Abstract

Lacosamide is an anticonvulsant hypothesized to enhance slow inactivation of neuronal Na⁺ channels for its therapeutic action. Cardiac Na⁺ channels display less and incomplete slow inactivation, but their sensitivity toward lacosamide remains unknown. We therefore investigated the action of lacosamide in human cardiac Na_v1.5 and Na_v1.5-CW inactivation-deficient Na⁺ channels. Lacosamide showed little effect on hNa_v1.5 Na⁺ currents at 300 µM when cells were held at −140 mV. With 30-second conditioning pulses from −90 to −50 mV; however, hNa_v1.5 Na⁺ channels became sensitive to lacosamide with IC₅₀ (50% inhibitory concentration) around 70–80 µM. Higher IC₅₀ values were found at −110 and −30 mV. The development of lacosamide block at −70 mV was slow in wild-type Na⁺ channels (τ; 8.04 ± 0.39 seconds, n = 8). This time constant was significantly accelerated in hNa_v1.5-CW inactivation-deficient counterparts. The recovery from lacosamide block at −70 mV for 10 seconds was relatively rapid in wild-type Na⁺ channels (τ; 639 ± 90 milliseconds, n = 8). This recovery was accelerated further in hNa_v1.5-CW counterparts. Unexpectedly, lacosamide elicited a time-dependent block of persistent hNa_v1.5-CW Na⁺ currents with an IC₅₀ of 242 ± 19 µM (n = 5). Furthermore, both hNa_v1.5-CW/F1760K mutant and batrachotoxin-activated hNa_v1.5 Na⁺ channels became completely lacosamide resistant, indicating that the lacosamide receptor overlaps receptors for local anesthetics and batrachotoxin. Our results together suggest that lacosamide targets the intermediate preopen and open states of hNa_v1.5 Na⁺ channels. Lacosamide may thus track closely the conformational changes at the hNa_v1.5-F1760 region along the activation pathway.