Characterization of a Slowly Inactivating Outward Current in Adult Mouse Ventricular Myocytes

We recently have reported that suppression of the slowly inactivating component of the outward current, Islow, in ventricular myocytes of transgenic mice (long QT mice) overexpressing the N-terminal fragment and S1 segment of Kv1.1 resulted in a significant prolongation of action potential duration and the QT interval. Here we describe the detailed biophysical properties and physiological role of Islow by applying the whole-cell patch-clamp technique at both room temperature and 37 degreesC. This current activates rapidly with time constants ranging from 3.8+/-0.8 ms at -20 mV to 2.1+/-0.5 ms at 50 mV at room temperature. The half-activation voltage and slope factor are -12.5+/-2.6 mV and 7. 7+/-1.0 mV, respectively. The inactivation of this current is slow compared with the fast inactivating component Ito, with time constants of approximately 100 ms at 37 degreesC. The steady-state inactivation of Islow is not temperature-dependent, with half-inactivation voltages and slope factors of -35.1+/-1.3 and -5. 4+/-0.4 mV at 37 degreesC, and -37.6+/-1.8 and -5.8+/-0.6 mV at room temperature. Double exponentials were required to describe the time-dependent recovery of Islow from steady-state inactivation, with time constants of 233+/-34 and 3730+/-702 ms at 37 degreesC, and 830+/-240 and 8680+/-2410 ms at room temperature. Islow is highly sensitive to 4-aminopyridine but is insensitive to tetraethylammonium, alpha-dendrotoxin, and E-4031. Stimulation with action-potential waveforms under voltage-clamp mode revealed that this current plays an important role in the early and middle phases of repolarization of the cardiac action potential. We conclude that the biophysical properties and pharmacological profiles of Islow are similar to those of Kv1.5-encoded currents.