A repolarization‐induced transient increase in the outward current of the inward rectifier K+ channel in guinea‐pig cardiac myocytes

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Abstract
Outward currents of the inwardly rectifying K+ current (IKir) in guinea‐pig ventricular myocytes were studied in the presence of 1 mM intracellular free Mg2+ using the whole‐cell patch‐clamp technique. During repolarizing voltage steps following a large depolarizing pulse (> 0 mV), outward IKir increased transiently at voltages positive to the K+ equilibrium potential (EK, ‐84 mV for 5.4 mM extracellular [K+]). The rising phase was almost instantaneous, while the decay was exponential. The decay rate was faster at voltages closer to EK (time constants, 33.9 ± 9.8 and 4.8 ± 1.4 ms at ‐30 and ‐50 mV, respectively). The transient outward IKir was absent when the preceding depolarization was applied from ‐40 mV. Larger transient currents developed as the voltage before the depolarization was shifted to more hyperpolarized levels. Shift of the depolarizing voltage from > 0 mV to more negative ranges diminished the amplitudes of transient outward IKir and instantaneous inward IKir during the subsequent repolarizing steps positive and negative to EK, respectively. Since blockage of IKir by internal Mg2+ occurs upon large depolarization, and the block is instantaneously relieved at voltages negative to EK, the rising phase of the transient outward IKir was attributed to the relief of Mg2+ block at voltages positive to EK. Transient outward IKir was absent when intracellular [Mg2+] was reduced to 10 μM or lower. Prolongation of the repolarizing voltage step increased the amplitude of time‐dependent inward IKir during the subsequent hyperpolarization, indicating the progress of a gating process (presumably the channel block by intracellular polyamine) during the decaying phase of outward IKir. Progressive prolongation of the depolarizing pulse (> 0 mV) from 100 to 460 ms decreased the transient outward IKir amplitude during the subsequent repolarizing step due to slow progress of the gating (polyamine block) at > 0 mV. Current‐voltage relations measured using repolarizing ramp pulses (‐3.4 mV ms−1) showed an outward hump at around ‐50 mV, the magnitude of which increased as the voltage before the conditioning depolarization (10 mV) was shifted to more negative levels. With slower ramp speeds (‐1.5 and ‐0.6 mV ms−1), the hump was depressed at voltages near EK. Our study suggests that the relief of Mg2+ block may increase outward IKir during repolarization of cardiac action potentials, and that the resting potential, the level/duration of action potential plateau and the speed of repolarization influence the outward IKir amplitude. A kinetic model incorporating a competition between polyamine block and Mg2+ block was able to account for the time dependence of outward IKir.