benzofuran] induces an Na+-dependent increase of [Ca2+] in ventricular myocytes

KB130015 [KB; 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl) benzofuran] is a novel amiodarone derivative designed to retain the antiarrhythmic effects without the side effects. Unlike amiodarone, KB slows Na+ current inactivation and could, via an increase in [Na+](i), potentially lead to Ca2+ overload. Therefore, we studied the effects of KB on Na+ and Ca2+ handling in single pig ventricular myocytes using the whole-cell ruptured patch-clamp technique and K(5)fluo-3 as [Ca2+](i) indicator. KB at 10 mu M did not prolong action potential duration but slightly increased the early plateau; spontaneous afterdepolarizations were not observed. The amplitude of the [Ca2+](i) transient was larger (434.9 +/- 37.2 versus 326.8 +/- 39.8 nM at baseline, n = 13, P < 0.05), and the time to peak [Ca2+](i) was prolonged. During voltage-clamp pulses, [Ca2+](i) transient peak was also larger (578.1 +/- 98.9 versus 346.4 +/- 52.6 nM at baseline, P < 0.05). Although L-type Ca2+ current was reduced (by 21.9% at +10 mV, n = 9, P = 0.05), sarcoplasmic reticulum Ca2+ content was significantly enhanced with KB. Forward Na+/Ca2+ exchange was significantly decreased after KB application, but reverse mode of the Na+/Ca2+ exchanger was significantly larger, suggesting an increase in [Na+](i) with KB. This was confirmed by a 2-fold increase of the [Na+]-dependent current generated by the Na/K-ATPase (from 0.17 +/- 0.02 to 0.38 +/- 0.06 pA/pF, P < 0.05). In conclusion, as predicted from the slowing of I-Na inactivation, KB130015 leads to an increase in [Na](i) and consequently in cellular Ca2+ load. This effect is partially offset by a decrease in I-CaL resulting in a mild inotropic effect without the signs of Ca2+ overload and related arrhythmias usually associated with Na+ channel openers.