Atrial fibrillation (AF), the most common sustained arrhythmia, is initiated by firing of high frequency reentrant sources (rotors). In the human atria, the height and duration of the plateau phase of the action potentials (APs) are determined by the balance between the L-type Ca²⁺ current (ICa,L) and two K⁺ currents: the ultrarapid delayed rectifier current (IKur), and the transient outward current, (Ito1). The blockade of IKur and/or Ito is critical for the termination of the rotors. Kv1.5 and Kv4.3 channels co-assembled with auxiliary b-subunits carry human IKur and Ito1, respectively. We identified two drugs that selectively block IKur and Ito at therapeutic doses: irbesartan, an angiotensin II type 1 receptor antagonist, and atorvastatin a statin. Their effects on IKur and Ito might contribute to their efficacy in diminishing the incidence and recurrence of AF. We also found that AF reduces the expression of type 3 NO-synthase (NOS3) in the human atria. At physiological concentrations, NO inhibits the K⁺ efflux through hKv1.5 and hKv4.3 channels by around 30%. Therefore, under AF conditions the decrease in NO production would increase the IKur and Ito1 amplitude producing a shortening in the duration and a decrease in the height of the plateau phase of the atrial APs that could lead to the maintenance of the rotors that generate the AF. Therefore, restoration of the physiological NO levels in the atria could be considered as a potential target for the treatment of AF. Supported by CICYT (SAF2005-04609), SEC, and HERACLES RD06/0009 grants.