Atrial-selective block of sodium channels by acehytisine in rabbit myocardium.
Acehytisine, a multi-ion channel blocker, can markedly inhibit INa, ICa, IKur, Ifat various concentrations and effectively terminate and prevent atrial fibrillation (AF) in patients and animal models, but the molecular mechanism underlying its blockage remains elusive. In this study, we investigated the effects of acehytisine on action potentials and sodium channels of atrial and ventricular myocytes isolated from rabbit, using whole-cell recording system. We found that acehytisine exerted stronger blocking effects on sodium channels in atria than in ventricles, especially at depolarization (IC50: 48.48 ± 7.75 μmol/L in atria vs. 560.17 ± 63.98 μmol/L in ventricles). It also significantly shifted steady state inactivation curves toward negative potentials in atrial myocytes, without affecting the recovery kinetics from inactivation of sodium channels in the same cells. In addition, acehytisine inhibited INain a use-dependent manner and regulated slow inactivation kinetics by different gating configurations. These findings indicate that acehytisine selectively blocks atrial sodium channels and possesses affinity to sodium channel in certain states, which provides additional evidence for the anti-AF of acehytisine.
Department of Cardiology, Institute of Cardiovascular Disease of Chengdu, The Third People's Hospital of Chengdu, Chengdu, China; The Key Laboratory of Medical Electrophysiology, Ministry of Education of China, and the Institute of Cardiovascular Research, Sichuan Medical University, Luzhou, China.
Xinrong
X
Fan
Department of Cardiology, Institute of Cardiovascular Disease of Chengdu, The Third People's Hospital of Chengdu, Chengdu, China.
Chao
C
Wang
The Key Laboratory of Medical Electrophysiology, Ministry of Education of China, and the Institute of Cardiovascular Research, Sichuan Medical University, Luzhou, China.
Na
N
Wang
The Key Laboratory of Medical Electrophysiology, Ministry of Education of China, and the Institute of Cardiovascular Research, Sichuan Medical University, Luzhou, China.
Xianhong
X
Ou
Department of Cardiology, Institute of Cardiovascular Disease of Chengdu, The Third People's Hospital of Chengdu, Chengdu, China.
Hanxiong
H
Liu
The Key Laboratory of Medical Electrophysiology, Ministry of Education of China, and the Institute of Cardiovascular Research, Sichuan Medical University, Luzhou, China.
Yan
Y
Yang
The Key Laboratory of Medical Electrophysiology, Ministry of Education of China, and the Institute of Cardiovascular Research, Sichuan Medical University, Luzhou, China.
Xitong
X
Dang
The Key Laboratory of Medical Electrophysiology, Ministry of Education of China, and the Institute of Cardiovascular Research, Sichuan Medical University, Luzhou, China. Electronic address: lyxjd7151@163.com.
Xiaorong
X
Zeng
Department of Cardiology, Institute of Cardiovascular Disease of Chengdu, The Third People's Hospital of Chengdu, Chengdu, China. Electronic address: Cailinwm@163.com.
Lin
L
Cai
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000378:metabolism; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011817:Rabbits; D026941:Sodium Channel Blockers / Q000494:pharmacology*
D006576:Heterocyclic Compounds, 4 or More Rings; D026941:Sodium Channel Blockers; C040615:Guan-fu base A
Acehytisine; Atrial fibrillation; Atrial-selective; Patch-clamp; Sodium channel