Effects of the transient outward potassium current on action potential upstroke velocities tested using the dynamic clamp technique

The voltage-gated transient outward potassium current (I
_to1
) plays a prominent role in the early repolarization phase of the cardiac action potential (AP) and thereby contributes to the refractory period and inotropic state of the myocardium. The current is largely responsible for differences in AP repolarization between species, between left and right ventricle, and transmurally, and it is affected by various pathophysiological conditions, such as heart failure. In voltage clamp experiments, I
_to1
already activates during depolarization to potentials near -50 to -30 mV, suggesting that I
_to1
may be active during the AP upstroke, but whether it modulates the maximal AP upstroke velocity (dV/dt
_max
) is unknown. In the present study, we addressed this issue using the dynamic clamp configuration of the patch-clamp technique. Experimental data were acquired from HEK-293 cells expressing the fast sodium current that is responsible for the rapid cardiac AP upstroke. The fast component of I
_to1
(I
_{to, f}
) was computed in real time and injected into the HEK-293 cell during its upstroke. I
_{to, f}
density, activation rate, and voltage dependence were varied. We conclude that I
_{to, f}
may modulate dV/dtmax and AP overshoot, but only if its activation is fast and its activation threshold is near -50 to -40 mV.