Kvl.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 (1,uJ, 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 IS., 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 ,umol/L atropine, or removal of Clin the superfusate. IS.U could be distinguished from the 4-aminopyridine (4AP)-sensitive transient outward current (Itol) by differences in voltage-dependent inactivation (1000-millisecond prepulse to -20 mV reduced 1,01 by 91.7+0.1% [mean+SEM], P<.001, versus 9.4+0.4% reduction of ISUS) and 4AP sensitivity (ICro for block of Iol, 1.96 mmol/L; for I,,, 49 j.mol/L). I,,. activation had a voltage threshold near -30 mV, a half-activation voltage of -4.3 mV, and a slope factor of 8.0 mV. IS., 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. IS,S activated very rapidly, with time constants (T-) 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, I,s activation was greatly slowed (r at +10 mV, 46.7±4.1 milliseconds; r at 250C, 7.1±0.8 milliseconds; P<.01), and the envelope of tails test was satisfied. The reversal potential of ISU, tail currents changed linearly with log [K']0 (slope, 55.3+2.9 mV per decade), and the fully activated current-voltage relation showed substantial outward rectification. Selective inhibition of IU with 50 &mol/L 4AP increased human atrial action potential duration by 66±11% (P<.01). In conclusion, IS,. 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 Kvl.5 group of cardiac cDNAs and may represent a physiologically significant manifestation of such channels in human atrium. (Circ Res. 1993;73:1061-1076.)