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Fig. 5. Unlike lidocaine (B), mexiletine (A) preferentially blocks  KPQ late current and does so independently of pacing frequency. Whereas the amplitude of late current resulting from the KPQ mutation exhibits rate-dependent changes, application of relatively low doses of mexiletine completely removes rate dependence and preferentially reduces the late current, whereas lidocaine appears to preferentially block the peak current. Shown is the INa elicited in response to a train of 20 depolarizing pulses with short recovery intervals (top, depolarizing pulse to –10 mV from –100 mV for 500 ms with 20-ms recovery intervals) and long recovery intervals (bottom, pulse to –10 mV from –100 mV for 500 ms with 1,000-ms recovery intervals). Arrows indicate the late current amplitude at the 20th pulse for control [no drug, (black), 10 µM (blue), and 100 µM (red) drug concentrations]. Additional red arrow (bottom in each panel) indicates peak current amplitude for 100 µM drug concentration. Insets show a magnified time course of current elicited during the last two pulses. In each panel, top trace shows the pacing protocol, middle trace shows INa on a scale that emphasizes the late current, and the bottom trace emphasizes the peak current on a larger scale. Note that 100 µM mexiletine completely blocks the late current but not the peak current. Like with mexiletine, at all concentrations of lidocaine (B: no drug, 10 µM, and 100µM), the peak currents recorded at slow rates with long recovery intervals (bottom) are larger than at fast rates with short recovery intervals (top). However, at a high concentration (100 µM) of lidocaine during rapid pacing the peak current was ablated (top, red lines). At both fast and slow pacing frequencies in the presence of low or high lidocaine concentrations, lidocaine fails to reduce the late component of current by more than 50%. Rather, the simulations suggest that lidocaine preferentially reduces peak current.
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