Abstract 18632: The Potent, Selective Cardiac Acetylcholine-Activated Potassium Current Inhibitor XEN-R0706 Prolongs Human Atrial Action Potential Duration

Aim: In the heart Kir3.1/3.4 conducts the acetylcholine-activated potassium current IKACh. Increased vagal-tone and constitutive-activation of IKACh are believed to be contributing factors to the substrate of atrial fibrillation (AF) in man. This study set out to characterise the novel drug XEN-R0706 and investigate its effect on human atrial IKACh and action potential duration (APD). Method: Ion channel pharmacology was investigated in whole-cell patch-clamp studies using either HEK293 or CHO cells expressing the ion channel gene of interest (~20°C) or isolated human atrial myocytes (37 °C). Action potentials were recorded (1Hz, 37 °C) from human atrial myocytes isolated from right atrial appendage obtained from consenting patients in sinus rhythm. The study was approved by the university ethics committee and complied with the declaration of Helsinki. Results: XEN-R0706 potently inhibited recombinant Kir3.1/3.4 (IC50 =30 nM, nH =0.7 ± 0.1) and had nominal effect on other cardiac channels displaying over ...