Myocardial ischemia-reperfusion alters regional and systemic platelet function. The aim of our study was to elucidate the role of the Mac-1 receptor in changes of platelet function by using the leumedin, NPC-15669, an inhibitor of Mac-1 upregulation. In an open-chest swine model (n = 15), the treatment group (n = 6) received NPC-15669 (10 mg/kg loading dose over 12 min at the rate of 5 ml/min at the onset of left-anterior descending coronary artery occlusion, followed by constant infusion at 6 mg kg-1 h-1 during 90 min of reperfusion). Regional platelet aggregation (response to 5 microM ADP) increased after 15 min occlusion (126% of baseline) and at 90 min of reperfusion (156% of baseline). This increase in platelet aggregability was inhibited by NPC-15669 (83% of baseline after 15 min occlusion and 98% of baseline at 90 min reperfusion, both p < 0.001 compared to control). Systemic platelet function was not affected by NPC-15669 after 15 min occlusion (102% of baseline vs. 96% of baseline for control, p = NS). At 90 min of reperfusion platelet function was increased in controls (131% of baseline) and not affected by NPC-15669 (126% of baseline, p = NS). Myocardial neutrophil accumulation did not differ between the control and treatment groups. Inhibition of Mac-1 upregulation by NPC-15669 attenuates the increased regional platelet aggregability resulting from myocardial ischemia-reperfusion, with a less marked effect on the systemic response. The data suggest that Mac-1 may modulate regional platelet responses induced by ischemia-reperfusion. The increased aggregability of platelets during ischemia and reperfusion and its attenuation by inhibition of Mac-1 may be relevant for future strategies to reduce coronary arterial occlusion by platelet thrombi.