Factor Xa inhibitors differently modulate electrical activities in pulmonary veins and the sinoatrial node

Chien Jung Chang, Chen Chuan Cheng, Yao Chang Chen, Satoshi Higa, Jen Hung Huang, Shih Ann Chen, Yi Jen Chen

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)462-471
Number of pages10
JournalEuropean Journal of Pharmacology
Volume833
DOIs
Publication statusPublished - Aug 15 2018

Fingerprint

Sinoatrial Node
Pulmonary Veins
Atrial Fibrillation
Rabbits
Cardiac Myocytes
Sodium
Factor Xa Inhibitors
PAR-1 Receptor
Microelectrodes
Action Potentials
Stroke
edoxaban
Rivaroxaban

Keywords

  • Atrial fibrillation
  • Factor Xa
  • Late sodium current
  • Protease-activated receptor
  • Pulmonary vein

ASJC Scopus subject areas

  • Pharmacology

Cite this

Factor Xa inhibitors differently modulate electrical activities in pulmonary veins and the sinoatrial node. / Chang, Chien Jung; Cheng, Chen Chuan; Chen, Yao Chang; Higa, Satoshi; Huang, Jen Hung; Chen, Shih Ann; Chen, Yi Jen.

In: European Journal of Pharmacology, Vol. 833, 15.08.2018, p. 462-471.

Research output: Contribution to journalArticle

Chang, Chien Jung ; Cheng, Chen Chuan ; Chen, Yao Chang ; Higa, Satoshi ; Huang, Jen Hung ; Chen, Shih Ann ; Chen, Yi Jen. / Factor Xa inhibitors differently modulate electrical activities in pulmonary veins and the sinoatrial node. In: European Journal of Pharmacology. 2018 ; Vol. 833. pp. 462-471.
@article{0ba848fe526044d49c690fd92fd64b6b,
title = "Factor Xa inhibitors differently modulate electrical activities in pulmonary veins and the sinoatrial node",
abstract = "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.",
keywords = "Atrial fibrillation, Factor Xa, Late sodium current, Protease-activated receptor, Pulmonary vein",
author = "Chang, {Chien Jung} and Cheng, {Chen Chuan} and Chen, {Yao Chang} and Satoshi Higa and Huang, {Jen Hung} and Chen, {Shih Ann} and Chen, {Yi Jen}",
year = "2018",
month = "8",
day = "15",
doi = "10.1016/j.ejphar.2018.07.003",
language = "English",
volume = "833",
pages = "462--471",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",

}

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

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

VL - 833

SP - 462

EP - 471

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

ER -