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

From the Cardiovascular Research Division (J.Z., A.J., X.H., G.K.), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass, and the Division of Cardiology (B.L.), University of Pittsburgh Medical Center, Pa.

Correspondence to Gideon Koren, MD, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115. E-mail koren{at}calvin.bwh.harvard.edu

Abstract—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_to, 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, -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.

Key Words: K⁺ channel • electrophysiology • mouse • heart • cardiac arrhythmia

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