TY - JOUR
T1 - Factor Xa inhibitors differently modulate electrical activities in pulmonary veins and the sinoatrial node
AU - Chang, Chien Jung
AU - Cheng, Chen Chuan
AU - Chen, Yao Chang
AU - Higa, Satoshi
AU - Huang, Jen Hung
AU - Chen, Shih Ann
AU - Chen, Yi Jen
N1 - Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/8/15
Y1 - 2018/8/15
N2 - Factor Xa inhibitors reduce stroke in patients with atrial fibrillation. Pulmonary veins (PVs) and the sinoatrial node (SAN) are crucial for genesis of atrial fibrillation. However, the electrophysiological effects of factor Xa inhibitors (edoxaban and rivaroxaban) on PVs and the SAN remain unclear. Conventional microelectrodes were used to record the action potential in isolated rabbit PVs and SAN preparations before and after administration of edoxaban (0.1, 0.3, and 1 μM) or rivaroxaban (0.01, 0.03, 0.1, and 0.3 μM). A whole-cell patch-clamp was used to record the late sodium current (INa-late) in isolated single rabbit PV cardiomyocytes. Edoxaban significantly reduced PV spontaneous beating rates at 0.3 and 1 μM (N = 6 rabbits, P < 0.05), and reduced SAN beating rates at 1 μM (N = 6, P < 0.05). Similarly, rivaroxaban reduced PV spontaneous beating rates at 0.1 and 0.3 μM (N = 7, P < 0.05), and reduced SAN beating rates at 0.3 μM (N = 6, P < 0.05). However, neither edoxaban (1 μM) nor rivaroxaban (0.3 μM) reduced PV spontaneous beating rates in the presence of 1 μM BMS200261 (an inhibitor of protease-activated receptors type 1, PAR1 inhibitor) or 10 μM ranolazine (an inhibitor of late sodium current, INa-late inhibitor). Edoxaban (0.3 and 1 μM) and rivaroxaban (0.1 and 0.3 μM) respectively decreased the INa-late by 47%, 47%, 36%, and 49% (n = 9 PV cardiomyocytes from 5 rabbits, P < 0.05). In conclusion, Factor Xa inhibitors reduce PV spontaneous activities and may modulate occurrence of atrial fibrillation by inhibiting PAR1 and reducing the INa-late in PVs.
AB - Factor Xa inhibitors reduce stroke in patients with atrial fibrillation. Pulmonary veins (PVs) and the sinoatrial node (SAN) are crucial for genesis of atrial fibrillation. However, the electrophysiological effects of factor Xa inhibitors (edoxaban and rivaroxaban) on PVs and the SAN remain unclear. Conventional microelectrodes were used to record the action potential in isolated rabbit PVs and SAN preparations before and after administration of edoxaban (0.1, 0.3, and 1 μM) or rivaroxaban (0.01, 0.03, 0.1, and 0.3 μM). A whole-cell patch-clamp was used to record the late sodium current (INa-late) in isolated single rabbit PV cardiomyocytes. Edoxaban significantly reduced PV spontaneous beating rates at 0.3 and 1 μM (N = 6 rabbits, P < 0.05), and reduced SAN beating rates at 1 μM (N = 6, P < 0.05). Similarly, rivaroxaban reduced PV spontaneous beating rates at 0.1 and 0.3 μM (N = 7, P < 0.05), and reduced SAN beating rates at 0.3 μM (N = 6, P < 0.05). However, neither edoxaban (1 μM) nor rivaroxaban (0.3 μM) reduced PV spontaneous beating rates in the presence of 1 μM BMS200261 (an inhibitor of protease-activated receptors type 1, PAR1 inhibitor) or 10 μM ranolazine (an inhibitor of late sodium current, INa-late inhibitor). Edoxaban (0.3 and 1 μM) and rivaroxaban (0.1 and 0.3 μM) respectively decreased the INa-late by 47%, 47%, 36%, and 49% (n = 9 PV cardiomyocytes from 5 rabbits, P < 0.05). In conclusion, Factor Xa inhibitors reduce PV spontaneous activities and may modulate occurrence of atrial fibrillation by inhibiting PAR1 and reducing the INa-late in PVs.
KW - Atrial fibrillation
KW - Factor Xa
KW - Late sodium current
KW - Protease-activated receptor
KW - Pulmonary vein
UR - http://www.scopus.com/inward/record.url?scp=85049737969&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049737969&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2018.07.003
DO - 10.1016/j.ejphar.2018.07.003
M3 - Article
AN - SCOPUS:85049737969
SN - 0014-2999
VL - 833
SP - 462
EP - 471
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
ER -