Fig. 5. Positive inotropic effect of raising extracellular Ca²⁺. Progressive centripetal propagation of Ca²⁺ signals promotes contraction of atrial cardiomyocytes. The traces shown were obtained from a single atrial myocyte that was electrically paced and loaded with the Ca²⁺ indicator fluo3. Ca²⁺ elevation is denoted by an increase in fluo3 emission. The cell was electrically paced at a constant frequency, just as if it was receiving a regular action potential from the sinoatrial node. To simulate the effect of a positive inotropic agonist, the extracellular Ca²⁺ concentration was elevated from 1 to 10 mM as indicated. This provides a larger Ca²⁺ influx signal and ultimately leads to increased SR Ca²⁺ content, thereby mimicking the effect of ß-adrenergic stimulation (Huser et al., 1996; Mackenzie et al., 2004a), but without changing the phosphorylation status of any of the proteins involved in EC coupling. The inward movement of Ca²⁺ within the cell was monitored by observing changes in nuclear Ca²⁺ concentration. Since atrial cell nuclei are centrally positioned, and nuclear Ca²⁺ derives almost exclusively from the surrounding cytoplasm, they are ideal cellular areas in which the ability of Ca²⁺ to penetrate into cells can be assessed. The change of extracellular Ca²⁺ did not affect the amplitude of Ca²⁺ signals in the sub-sarcolemmal region where EC coupling was initiated, but it caused a progressive increase in Ca²⁺ signalling in the remainder of the cell, as shown by the increased amplitude of the signals in the nuclear region. Concomitantly with greater inward movement of Ca²⁺, the cellular contraction was enhanced.