title: Inefficacy of a highly selective T-type calcium channel blocker in preventing atrial fibrillation related remodeling.
abstract: BACKGROUND
  The T-type Ca(2+) channel (I(CaT)) blocker mibefradil prevents AF-promoting remodeling occurring with atrial tachycardia, an action that has been attributed to I(CaT) inhibition. However, mibefradil has other effects, including ability to inhibit L-type Ca(2+) channels, Na(+) channels and cytochromes. Thus, the relationship between I(CaT) inhibition and remodeling protection in AF is still unknown.
  
  
  OBJECTIVE
  To assess the effects of a novel highly selective Cav3 (I(CaT)) blocker, AZ9112, on atrial remodeling induced by 1-week atrial tachypacing (AT-P) in dogs.
  
  
  METHODS
  Mongrel dogs were subjected to AT-P at 400 bpm for 7 days, with atrioventricular-node ablation and right-ventricular demand pacing (80 bpm) to control ventricular rate. Four groups of dogs were studied in investigator-blinded fashion: (1) a sham group, instrumented but without tachypacing or drug therapy (n = 5); (2) a placebo group, tachypaced but receiving placebo (n = 6); (3) a positive control tachypacing group receiving mibefradil (n = 6); and (4) a test drug group, subjected to tachypacing during oral treatment with AZ9112 (n = 8).
  
  
  RESULTS
  One-week AT-P decreased atrial effective refractory period (ERP) at 6 of 8 sites and diminished rate-dependent atrial ERP abbreviation. Mibefradil eliminated AT-P-induced ERP-abbreviation at 4 of these 6 sites, while AZ9112 failed to affect ERP at any. Neither drug significantly affected AF vulnerability or AF duration.
  
  
  CONCLUSIONS
  I(CaT) blockade with the highly selective compound AZ9112 failed to prevent rate-related atrial remodeling. Thus, prevention of atrial electrophysiological remodeling by mibefradil cannot be attributed exclusively to I(CaT) blockade. These results indicate that I(CaT) inhibition is not likely to be a useful approach for AF therapy.
authors: Department of Medicine and Research Center, Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada.
authors: Takeshi
authors: T
authors: Kato
authors: Department of Medicine and Research Center, Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada.
authors: Yu-Ki
authors: YK
authors: Iwasaki
authors: Departments of Bioscience, AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors: Goran
authors: G
authors: Duker
authors: Medicinal Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors: Ola
authors: O
authors: Fjellstrom
authors: Medicinal Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors: Fabrizio
authors: F
authors: Giordanetto
authors: DMPK, Cardiovascular & Metabolic Diseases iMed, AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors: Monika
authors: M
authors: Sundqvist
authors: DMPK, Cardiovascular & Metabolic Diseases iMed, AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors: Anita
authors: A
authors: Wallin
authors: Departments of Bioscience, AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors: Qing-Dong
authors: QD
authors: Wang
authors: Department of Medicine and Research Center, Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada.
authors: Stanley
authors: S
authors: Nattel
mesh_terms: D000200:Action Potentials; D000818:Animals; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D064752:Atrial Remodeling / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects* / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004285:Dogs; D022062:Electrophysiologic Techniques, Cardiac; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D020748:Mibefradil / Q000494:pharmacology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013997:Time Factors
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D020748:Mibefradil
keywords: Ca channel; arrhythmia; atrial fibrillation; atrial remodeling; mibefradil