title: Combined effects of up- and downstream therapies on atrial fibrillation in a canine rapid stimulation model.
abstract: BACKGROUND
  Recent reports suggest angiotensin receptor blockers (ARBs) and some antiarrhythmic agents affect atrial remodeling in atrial fibrillation (AF). We evaluated the effect of combination therapy with olmesartan (Olm) and bepridil (Bep) in a canine model of AF.
  
  
  RESULTS
  An atrial stimulation device was implanted in 10 dogs undergoing 6-week pacing at 400 bpm. They were divided into Olm (2 mg/kg/day) (n=5) and Olm+Bep (Olm, 2 mg/kg/day; Bep, 10 mg/kg/day) groups (n=5). Atrial effective refractory period (AERP), conduction velocity (CV), and AF inducibility were evaluated weekly, and hemodynamics, atrial histology, and mRNA expression and protein expression of ion-channel and gap junction-related molecules at 6 weeks. Data were compared between groups and with non-pacing control and pacing-control groups from our previous report. The pacing-control group exhibited shortened AERP, decreased CV, increased AF inducibility and tissue fibrosis, and down-regulated L-type Ca(2+) channel (LCC), SCN5A, Kv4.3 and connexin43 (Cx43). By comparison, the Olm group exhibited suppression of the decrease in CV and of the increase in AF inducibility, but no change in AERP shortening. The Olm+Bep group exhibited suppression of AERP shortening as well as the greatest decrease in AF inducibility. Histologically, tissue fibrosis was suppressed in Olm and Olm+Bep groups. Down-regulation of Cx43 was partly suppressed in the Olm group while that of LCC, SCN5A, and Cx43 was suppressed in the Olm+Bep group.
  
  
  CONCLUSIONS
  Olm and Bep in combination suppressed AF inducibility more strongly than Olm alone, and may be more useful in the suppression of AF.
authors.affiliation: Kitasato University, School of Medicine, Department of Cardio-Angiology, Sagamihara, Japan. hidehira@med.kitasato-u.ac.jp
authors.forename: Hidehira
authors.initials: H
authors.lastname: Fukaya
authors.forename: Shinichi
authors.initials: S
authors.lastname: Niwano
authors.forename: Hiroe
authors.initials: H
authors.lastname: Niwano
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Masaki
authors.forename: Michiro
authors.initials: M
authors.lastname: Kiryu
authors.forename: Shoji
authors.initials: S
authors.lastname: Hirasawa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sato
authors.forename: Masahiko
authors.initials: M
authors.lastname: Moriguchi
authors.forename: Tohru
authors.initials: T
authors.lastname: Izumi
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D015764:Bepridil / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004285:Dogs; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004359:Drug Therapy, Combination; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000008:administration & dosage*; D013777:Tetrazoles / Q000008:administration & dosage*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000889:Anti-Arrhythmia Agents; D007093:Imidazoles; D013777:Tetrazoles; D015764:Bepridil; C437965:olmesartan