The effect of ischemic preconditioning (IP; 3 min ischemia plus 3 min reperfusion) on the recovery of cardiac function after Ca2+ depletion was investigated. Isolated rat hearts were subjected to different cycles of IP episodes followed by Ca2+ free perfusion and repletion. Perfusion of control hearts with Ca2+ free medium for 5 min followed by repletion of Ca2+ for 30 min resulted in a marked decrease in the left ventricular (LV) developed pressure and an increase in LV end-diastolic pressure (Ca2+ paradox). The depressed function due to Ca2+ paradox recovered with three cycles of IP. Myoglobin release during Ca2+ repletion also decreased significantly by three cycles of IP. The beneficial effects of IP were also evident when the hearts were subjected to a mild form of Ca2+ paradox involving 3 min Ca2+ depletion. The protective effect rendered by IP disappeared when 10 microM of 8-(p-sulfophenyl)-theophylline, adenosine antagonist was perfused for 10 min before IP. These results suggest that IP exerts beneficial effects on Ca2+ paradox which may be mediated by adenosine.