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

Abstract

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. 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 µM chromanol 293B in the presence of 0.5 µM HMR 1556, which fully blocks I(Ks). 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 µM dofetilide and this caused the occurrence of early afterdepolarizations. The results were confirmed by computer simulation. 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.