Pharmacological changes in cellular Ca2+homeostasis parallel initiation of atrial arrhythmogenesis in murine langendorff-perfused hearts

P>Intracellular Ca2+ 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 Ca2+ homeostasis in isolated atrial myocytes following pharmacological procedures that modified the storage or release of sarcoplasmic reticular (SR) Ca2+ or inhibited entry of extracellular Ca2+. Caffeine (1 mmol/L) elicited diastolic Ca2+ 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 Ca2+ depletion. Cyclopiazonic acid (CPA; 0.15 mu mol/L) produced more gradual reductions in evoked Ca2+ transients and abolished diastolic Ca2+ events produced by the further addition of caffeine. Nifedipine (0.5 mu mol/L) produced immediate reductions in evoked Ca2+ transients. Further addition of caffeine produced an immediate increase followed by a decline in the amplitude of the evoked Ca2+ transients, without eliciting diastolic Ca2+ events. 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. Together, these findings relate acute atrial arrhythmogenesis in intact hearts to diastolic Ca2+ events in atrial myocytes that, in turn, depend upon a finite SR Ca2+ store and diastolic Ca2+ release following Ca2+-induced Ca2+ release initiated by the entry of extracellular Ca2+.