Running Head: Role of Ito in Shaping Cardiac Action Potential

The transient outward current (Ito) is a major repolarizing current in the heart. Marked reduction of Ito density occurs in heart failure, and is accompanied by significant action potential duration (APD) prolongation. To understand the species-dependent role of Ito in regulating the ventricular action potential morphology and duration, we introduced simulated Ito conductance in guinea pig and canine endocardial ventricular myocytes using the dynamic clamp technique and perforated patch clamp recordings. The effects of simulated Ito in both types of cells were complex and bi-phasic, separated by a clear density threshold of about 40 pA/pF. Below this threshold, simulated Ito resulted in a distinct phase 1 notch, and had little effect on or moderately prolonged the APD. Ito above the threshold resulted in all-or-none repolarization and precipitously reduced the APD. Qualitatively, these results agreed with our previous studies in canine ventricular cells using whole-cell recordings. We conclude that, contrary to previous gene transfer studies involving the Kv4.3 current, the response of guinea pig ventricular myocytes to a fully-inactivating Ito is similar to that of canine ventricular cells, and that in animals such as dogs that have a broad cardiac action potential, Ito does not play a major role in setting the APD