Background: NPC is a member of the leumedins and is an inhibitor of leukocyte adhesion to endothelium via blockage of integrin binding. NPC 15669 also may have antiplatelet effects. We tested the efficacy of the novel leukocyte recruitment inhibitor NPC 15669 on myocardial stunning (MS) and preconditioned myocardial infarction (MI). Methods and Results: In an open-chested swine model, NPC 15669 (10 rng NPC/kg loading dose followed by constant infusion at 6 mg/kg/hr) was administered in six animals. Myocardial thickening (MT) was determined by epicardial ultrasound. The left anterior descending artery was occluded for 8 minutes followed by 90 minutes of reperfusion, during which myocardial MT was recorded at regular intervals. We have found that treatment with NPC 15669 increases myocardial contractility and significantly decreases MS time compared to controls (26.7 +/- 4.0 minutes vs. 50.0 +/- 4.3 minutes, p =.0026). In NPC 15669-treated animals we observed a reduction of MI size (23.4 +/- 6.7% of tissue at risk became necrotic compared to 53.0 +/- 6.6% in controls, p =.0102). Conclusions: Our data suggest that NPC 15669 significantly reduces myocardial injury in both the stunning and infarction models.