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 100-fold selectivity over hERG (IC50 3.3 μM, nH = 0.98 ± 0.1) and >300-fold selectivity over Nav1.5, Cav1.2, Kir2.1, Kir6.2/SUR2A (IC50 >> 10 μM for each). In human right atrial cardiomyocytes, carbachol (CCh, 10 μM) activated IKACh from 6.8 ± 0.76 pA/pF to a maximum of 9.7 ± 0.9 pA/pF which quickly desensitized to 8.8 ± 0.8 pA/pF within 20 s (n=24). This current was completely inhibited by XEN-R0706 (0.3 - 3 μM) whereas basal IK1 was not affected. XEN-R0706 completely reversed the CCh-shortened APD in isolated atrial cardiomyocytes, i.e. mean APD90 values were: control 186.3 ± 20.3 ms, CCh (2 μM) 111.7 ± 11.1 ms (P<0.05 vs control), CCh plus XEN-R0706 (1 μM) 168.2 ± 19.4 ms (P<0.05 vs CCh, n=5).
Conclusion: This is the first report of the effect of a potent, small-molecule inhibitor of IKACh on the human atrial APD. The selective IKACh inhibitor XEN-R0706 prolonged the CCh-shortened atrial APD90. Selective IKACh inhibitors have the potential to be new, safe and effective anti-arrhythmic therapies for the treatment of AF.
- © 2013 by American Heart Association, Inc.