Figure 4

Ranolazine block of ramp currents. The response to slow gradual depolarization (ramp) stimulus protocol (-100 mV to +20 mV over 600 msec) from representative cells is normalized to the peak inward current for that cell as described in Methods. Separate cells were exposed to either 0.1% HCl vehicle control (grey line) or 10 μM ranolazine (bold line). In each panel the two traces are overlaid to compare the response to ranolazine. (A) HEK 293 cells expressing WT show a peak ramp response of 0.58 ± 0.15% and the voltage peaks at -43.0 ± 1.2 mV in the presence of 0.1% HCl vehicle control (n = 3). In the presence of 10 μM ranolazine (n = 4), the peak ramp response was 0.79 ± 0.22% and the voltage peaks at -48.0 ± 3.9 mV. (B) HEK 293 cells expressing, the IEM mutant L858H show a peak ramp response of 4.48 ± 1.13% and the voltage peaks at -55.8 ± 2.2 mV in the presence of 0.1% HCl vehicle control (n = 5). In the presence of 10 μM ranolazine (n = 4), the peak ramp response was 3.31 ± 0.60% and the voltage peaks at -54.1 ± 2.0 mV. (C) HEK 293 cells expressing the PEPD mutant V1298F show a peak ramp response of 1.05 ± 0.21% and the voltage peaks at -48.5 ± 2.2 mV in the presence of 0.1% HCl vehicle control (n = 8). In the presence of 10 μM ranolazine (n = 7), the peak ramp response was 0.84 ± 0.11% and the voltage peaks at -49.7 ± 2.7 mV.