Analysis of the contribution of Ito to repolarization in canine ventricular myocardium

BACKGROUND AND PURPOSE The contribution of the transient outward potassium current (I-to) to ventricular repolarization is controversial as it depends on the experimental conditions, the region of myocardium and the species studied. The aim of the present study was therefore to characterize I-to and estimate its contribution to repolarization reserve in canine ventricular myocardium. EXPERIMENTAL APPROACH Ion currents were recorded using conventional whole-cell voltage clamp and action potential voltage clamp techniques in canine isolated ventricular cells. Action potentials were recorded from canine ventricular preparations using microelectrodes. The contribution of I-to to repolarization was studied using 100 mu M chromanol 293B in the presence of 0.5 mu M HMR 1556, which fully blocks I-Ks. KEY RESULTS The high concentration of chromanol 293B used effectively suppressed I-to without affecting other repolarizing K+ currents (I-K1, I-Kr, I-p). Action potential clamp experiments revealed a slowly inactivating and a 'late' chromanol-sensitive current component occurring during the action potential plateau. Action potentials were significantly lengthened by chromanol 293B in the presence of HMR 1556. This lengthening effect induced by I-to inhibition was found to be reverse rate-dependent. It was significantly augmented after additional attenuation of repolarization reserve by 0.1 mu M dofetilide and this caused the occurrence of early after depolarizations. The results were confirmed by computer simulation. CONCLUSIONS AND IMPLICATIONS The results indicate that I-to is involved in regulating repolarization in canine ventricular myocardium and that it contributes significantly to the repolarization reserve. Therefore, blockade of I-to may enhance pro-arrhythmic risk.