Acute arsenic trioxide inhibits the cardiac transient outward K+ current (Ito) and human Kv4.3/KChIP2c channels

: Arsenic trioxide (As 2 O 3 ) has been useful to treat acute promyelocytic leukaemia, as it inhibits the growth of various tumour cell lines and promotes apoptosis. However, its employment has been hindered by its cardiotoxic potential, since it prolongs cardiac repolarization. The transient outward K + current (I to ) in the heart is a critical component of the early repolarization phase and a plateau of the cardiac action potential. While the molecular changes that explain the chronic effects of As 2 O 3 on cardiac K + currents are known, its immediate repercussions remain elusive. In the present work, we characterize the acute electrophysiological effects of As 2 O 3 on the I to in rat myocytes and on K v 4.3 channels co-expressed with their auxiliary subunit KChIP2c, which constitute the principal mediator of the I to in the human ventricle. We found that this anion causes a reversible, voltage and concentration dependent inhibition (IC 50 ≈ 4μM), reaching a maximum (38% block) at 100 μM, on both cell types. Bath perfusion of 4 μM As 2 O 3 had no significant effect on the current kinetics or on the steady-state inactivation of the I to , but it shifted the steady-state tail activation curve to more depolarized potentials. The development of As 2 O 3 inhibition was fourfold faster upon intracellular administration. A ligand and structure-based computational strategy including pharmacophore and molecular docking was implemented to identify the stereochemistry of the ligand-protein binding.