AIM: To study the mediating effect of calcitonin gene-related peptide (CGRP) in ischemic preconditioning in the isolated perfused rat heart. METHODS: Isolated rat hearts were subjected to 3 cycles of a 5-min ischemia and a 5-min reperfusion before a 30-min global ischemia followed by a 30-min reperfusion. RESULTS: Ischemic preconditioning caused an improvement of heart functions, reduced the incidence of ventricular arrhythmias and decreased the release of creatine kinase (CK) during reperfusion (CK activities = 0.30 +/- 0.07, 2.03 +/- 0.49, and 0.92 +/- 0.40 U . min(-1)/g wet wt for control, ischemia-reperfusion, and preconditioning, respectively). However, pretreatment with CGRP(8-37) (0.1 mu mol . L(-1)) abolished the improvement of cardiac contractivity, the reduction of the incidence of arrhythmias, and the inhibition of CK release by preconditioning (CK activities = 0.9 +/- 0.4 vs 2.55 +/- 0.32 U . min(-1)/g wet wt, P < 0.01). CONCLUSION: CGRP is an endogenous myocardial protective substance that played an important role in mediation of ischemic preconditioning.