Pharmacological changes in cellular Ca2+ homeostasis parallel initiation of atrial arrhythmogenesis in murine Langendorff-perfused hearts.
1. Intracellular Ca(2+) overload has been associated with established atrial arrhythmogenesis. The present experiments went on to correlate acute initiation of atrial arrhythmogenesis in Langendorff-perfused mouse hearts with changes in Ca(2+) homeostasis in isolated atrial myocytes following pharmacological procedures that modified the storage or release of sarcoplasmic reticular (SR) Ca(2+) or inhibited entry of extracellular Ca(2+). 2. Caffeine (1 mmol/L) elicited diastolic Ca(2+) waves in regularly stimulated atrial myocytes immediately following addition. This was followed by a decline in the amplitude of the evoked transients and the disappearance of such diastolic events, suggesting partial SR Ca(2+) depletion. 3. Cyclopiazonic acid (CPA; 0.15 micromol/L) produced more gradual reductions in evoked Ca(2+) transients and abolished diastolic Ca(2+) events produced by the further addition of caffeine. 4. Nifedipine (0.5 micromol/L) produced immediate reductions in evoked Ca(2+) transients. Further addition of caffeine produced an immediate increase followed by a decline in the amplitude of the evoked Ca(2+) transients, without eliciting diastolic Ca(2+) events. 5. These findings correlated with changes in spontaneous and provoked atrial arrhythmogenecity in mouse isolated Langendorf-perfused hearts. Thus, caffeine was pro-arrhythmogenic immediately following but not > 5 min after application and both CPA and nifedipine pretreatment inhibited such arrhythmogenesis. 6. Together, these findings relate acute atrial arrhythmogenesis in intact hearts to diastolic Ca(2+) events in atrial myocytes that, in turn, depend upon a finite SR Ca(2+) store and diastolic Ca(2+) release following Ca(2+)-induced Ca(2+) release initiated by the entry of extracellular Ca(2+).
Zhang
Yanmin
Y
Physiological Laboratory, University of Cambridge, Cambridge, UK.
Schwiening
Christof
C
Killeen
Matthew J
MJ
Zhang
Yanhui
Y
Ma
Aiqun
A
Lei
Ming
M
Grace
Andrew A
AA
Huang
Christopher L-H
CL
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D010477:Perfusion / Q000379:methods; D000069437:Pharmacological Phenomena / Q000502:physiology
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D007211:Indoles; D002110:Caffeine; D009543:Nifedipine; D002118:Calcium; C000543:cyclopiazonic acid