The calcium paradox occurs immediately upon perfusion with calcium-containing medium after a period of calcium-free perfusion. The sequence of events occur so rapidly that it is difficult to distinguish causal factors from resultant. The present study describes a model in which calcium induced damage is produced more gradually. Isolated perfused rat hearts were subjected to brief periods of hypocalcium perfusion (< 50 μm) alternated with normal calcium perfusion (1.25 mm) over 60 min. Changes in high energy phosphate content were monitored using 31P-NMR. With repeated sequential 2-min periods of alternate hypo- and normocalcium perfusion, there was a gradual reduction in ATP and phosphocreatine with a concomitant loss of function and decline in coronary flow. There was no change in inorganic phosphate content and a small degree of acidosis. Increasing the hypocalcium concentration from 5 to 40 μm resulted in a more gradual depletion in energy stores. Trifluoroperazine (a calmodulin inhibitor) had no effect on the energetic changes. Electron microscopic studies reveal that this model of damage induced by repeated low and normal calcium perfusion has some features in common with the calcium paradox. The extent of damage induced is greater when lower calcium concentrations (5 μm) are used. © 1990.