1. This study examined the potential role of tumor necrosis factor-alpha (TNF-alpha) in myocardial ischemia-reperfusion injury using an anesthetized rat model of myocardial infarction. 2. The key endpoints were infarct size and serum TNF-alpha levels (measured by a specific ELISA technique). 3. Three groups of rats were studied: vehicle controls (n=6); positive controls for infarct size reduction (ischemic preconditioning; n=6); and a group treated with the selective inhibitor of PDE-IV and TNF-alpha production, rolipram (1 mg/kg i.v. 10-min prereperfusion + 1 microg/kg per minute through 1-hr reperfusion, n=6). 4. Baseline preischemia levels of serum TNF-alpha were low (approximately 0.1 nM) and showed a trend for further reduction in all treatment groups at 1 min and 3 hr into the postischemia reperfusion period. 5. Infarct size (68+/-2% of the ischemic area in controls) was significantly reduced (41% decrease) by preconditioning, but was unchanged in rolipram-treated animals. 6. Collectively, these data argue against an important role for TNF-alpha in lethal reperfusion injury in this rat model of myocardial infarction.