Characterization of two distinct depolarization-activated K⁺ currents in isolated adult rat ventricular myocytes

Depolarization-activated outward K⁺ currents in isolated adult rat ventricular myocytes were characterized using the whole-cell variation of the patch-clamp recording technique. During brief depolarizations to potentials positive to -40 mV, Ca²⁺-independent outward K⁺ currents in these cells rise to a transient peak, followed by a slower decay to an apparent plateau. The analyses completed here reveal that the observed outward current waveforms result from the activation of two kinetically distinct voltage-dependent K⁺ currents: one that activates and inactivates rapidly, and one that activates and inactivates slowly, on membrane depolarization. These currents are referred to here as I_to (transient outward) and I_k (delayed rectifier), respectively, because their properties are similar (although not identical) to these K⁺ current types in other cells. Although the voltage dependences of I_to and I_k activation are similar, I_to activates ≈ 10-fold and inactivates ≈30-fold more rapidly than I_k at all test potentials. In the composite current waveforms measured during brief depolarizations, therefore, the peak current predominantly reflects I_to, whereas I_k is the primary determinant of the plateau. There are also marked differences in the voltage dependences of steady-state inactivation of these two K⁺ currents: I⁺ undergoes steady-state inactivation at all potentials positive to -120 mV, and is 50% inactivated at -69 mV; I_to, in contrast, is insensitive to steady-state inactivation at membrane potentials negative to -50 mV. In addition, I_to recovers from steady-state inactivation faster than I_k: at -90 mV, for example, ≈ 70% recovery from the inactivation produced at -20 mV is observed within 20 ms for I_to; I_K recovers ≈ 25-fold more slowly. The pharmacological properties of I_to and I s are also distinct: 4-aminopyridine preferentially attenuates I_to, and tetraethylammonium suppresses predominantly I s. The voltage and time-dependent properties of these currents are interpreted here in terms of a model in which Ito underlies the initial, rapid repolarization phase of the action potential (AP), and I_k is responsible for the slower phase of AP repolarization back to the resting membrane potential, in adult rat ventricular myocytes.