Evidence for state-dependent block of DPI 201-106, a synthetic inhibitor of Na+ channel inactivation, on delayed-rectifier K+ current in pituitary tumor (GH3) cells.

DPI 201-107 (DPI), a diphenylpiperazinylindole derivative, was reported to be a cardio-selective modifier of voltage-gated Na+ channels. It remains unclear whether DPI has any effects on ion currents. The effects of DPI on ion currents and membrane potential in pituitary tumor (GH3) cells were investigated in this study. DPI (1-100 microM) suppressed the amplitude of delayed-rectifier K+ current (I(K(DR))) in a concentration-dependent manner with an IC(50) value of 9.4 microM. The presence of DPI also enhanced the rate and extent of I(K(DR)) inactivation. Recovery from block by DPI (10 microM) was fitted by a single exponential. Crossover of tail currents during the exposure to DPI was also observed. Under current-clamp recordings, DPI prolonged action potential duration in GH3 cells. With a minimal binding scheme, DPI-induced block of I(K(DR))) was quantitatively provided. The exposure to DPI also blocked I(K(DR))) with a concomitant increase in current inactivation in NG108-15 neuronal cells. Taken together, the results imply that DPI acts as an open-channel blocker of delayed-rectifier K+ channels in these cells. The widening of action potentials induced by DPI in these cells may be explained mainly by its block of I(K(DR))) in a state-dependent manner.