I_Kur/Kv1.5 channel blockers for the treatment of atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia. Anti-arrhythmic drugs remain the mainstay of therapy, but the available class I and III anti-arrhythmic drugs are only moderately effective in long-term restoring/maintaining sinus rhythm (SR) and can produce potentially fatal ventricular pro-arrhythmia. In an attempt to identify safer and more effective anti-arrhythmic drugs, drug discovery efforts have focused on ‘atrial selective drugs’ that target cardiac ion channel(s) that are exclusively or predominantly expressed in the atria. The ultra-rapid activating delayed rectifier K⁺ current (I_Kur), carried by Kv1.5 channels, is a major repolarizing current in human atria, but seems to play no role in the ventricle. This finding offers the possibility of developing selective I_Kur blockers to restore and maintain SR without a risk of ventricular pro-arrhythmia. Several I_Kur blockers are now being developed but clinical data are still limited, so the precise role of these agents in the treatment of AF remains to be defined. In this review we analyze the possible advantages and disadvantages of the developmental I_Kur blockers as they represent the first step for the development of potential atrial selective drugs for a more effective and safer treatment and prevention of AF.

Keywords::

• atrial fibrillation
• cardiac action potential
• cardiac ion channels
• I_Kur
• Kv1.5 channels
• pharmacology

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