Contribution of IKs to ventricular repolarization in canine myocytes

The role of the slow delayed rectifier K+ current (I-Ks) in cardiac repolarization seems to be largely influenced by the experimental conditions including the species and tissue studied. The aim of this study was to determine the contribution of I-Ks, to repolarization in canine ventricular myocytes by measuring the frequency dependent action potential lengthening effect of 10 mu M chromanol 293B using sharp microelectrodes. Pretreatment with isoproterenol (2 nM), E-4031 (1 mu M), and injection of inward current pulses were applied to modify action potential configuration. Chromanol alone caused moderate but statistically significant lengthening of action potentials at cycle lengths longer than 500 ms. The lengthening effect of chromanol, which was strongly enhanced in the presence of either isoproterenol or E-4031, was proportional to the amplitude of plateau, whereas poor correlation was found with action potential duration. Similar results were obtained when action potential configuration was modified by injection of depolarizing current pulses. Computer simulations revealed that activation of I-Ks is a sharp function of the plateau amplitude within the physiological range, while elongation of repolarization may enhance I-Ks only when it is excessive. It was concluded that the effect of I-Ks on ventricular repolarization critically depends on the level of action potential plateau; however, other factors, like action potential duration, cycle length, or suppression of other K+ currents can also influence its contribution.