Post-ischemic reperfusion worsens myocardial injury. Ischemic preconditioning limits the damage by ischemia and reperfusion. Both adenosine and nitric oxide (NO) pathways are involved in protection. Preconditioning, however, is of little, if any, practical use as the onset of an infarction is usually unpredictable. Recently, it has been shown that the heart can be protected against the extension of reperfusion injuries if 3 or 4 brief (10-30 s) coronary occlusions are performed just at the beginning of the reperfusion. This procedure has been called post-conditioning. Post-conditioning reduces the oxidant-induced injury; moreover, it attenuates the local inflammatory response to reperfusion. Post-conditioning also activates triggers, signaling pathways and effectors implicated in other cardioprotective maneuvers, such as ischemic and pharmacological preconditioning. Post-conditioning seems to trigger the up-regulation of survival kinases principally known to attenuate the pathogenesis of apoptosis and possibly necrosis. As regards the possibility of pharmacological post-conditioning, several agents have been tested. We are testing NO donor(s), which can reduce infarct size in the rat in the absence of post-conditioning. Since during reperfusion there is a large production of reactive oxygen species, also the effect of administration of an antioxidant compound during reperfusion was studied. In the rat, such a procedure reduced the infarct size to a greater extent than post-conditioning. Moreover, an additive effect of NO donors and antioxidant compounds is possible.