title: Norepinephrine-Induced Adrenergic Activation Strikingly Increased the Atrial Fibrillation Duration through β1- and α1-Adrenergic Receptor-Mediated Signaling in Mice.
abstract: BACKGROUND
  Atrial fibrillation (AF) is the most common arrhythmias among old people. It causes serious long-term health problems affecting the quality of life. It has been suggested that the autonomic nervous system is involved in the onset and maintenance of AF in human. However, investigation of its pathogenesis and potential treatment has been hampered by the lack of suitable AF models in experimental animals.
  
  
  OBJECTIVE
  Our aim was to establish a long-lasting AF model in mice. We also investigated the role of adrenergic receptor (AR) subtypes, which may be involved in the onset and duration of AF.
  
  
  RESULTS
  Trans-esophageal atrial burst pacing in mice could induce AF, as previously shown, but with only a short duration (29.0 ± 8.1 sec). We found that adrenergic activation by intraperitoneal norepinephrine (NE) injection strikingly increased the AF duration. It increased the duration to more than 10 minutes, i.e., by more than 20-fold (656.2 ± 104.8 sec; P<0.001). In this model, a prior injection of a specific β1-AR blocker metoprolol and an α1-AR blocker prazosin both significantly attenuated NE-induced elongation of AF. To further explore the mechanisms underlying these receptors' effects on AF, we assessed the SR Ca(2+) leak, a major trigger of AF, and consequent spontaneous SR Ca(2+) release (SCR) in atrial myocytes. Consistent with the results of our in-vivo experiments, both metoprolol and prazosin significantly inhibited the NE-induced SR Ca(2+) leak and SCR. These findings suggest that both β1-AR and α1-AR may play important roles in the development of AF.
  
  
  CONCLUSIONS
  We have established a long-lasting AF model in mice induced by adrenergic activation, which will be valuable in future AF study using experimental animals, such as transgenic mice. We also revealed the important role of β1- and α1-AR-mediated signaling in the development of AF through in-vivo and in-vitro experiments.
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suita
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Hasegawa
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Wenqian
authors.initials: W
authors.lastname: Cai
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Huiling
authors.initials: H
authors.lastname: Jin
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hidaka
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Prajapati
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Masanari
authors.initials: M
authors.lastname: Umemura
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Utako
authors.initials: U
authors.lastname: Yokoyama
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Physiology, Aichi Medical University School of Medicine, Aichi, Japan.
authors.forename: Motohiko
authors.initials: M
authors.lastname: Sato
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okumura
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001281:Atrial Fibrillation / Q000139:chemically induced* / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000008:administration & dosage / Q000633:toxicity*; D011224:Prazosin / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000502:physiology; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects* / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D018340:Receptors, Adrenergic, alpha-1; D018342:Receptors, Adrenergic, beta-1; D008790:Metoprolol; D009638:Norepinephrine; D011224:Prazosin