‘Reverse Use-Dependent’ Effects of 4-Aminopyridine on the Transient Outward Potassium Current in Ferret Right Ventricular Myocytes
A transient outward potassium current “Ito” has recently been described in many different mammalian single isolated myocyte preparations. Due to the role of Ito both in (i) initiating early “phase 1” repolarization and (ii) frequency-dependent modulation of the action potential configuration Ito can act as an important modulator of the EC coupling characteristics of cardiac myocytes. It has been hypothesized that the net macroscopic Ito in many cardiac myocytes is composed of two separate current components: “Ito,1”, a larger 4-aminopyridine (4-AP) sensitive Ca2+-independent transient outward K+ current, and “Ito, 2”‘a smaller Ca2+-activated current that remains after block of Ito1 by 4-AP. Ito1 and Ito2 have been reported to have different characteristics that could be of fundamental importance. For example, recovery of Ito2 has been reported to be more rapid than Ito1, and upon rapid stimulation Ito2 amplitude increases to a size approaching that of Ito1. This has lead to the interesting suggestions that (i) Ito1 mainly contributes to repolarization at slow heart rates, (ii) Ito2 plays the more prominent role in repolarization at normal heart rates, and (iii) during tachyarrhythmias Ito2 would help to protect the myocyte from Ca2+ overload.