Integrative Analysis of Calcium Cycling in Cardiac Muscle

<jats:p> <jats:italic>Abstract</jats:italic> —The control of intracellular calcium is central to regulation of contractile force in cardiac muscle. This review illustrates how analysis of the control of calcium requires an integrated approach in which several systems are considered. Thus, the calcium content of the sarcoplasmic reticulum (SR) is a major determinant of the amount of Ca <jats:sup>2+</jats:sup> released from the SR and the amplitude of the Ca <jats:sup>2+</jats:sup> transient. The amplitude of the transient, in turn, controls Ca <jats:sup>2+</jats:sup> fluxes across the sarcolemma and thence SR content. This control of SR content influences the response to maneuvers that modify, for example, the properties of the SR Ca <jats:sup>2+</jats:sup> release channel or ryanodine receptor. Specifically, modulation of the open probability of the ryanodine receptor produces only transient effects on the Ca <jats:sup>2+</jats:sup> transient as a result of changes of SR content. These interactions between various Ca <jats:sup>2+</jats:sup> fluxes are modified by the Ca <jats:sup>2+</jats:sup> buffering properties of the cell. Finally, we predict that, under some conditions, the above interactions can result in instability (such as alternans) rather than ordered control of contractility. </jats:p>