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

Keiko Ishihara and Tsuguhisa Ehara

1. Outward currents of the inwardly rectifying K⁺ current (I_Kir) in guinea-pig ventricular myocytes were studied in the presence of 1 mM intracellular free Mg²⁺ using the whole-cell patch-clamp technique.

2. During repolarizing voltage steps following a large depolarizing pulse (> 0 mV), outward I_Kir increased transiently at voltages positive to the K⁺ equilibrium potential (E_K, -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 E_K (time constants, 33·9 ± 9·8 and 4·8 ± 1·4 ms at -30 and -50 mV, respectively).

3. The transient outward I_Kir 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.

4. Shift of the depolarizing voltage from > 0 mV to more negative ranges diminished the amplitudes of transient outward I_Kir and instantaneous inward I_Kir during the subsequent repolarizing steps positive and negative to E_K, respectively. Since blockage of I_Kir by internal Mg²⁺ occurs upon large depolarization, and the block is instantaneously relieved at voltages negative to E_K, the rising phase of the transient outward I_Kir was attributed to the relief of Mg²⁺ block at voltages positive to E_K. Transient outward I_Kir was absent when intracellular [Mg²⁺] was reduced to 10 µM or lower.

5. Prolongation of the repolarizing voltage step increased the amplitude of time-dependent inward I_Kir during the subsequent hyperpolarization, indicating the progress of a gating process (presumably the channel block by intracellular polyamine) during the decaying phase of outward I_Kir.

6. Progressive prolongation of the depolarizing pulse (> 0 mV) from 100 to 460 ms decreased the transient outward I_Kir amplitude during the subsequent repolarizing step due to slow progress of the gating (polyamine block) at > 0 mV.

7. 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 E_K.

8. Our study suggests that the relief of Mg²⁺ block may increase outward I_Kir 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 I_Kir amplitude.

9. A kinetic model incorporating a competition between polyamine block and Mg²⁺ block was able to account for the time dependence of outward I_Kir.

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