The effects of modulating Ca²⁺‐induced Ca²⁺ release (CICR) in single cardiac myocytes were investigated using low concentrations of caffeine (< 500 μm) in reduced external Ca²⁺ (0.5 mm). Caffeine produced a transient potentiation of systolic [Ca²⁺]_i (to 800 % of control) which decayed back to control levels.

Caffeine decreased the steady‐state sarcoplasmic reticulum (SR) Ca²⁺ content. As the concentration of caffeine was increased, both the potentiation of the systolic Ca²⁺ transient and the decrease in SR Ca²⁺ content were increased. At higher concentrations, the potentiating effect decayed more rapidly but the rate of recovery on removal of caffeine was unaffected.

A simple model in which caffeine produces a fixed increase in the fraction of SR Ca²⁺ which is released could account qualitatively but not quantitatively for the above results.

The changes in total [Ca²⁺] during systole were obtained using measurements of the intracellular Ca²⁺ buffering power. Caffeine initially increased the fractional release of SR Ca²⁺. This was followed by a decrease to a level greater than that under control conditions. The fraction of systolic Ca²⁺ which was pumped out of the cell increased abruptly upon caffeine application but then recovered back to control levels. The increase in fractional loss is due to the fact that, as the cytoplasmic buffers become saturated, a given increase in systolic total[Ca²⁺] produces a larger increase in free [Ca²⁺] and thence of Ca²⁺ efflux.

These results confirm that modulation of the ryanodine receptor has no maintained effect on systolic Ca²⁺ and show the interdependence of SR Ca²⁺ content, cytoplasmic Ca²⁺ buffering and sarcolemmal Ca²⁺ fluxes. Such analysis is important for understanding the cellular basis of inotropic interventions in cardiac muscle.