AIM: To study the cardioprotective effects of oxygen free radicals (OFR) and calcitonin gene-related peptide (CGRP) pretreatment on myocardial damages due to OFR in isolated perfused rat heart. METHODS: The hearts were perfused in a Langendorff mode. OFR were generated by electrolysis of Krebs-Henseleit (K-H) solution. RESULTS: OFR pretreatment reduced the impairment of cardiac contractile function, the decrease of coronary flow and the increase of creatinine kinase (CK) release due to OFR, and the effect exhibited period dependence and cycle-dependence. 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), an inhibitor of protein kinase C, abolished the protection of OFR pretreatment (CK release = 110 +/- 7, 215 +/- 23, 169 +/- 14, 240 +/- 30, and 113 +/- 19 kU.L-1 for control, OFR, OFR pretreatment, OFR pretreatment plus H-7, and H-7, respectively). CGRP pretreatment also protected the myocardium damages elicited by OFR in isolated perfused rat heart. CONCLUSIONS: OFR or CGRP pretreatment protected myocardium against injury elicited by OFR, and the effect of OFR pretreatment was related to the activation of PKC.