Activator protein 1 (AP-1) is thought to play an important role in the expression of genes expressed in response to ischemia/reperfusion injury. In this report, the activation of AP-1 in rat skeletal muscle during reperfusion following a 4-hour ischemic period was studied. AP-1 activation displayed a biphasic pattern, showing peak activities at one hour postperfusion and from 4 h to 12 h postperfusion. Inhibition of AP-1 activation was investigated using a potent antioxidant and nuclear factor kappa B inhibitor, proline dithiocarbamate (Pro-DTC). AP-1 binding activity at one hour of reperfusion was significantly reduced [29.0 +/- 10.1 %, SEM (P<0.05)] following intravenous administration of Pro-DTC (n=7 animals in each group). Caspase activity to assess apoptosis showed decreased caspase activity [69.3 +/- 10.8 %, SEM (P<0.05)] at one hour of reperfusion in the ProDTC treated muscle. AP-1 activity appears to be induced by free radicals an closely related to nuclear factor kappa B activity. In addition, we observed a decrease in apoptotic activity inhibition of both AP-1 and nuclear factor kappa B. Further elucidation of the role of AP-1 is warranted in hopes of developing strategies to reduce the deleterious effects of ischemia/reperfusion injury.