Rufinamide, a Triazole-Derived Antiepileptic Drug, Stimulates Ca(2+)-Activated K(+) Currents While Inhibiting Voltage-Gated Na(+) Currents

Rufinamide (RFM) is a clinically utilized antiepileptic drug that, as a triazole derivative, has a unique structure. The extent to which this drug affects membrane ionic currents remains incompletely understood. With the aid of patch clamp technology, we investigated the effects of RFM on the amplitude, gating, and hysteresis of ionic currents from pituitary GH(3) lactotrophs. RFM increased the amplitude of Ca(2+)-activated K(+) currents (I(K(Ca))) in pituitary GH(3) lactotrophs, and the increase was attenuated by the further addition of iberiotoxin or paxilline. The addition of RFM to the cytosolic surface of the detached patch of membrane resulted in the enhanced activity of large-conductance Ca(2+)-activated K(+) channels (BK(Ca) channels), and paxilline reversed this activity. RFM increased the strength of the hysteresis exhibited by the BK(Ca) channels and induced by an inverted isosceles-triangular ramp pulse. The peak and late voltage-gated Na(+) current (I(Na)) evoked by rapid step depolarizations were differentially suppressed by RFM. The molecular docking approach suggested that RFM bound to the intracellular domain of K(Ca)1.1 channels with amino acid residues, thereby functionally affecting BK(Ca) channels’ activity. This study is the first to present evidence that, in addition to inhibiting the I(Na), RFM effectively modifies the I(K(Ca)), which suggests that it has an impact on neuronal function and excitability.