EFFECTS OF ANTIARRHYTHMIC DRUGS ON THECURRENTS OFXENOPUS OOCYTES EXPRESSING HERG ANDKvLQTl/minK CHANNELS

摘要

We have previously reported that steady-state block of HERG current by E-4031 is not frequency-dependent and that dissociation of E-4031 from the HERG 1647 mutant channels results in greater block at high stimulation frequency. In this study, we examined the effects of E-4031 on the currents of Xenopus oocytes expressing HERG and KvLQTl/minK channels. Membrane potential of oocytes was stepped to +20 mV from a holding potential of-80 mV for 400 ms followed by 100-ms ramp voltage to -80 mV. The current amplitudes were steady during control recordings at 0.1 Hz stimulation frequency, whereas they gradually increased at 1.67 Hz reflecting the slow deactivation of Iks. Inhibition of the currents by E-4031 (3 uM) was reverse frequency-dependent: 61.5 +- 0.6% at 0.1 Hz (n - 7) and 28.5 +- 0.6% at 1.67 Hz (n = 6). When the HERG I647F mutant was coexpressed with KvLQTl/minK, E-4031 (10 muM) inhibited the currents in a frequency-dependent manner: 24.0 +- 0.7% at 0.1 Hz (n = 20) and 47.4 +- 0.7% at 1.67 Hz (n = 12). The frequency-dependent inhibition was attributed to 10% recovery from the block by E-4031 of the I647F channel.