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

KB-R7943, an isothiourea derivative, has been recognized as an inhibitor in the reverse mode of the Na(+)-Ca(2+) exchanging process. This compound was demonstrated to prevent intracellular Na(+)-dependent Ca(2+) uptake in intact cells; however, it is much less effective at preventing extracellular Na(+)-dependent Ca(2+) 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 GH(3) 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 IC(50) 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(V)1.2 or hNa(V)1.7 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.