Cardiac contractility is regulated by changes in intracellular Ca concentration ([Ca2+]i). Normal function requires that [Ca2+]i be sufficiently high in systole and low in diastole. Much of the Ca needed for contraction comes from the sarcoplasmic reticulum and is released by the process of calcium-induced calcium release. The factors that regulate and fine-tune the initiation and termination of release are reviewed. The precise control of intracellular Ca cycling depends on the relationships between the various channels and pumps that are involved. We consider 2 aspects: (1) structural coupling: the transporters are organized within the dyad, linking the transverse tubule and sarcoplasmic reticulum and ensuring close proximity of Ca entry to sites of release. (2) Functional coupling: where the fluxes across all membranes must be balanced such that, in the steady state, Ca influx equals Ca efflux on every beat. The remainder of the review considers specific aspects of Ca signaling, including the role of Ca buffers, mitochondria, Ca leak, and regulation of diastolic [Ca2+]i.

Abstract-The aim of this work was to investigate whether beat-to-beat alternation in the amplitude of the systolic Ca 2ϩ transient (Ca 2ϩ alternans) is due to changes of sarcoplasmic reticulum (SR) Ca 2ϩ content, and if so, whether the alternans arises due to a change in the gain of the feedback controlling SR Ca 2ϩ content. We found that, in rat ventricular myocytes, stimulating with small (20 mV) depolarizing pulses produced alternans of the amplitude of the Ca 2ϩ transient. Confocal measurements showed that the larger transients resulted from propagation of Ca 2ϩ waves. SR Ca 2ϩ content (measured from caffeine-evoked membrane currents) alternated in phase with the alternans of Ca 2ϩ transient amplitude. After a large transient, if SR Ca 2ϩ content was elevated by brief exposure of the cell to a Na ϩ -free solution, then the alternans was interrupted and the next transient was also large. This shows that changes of SR Ca 2ϩ content are sufficient to produce alternans. The dependence of Ca 2ϩ transient amplitude on SR content was steeper under alternating than under control conditions. During alternation, the Ca 2ϩ efflux from the cell was also a steeper function of SR Ca 2ϩ 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 Ca 2ϩ content.

Abstract-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 2ϩ released from the SR and the amplitude of the Ca 2ϩ transient. The amplitude of the transient, in turn, controls Ca 2ϩ 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 2ϩ release channel or ryanodine receptor. Specifically, modulation of the open probability of the ryanodine receptor produces only transient effects on the Ca 2ϩ transient as a result of changes of SR content. These interactions between various Ca 2ϩ fluxes are modified by the Ca 2ϩ 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.

Voltage clamp experiments on isolated sheep Purkinje fibres showed an increase of the steady state outward membrane current, over the potential range -65mV to -15 mV, in the presence of tetrodotoxin (TTX, 3.10(-5 M). This "window" current is considered to be the steady state component of the fast sodium current (INa), resulting from the crossover of the activation and inactivation curves which govern the opening of the sodium channel. TTX had no significant effect on the reversal potential, activation curve, kinetics or instantaneous I-V relationship of the pacemaker current IK2. The window found in these experiments extends to potentials well into the range of the action potential plateau. Consequently small changes of the steady state INa might have large effects on the action potential duration. The effects of TTX and local anaesthetics are discussed in this context.