Inhibition of Voltage-Gated Na⁺ Currents Exerted by KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea), an Inhibitor of Na⁺-Ca²⁺ Exchanging Process

KB-R7943, an isothiourea derivative, has been recognized as an inhibitor in the reverse mode of the Na⁺-Ca²⁺ exchanging process. This compound was demonstrated to prevent intracellular Na⁺-dependent Ca²⁺ uptake in intact cells; however, it is much less effective at preventing extracellular Na⁺-dependent Ca²⁺ efflux. Therefore, whether or how this compound may produce any perturbations on other types of ionic currents, particularly on voltage-gated Na⁺ current (I_Na), needs to be further studied. In this study, the whole-cell current recordings demonstrated that upon abrupt depolarization in pituitary GH₃ cells, the exposure to KB-R7943 concentration-dependently depressed the transient (I_Na(T)) or late component (I_Na(L)) of I_Na with an IC₅₀ value of 11 or 0.9 μM, respectively. Likewise, the dissociation constant for the KB-R7943-mediated block of I_Na on the basis of a minimum reaction scheme was estimated to be 0.97 μM. The presence of benzamil or amiloride could suppress the I_Na(L) magnitude. The instantaneous window Na⁺ current (I_Na(W)) activated by abrupt ascending ramp voltage (V_ramp) was suppressed by adding KB-R7943; however, subsequent addition of deltamethrin or tefluthrin (Tef) effectively reversed KB-R7943-inhibted I_Na(W). With prolonged duration of depolarizing pulses, the I_Na(L) amplitude became exponentially decreased; moreover, KB-R7943 diminished I_Na(L) magnitude. The resurgent Na⁺ current (I_Na(R)) evoked by a repolarizing V_ramp was also suppressed by adding this compound; moreover, subsequent addition of ranolazine or Tef further diminished or reversed, respectively, its reduction in I_Na(R) magnitude. The persistent Na⁺ current (I_Na(P)) activated by sinusoidal voltage waveform became enhanced by Tef; however, subsequent application of KB-R7943 counteracted Tef-stimulated I_Na(P). The docking prediction reflected that there seem to be molecular interactions of this molecule with the hNa_V1.2 or hNa_V1.7 channels. Collectively, this study highlights evidence showing that KB-R7943 has the propensity to perturb the magnitude and gating kinetics of I_Na (e.g., I_Na(T), I_Na(L), I_Na(W), I_Na(R), and I_Na(P)) and that the Na_V channels appear to be important targets for the in vivo actions of KB-R7943 or other relevant compounds.