Aim To observe the effect of cyclosporin A( a inhibitor of calcineurin). On cardioprotection induced by ischemia preconditioning (IPC) and explore the role of calcineurin (CaN) signal pathway in IPC. Methods The model of ischemia /reperfusion (I/R) was produced in isolated rat heart. The cardic functions and the activity of myocardium calcineurin were mersured. Results It was found that IPC apparently attenuated the inhibition of cardic function induced by I/R. Compared with I/R group, in IPC group coronary perfusion flow(CPF),+LVdp/dt max and -LVdp/dt max decreased by 39%(P<0.01),33%(P<0.01) and 52%(P<0.01) respectively. Myocardial calcium content decreased by 21%(P<0.01). However CsA, the inhibitor of CaN, can conteract the cardioprotection effect of IPC. In addition, the activity of cardiac calcineurin was activated by cardiac I/R, compared with control group, the activity of CaN increased by 1.9 folds; ischemia preconditoning alone activated the activity of cardiac calcineurin and increased by 2.3 folds (P<0.01) compared with control group. Before ischemia preconditioning administration of CsA completely blocked the activation of calcineurin stimulated by IPC. Compared with IPC group, its activity decreased by 75%(P<0.01). Conclusion The results suggest that IPC-induced cardioprotective efffects are mediated by calcineurin pathway.