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Pharmacological changes in cellular Ca2+ homeostasis parallel initiation of atrial arrhythmogenesis in murine langendorff-perfused hearts
Article first published online: 2 MAR 2009
© 2009 The Authors. Journal compilation © 2009 Blackwell Publishing Asia Pty Ltd
Clinical and Experimental Pharmacology and Physiology
Volume 36, Issue 10, pages 969–980, October 2009
How to Cite
Zhang, Y., Schwiening, C., Killeen, M. J., Zhang, Y., Ma, A., Lei, M., Grace, A. A. and Huang, C. L.-H. (2009), Pharmacological changes in cellular Ca2+ homeostasis parallel initiation of atrial arrhythmogenesis in murine langendorff-perfused hearts. Clinical and Experimental Pharmacology and Physiology, 36: 969–980. doi: 10.1111/j.1440-1681.2009.05170.x
- Issue published online: 20 OCT 2009
- Article first published online: 2 MAR 2009
- Received 28 November 2008; revision 30 January 2009; accepted 12 February 2009.
- atrial arrhythmogenesis;
- Ca2+ homeostasis;
- murine hearts
- 1Intracellular 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+.
- 2Caffeine (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.
- 3Cyclopiazonic 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.
- 4Nifedipine (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.
- 5These 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.
- 6Together, 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+.