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Sarcoplasmic Reticulum Calcium Content Fluctuation Is the Key to Cardiac Alternans

From the Unit of Cardiac Physiology, School of Medicine, University of Manchester, Manchester, UK.

Correspondence to David A. Eisner and Mary E. Díaz, Unit of Cardiac Physiology, School of Medicine, University of Manchester, 1.524 Stopford Building, Oxford Road, Manchester M13 9PT, UK. E-mail eisner{at}man.ac.uk and mary.e.diaz@man.ac.uk

The aim of this work was to investigate whether beat-to-beat alternation in the amplitude of the systolic Ca²⁺ transient (Ca²⁺ alternans) is due to changes of sarcoplasmic reticulum (SR) Ca²⁺ content, and if so, whether the alternans arises due to a change in the gain of the feedback controlling SR Ca²⁺ content. We found that, in rat ventricular myocytes, stimulating with small (20 mV) depolarizing pulses produced alternans of the amplitude of the Ca²⁺ transient. Confocal measurements showed that the larger transients resulted from propagation of Ca²⁺ waves. SR Ca²⁺ content (measured from caffeine-evoked membrane currents) alternated in phase with the alternans of Ca²⁺ transient amplitude. After a large transient, if SR Ca²⁺ content was elevated by brief exposure of the cell to a Na⁺-free solution, then the alternans was interrupted and the next transient was also large. This shows that changes of SR Ca²⁺ content are sufficient to produce alternans. The dependence of Ca²⁺ transient amplitude on SR content was steeper under alternating than under control conditions. During alternation, the Ca²⁺ efflux from the cell was also a steeper function of SR Ca²⁺ content than under control. We attribute these steeper relationships to the fact that the larger responses in alternans depend on wave propagation and that wave propagation is a steep function of SR Ca²⁺ content. In conclusion, alternans of systolic Ca²⁺ appears to depend on alternation of SR Ca²⁺ content. This, in turn results from the steep dependence on SR Ca²⁺ content of Ca²⁺ release and therefore Ca²⁺ efflux from the cell as a consequence of wave propagation.

Key Words: calcium • excitation-contraction coupling • alternans • sarcoplasmic reticulum

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