The Anti-Epileptic Drugs Lamotrigine and Valproic Acid Reduce the Cardiac Sodium Current

Anti-epileptic drugs (AEDs) are associated with increased risk of sudden cardiac death. To establish whether gabapentin, lamotrigine, levetiracetam, pregabalin, and valproic acid reduce the Na(v)1.5 current, we conducted whole-cell patch-clamp studies to study the effects of the five AEDs on currents of human cardiac Na(v)1.5 channels stably expressed in HEK293 cells, and on action potential (AP) properties of freshly isolated rabbit ventricular cardiomyocytes. Lamotrigine and valproic acid exhibited inhibitory effects on the Na(v)1.5 current in a concentration-dependent manner with an IC(50) of 142 ± 36 and 2022 ± 25 µM for lamotrigine and valproic acid, respectively. In addition, these drugs caused a hyperpolarizing shift of steady-state inactivation and a delay in recovery from inactivation. The changes on the Na(v)1.5 properties were reflected by a reduction in AP upstroke velocity (43.0 ± 6.8% (lamotrigine) and 23.7 ± 10.6% (valproic acid) at 1 Hz) and AP amplitude; in contrast, AP duration was not changed. Gabapentin, levetiracetam, and pregabalin had no effect on the Na(v)1.5 current. Lamotrigine and valproic acid reduce the Na(v)1.5 current density and affect its gating properties, resulting in a decrease of the AP upstroke velocity. Gabapentin, levetiracetam, and pregabalin have no effects on the Na(v)1.5 current.