SUSTAINED DEPOLARIZATION-INDUCED OUTWARD CURRENT IN HUMAN ATRIAL MYOCYTES - EVIDENCE FOR A NOVEL DELAYED RECTIFIER K+ CURRENT SIMILAR TO KV1.5 CLONED CHANNEL CURRENTS

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 (I(sus)), 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 I(sus) 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 mumol/L atropine, or removal of Cl- in the superfusate. I(sus) could be distinguished from the 4-aminopyridine (4AP)-sensitive transient outward current (I(tol)) by differences in voltage-dependent inactivation (1000-millisecond prepulse to -20 mV reduced I(tol) by 91.7+/-0.1% [mean+/-SEM], P<.001, versus 9.4+/-0.4% reduction of I(sus)) and 4AP sensitivity (IC50 for block of I(tol), 1.96 mmol/L; for I(sus), 49 mumol/L). I(sus) activation had a voltage threshold near -30 mV, a half-activation voltage of -4.3 mV, and a slope factor of 8.0 mV. I(sus) 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. I(sus) activated very rapidly, with time constants (tau) at 25-degrees-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-degrees-C, I(sus), activation was greatly slowed (tau at +10 mV, 46.7+/-4.1 milliseconds; tau at 25-degrees-C, 7.1+/-0.8 milliseconds; P<.01), and the envelope of tails test was satisfied. The reversal potential of I(sus), 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 I(sus), with 50 mumol/L 4AP increased human atrial action potential duration by 66+/-11% (P<.01). In conclusion, I(sus) 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.