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

• 1 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⁺.
• 2 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.
• 3 Cyclopiazonic acid (CPA; 0.15 µmol/L) produced more gradual reductions in evoked Ca²⁺ transients and abolished diastolic Ca²⁺ events produced by the further addition of caffeine.
• 4 Nifedipine (0.5 µmol/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.
• 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 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⁺.