title: Increment of late sodium currents in the left atrial myocytes and its potential contribution to increased susceptibility of atrial fibrillation in castrated male mice.
abstract: The incidence of atrial fibrillation (AF) is correlated with decreased levels of testosterone in elderly men. Late sodium current may exert a role in AF pathogenesis.
  
  
  
  The purpose of this study was to explore the effect of testosterone deficiency on AF susceptibility and the therapeutic effect of late sodium current inhibitors in mice.
  
  
  
  Male ICR mice (5 weeks old) were castrated to establish a testosterone deficiency model. One month after castration, dihydrotestosterone 5 mg/kg was administered subcutaneously for 2 months. Serum total testosterone level was assessed by enzyme-linked immunosorbent assay. High-frequency electrical stimulation was used to induce atrial arrhythmias. Whole-cell patch-clamp technique was used to for single-cell electrophysiologic study.
  
  
  
  Serum dihydrotestosterone levels of castration mice declined significantly but recovered with administration of exogenous dihydrotestosterone. In comparison with sham mice, the number of AF episodes significantly increased by 13.5-fold, AF rate increased by 3.75-fold, and AF duration prolonged in castrated mice. Dihydrotestosterone administration alleviated the occurrence of AF. Action potential duration at both 50% and 90% repolarization were markedly increased in castrated mice compared to sham controls. The late sodium current was enhanced in castrated male mice. These alterations were alleviated by treatment with dihydrotestosterone. Systemic application of the INa-Linhibitors ranolazine, eleclazine, and GS967 inhibited the occurrence of AF in castrated mice.
  
  
  
  Testosterone deficiency contributed to the increased late sodium current, prolonged action potential repolarization, and increased susceptibility to AF. Blocking of late sodium current is beneficial against the occurrence of AF in castrated mice.
authors.affiliation: Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Wang
authors.affiliation: Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Ying-Zhe
authors.initials: YZ
authors.lastname: Wang
authors.affiliation: Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Yi-Yuan
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Xue-Xin
authors.initials: XX
authors.lastname: Jin
authors.affiliation: Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Sun
authors.affiliation: Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Gen-Long
authors.initials: GL
authors.lastname: Xue
authors.affiliation: Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Peng-Hui
authors.initials: PH
authors.lastname: Li
authors.affiliation: Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Qi-He
authors.initials: QH
authors.lastname: Huang
authors.affiliation: Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy Harbin Medical University, Harbin, Heilongjiang, People's Republic of China; Department of Pharmacology and Therapeutics, Melbourne School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia.
authors.forename: Bao-Feng
authors.initials: BF
authors.lastname: Yang
authors.affiliation: Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy Harbin Medical University, Harbin, Heilongjiang, People's Republic of China. Electronic address: panzw@ems.hrbmu.edu.cn.
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Pan
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000375:Aging / Q000378:metabolism*; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology / Q000378:metabolism / Q000628:therapy; D013196:Dihydrotestosterone / Q000494:pharmacology*; D008297:Male; D051379:Mice; D023421:Models, Animal; D009919:Orchiectomy / Q000009:adverse effects*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism; D013739:Testosterone / Q000172:deficiency / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000728:Androgens; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013196:Dihydrotestosterone; D013739:Testosterone
keywords: Action potential duration; Atrial fibrillation; Castration; Late sodium current; Testosterone