title: Acute atrial arrhythmogenesis in murine hearts following enhanced extracellular Ca(2+) entry depends on intracellular Ca(2+) stores.
abstract: OBJECTIVE
  To investigate the effect of increases in extracellular Ca(2+) entry produced by the L-type Ca(2+) channel agonist FPL-64176 (FPL) upon acute atrial arrhythmogenesis in intact Langendorff-perfused mouse hearts and its dependence upon diastolic Ca(2+) release from sarcoplasmic reticular Ca(2+) stores.
  
  
  METHODS
  Confocal microscope studies of Fluo-3 fluorescence in isolated atrial myocytes were performed in parallel with electrophysiological examination of Langendorff-perfused mouse hearts.
  
  
  RESULTS
  Atrial myocytes stimulated at 1 Hz and exposed to FPL (0.1 microm) initially showed (<10 min) frequent, often multiple, diastolic peaks following the evoked Ca(2+) transients whose amplitudes remained close to control values. With continued pacing (>10 min) this reverted to a regular pattern of evoked transients with increased amplitudes but in which diastolic peaks were absent. Higher FPL concentrations (1.0 microm) produced sustained and irregular patterns of cytosolic Ca(2+) activity, independent of pacing. Nifedipine (0.5 microm), and caffeine (1.0 mm) and cyclopiazonic acid (CPA) (0.15 microm) pre-treatments respectively produced immediate and gradual reductions in the F/F(0) peaks. Such nifedipine and caffeine, or CPA pre-treatments, abolished, or reduced, the effects of 0.1 and 1.0 microm FPL on cytosolic Ca(2+) signals. FPL (1.0 microm) increased the incidence of atrial tachycardia and fibrillation in intact Langendorff-perfused hearts without altering atrial effective refractory periods. These effects were inhibited by nifedipine and caffeine, and reduced by CPA.
  
  
  CONCLUSIONS
  Enhanced extracellular Ca(2+) entry exerts acute atrial arrhythmogenic effects that is nevertheless dependent upon diastolic Ca(2+) release. These findings complement reports that associate established, chronic, atrial arrhythmogenesis with decreased overall inward Ca(2+) current.
authors.affiliation: Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: J A
authors.initials: JA
authors.lastname: Fraser
authors.forename: C
authors.initials: C
authors.lastname: Schwiening
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: M J
authors.initials: MJ
authors.lastname: Killeen
authors.forename: A A
authors.initials: AA
authors.lastname: Grace
authors.forename: C L-H
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D014966:Xanthenes / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D000889:Anti-Arrhythmia Agents; D020746:Calcium Channels, L-Type; D011758:Pyrroles; D014966:Xanthenes; C071658:FPL 64176; C059715:Fluo-3; D002110:Caffeine; D009543:Nifedipine; D002118:Calcium