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.