Total coronary artery occlusion and reperfusion result in attenuation of coronary blood flow reserve, regional myocardial dysfunction, and myocardial leukocyte infiltration. To examine the effects of intracoronary adenosine on these occlusion and reperfusion-induced perturbations, we subjected 14 dogs to total left anterior descending (LAD) coronary artery occlusion (1 hour) and reperfusion (1 hour). Seven dogs received adenosine (3.75 mg/min into the LAD distal to the occlusion) over a 1-hour period starting 5 minutes before reperfusion, and the remaining seven dogs received saline solution. One dog in each group died of ventricular fibrillation during coronary artery occlusion. Coronary flow reserve, measured as peak reactive hyperemia (10 and 20 seconds of total coronary artery occlusion) and peak coronary blood flow response to acetylcholine (0.01 to 1.0 micrograms) and nitroglycerin (5 to 25 micrograms), was impaired in the LAD region after LAD occlusion and reperfusion in the saline-treated dogs (all p < 0.01 vs before occlusion and reperfusion); LAD regional myocardial shortening fraction measured by ultrasonic crystals was also diminished after occlusion and reperfusion in saline-treated dogs (-5% +/- 1% vs 12% +/- 2%; p < 0.02). The adenosine-treated dogs showed total protection against loss of coronary flow reserve (peak reactive hyperemia and blood flow increase in response to acetylcholine and nitroglycerin; all p values not significant vs before LAD occlusion and reperfusion). LAD regional myocardial shortening fraction was also preserved in adenosine-treated dogs (9% +/- 2% vs 14% +/- 2%; p not significant). Myocardial myeloperoxidase activity, measured as an index of myocardial leukocyte infiltration, was greater (p < 0.02) in the LAD ischemic-reperfused regions than in nonischemic circumflex regions in the saline-treated dogs. A similar difference in myeloperoxidase activities in the reperfused and control regions was not observed in the adenosine-treated dogs. Thus adenosine protects against loss of coronary flow reserve and regional myocardial function in dogs subjected to coronary artery occlusion and reperfusion.