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, I(slow), 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 I(slow) by applying the whole-cell patch-clamp technique at both room temperature and 37°C. 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 I(slow), with time constants of ≃100 ms at 37°C. The steady- state inactivation of I(slow) is not temperature-dependent, with half- inactivation voltages and slope factors of -35.1±1.3 and -5.4±0.4 mV at 37°C, 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 I(slow) from steady-state inactivation, with time constants of 233±34 and 3730±702 ms at 37°C, and 830±240 and 8680±2410 ms at room temperature. I(slow) is highly sensitive to 4-aminopyridine but is insensitive to tetraethylammonium, α-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 I(slow) are similar to those of Kv1.5-encoded currents.