Sustained Depolarization-Induced Outward Current in Human Atrial Myocytes: Evidence for a Novel Delayed Rectifier K+ Current Similar to Kv1.5 Cloned Channel Currents

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Abstract

Depolarization of human atrial myocytes activates a transient outward current that rapidly inactivates, leaving a sustained outward current after continued depolarization. To evaluate the ionic mechanism underlying this sustained current (Isus), we applied whole-cell voltage-clamp techniques to single myocytes isolated from right atrial specimens obtained from patients undergoing coronary bypass surgery. The magnitude of Isus was constant for up to 10 seconds at +30 mV and was unaffected by 40 mmol/L tetraethylammonium, 100 nmol/L dendrotoxin, 1 mmol/L Ba2+, 0.1 μmol/L atropine, or removal of Cl−in the superfusate. Isus could be distinguished from the 4-aminopyridine (4AP)-sensitive transient outward current (Ito1) by differences in voltage-dependent inactivation (1000-millisecond prepulse to −20 mV reduced 1to1 by 91.7±0.1% [mean±SEM], P<.001, versus 9.4±0.4% reduction of Isus) and 4AP sensitivity (IC50 for block of Ito1, 1.96 mmol/L; for Isus, 49 μmol/L). Isus activation had a voltage threshold near −30 mV, a half-activation voltage of −4.3 mV, and a slope factor of 8.0 mV. Isus was not inactivated by 1000-millisecond prepulses but was reduced by 16±8% (P<.05) at a holding potential of −20 mV relative to values at a holding potential of −80 mV. Isus activated very rapidly, with time constants (τ) at 25°C ranging from 18.2±1.8 to 2.1±0.2 milliseconds at −10 to +50 mV, two orders of magnitude faster than previously described kinetics of the rapid component of the delayed rectifier K+ current. At 16°C, Isus activation was greatly slowed (τ at +10 mV, 46.7±4.1 milliseconds; r at 25°C, 7.1±0.8 milliseconds; P<.01), and the envelope of tails test was satisfied. The reversal potential of Isus, tail currents changed linearly with log [K+]o (slope, 55.3 ±2.9 mV per decade), and the fully activated current-voltage relation showed substantial outward rectification. Selective inhibition of Isus with 50 μmol/L 4AP increased human atrial action potential duration by 66±11% (P<.01). In conclusion, Isus in human atrial myocytes is due to a very rapidly activating delayed rectifier K+ current, which shows limited slow inactivation, is insensitive to tetraethylammonium, Ba2+, and dendrotoxin, and is highly sensitive to 4AP. These properties resemble the characteristics of channels encoded by the Kv1.5 group of cardiac cDNAs and may represent a physiologically significant manifestation of such channels in human atrium.

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