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Pharmacological changes in cellular Ca 2+ homeostasis parallel initiation of atrial arrhythmogenesis in murine langendorff‐perfused hearts
Author(s) -
Zhang Yanmin,
Schwiening Christof,
Killeen Matthew J,
Zhang Yanhui,
Ma Aiqun,
Lei Ming,
Grace Andrew A,
Huang Christopher LH
Publication year - 2009
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2009.05170.x
Subject(s) - cyclopiazonic acid , caffeine , medicine , diastole , chemistry , myocyte , extracellular , nifedipine , homeostasis , calcium , endocrinology , ryanodine receptor , diastolic depolarization , heart rate , sinoatrial node , biochemistry , blood pressure
Summary1 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 µmol/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 µmol/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+ .