In the present study, the cardioprotective effects of insulin-like growth factor I (IGF-I) were examined in a murine model of myocardial ischemia reperfusion (i.e., 20 min + 24 hr). IGF-I (1-10 micrograms per rat) administered 1 hr prior to ischemia significantly attenuated myocardial injury (i.e., creatine kinase loss) compared to vehicle (P < 0.001). In addition, cardiac myeloperoxidase activity, an index of neutrophil accumulation, in the ischemic area was significantly attenuated by IGF-I (P < 0.001). This protective effect of IGF-I was not observed with des-(1-3)-IGF-I. Immunohistochemical analysis of ischemic-reperfused myocardial tissue demonstrated markedly increased DNA fragmentation due to programmed cell death (i.e., apoptosis) compared to nonischemic myocardium. Furthermore, IGF-I significantly attenuated the incidence of myocyte apoptosis after myocardial ischemia and reperfusion. Therefore, IGF-I appears to be an effective agent for preserving ischemic myocardium from reperfusion injury and protects via two different mechanisms--inhibition of polymorphonuclear leukocyte-induced cardiac necrosis and inhibition of reperfusion-induced apoptosis of cardiac myocytes.