Effects of a novel Mac-1 inhibitor, NPC 15669, on hemostatic parameters during preconditioned myocardial infarction

NPC 15669, a member of the leumedins family inhibits leukocyte adhesion to the endothelium by blockage of upregulation of a member of beta 2 integrin family Mac-1 (CD11b/CD18). Inhibition of neutrophil-endothelial interaction s may alter the course of myocardial reperfusion injury. However, the effec ts of NPC 15669 supplementation on the hemostatic profile during ischemia-r eperfusion are unknown. The aim of the present study was to define changes in the certain hemostatic factors in the natural course of preconditioned m yocardial infarction. Twelve consecutive Yorkshire swine underwent myocardi al stunning (8 min. left anterior descending artery occlusion followed by 9 0 min. of reperfusion) and then preconditioned myocardial infarction (50 mi n. occlusion followed by 3 hours of reperfusion) experiments. NPC 15669 (10 mg/kg loading dose followed by constant infusion at 6 mg.kg(-1).h(-1)) was administered in 6 animals; another 6 swine received saline and served as c ontrols. Blood samples were obtained at baseline, twice during occlusion; a nd three times during reperfusion. The levels of antithrombin-III, Protein C, total Protein S, fibronectin, endothelin-1, as well as the stable metabo lites of thromboxane (TxB(2)) and prostacyclin (6-keto-PGF(1a)), were deter mined. NPC 15669 treatment was associated with diminished endothelin-1, TxB 2 levels and increased fibronectin, 6-keto-PGF(1a), Protein C and total Pro tein S concentrations in the setting of preconditioned myocardial infarctio n. There were no changes in the plasma concentrations of antithrombin-III i n NPC 15669 group when compared with controls. The increase in Protein C, t otal Protein S, and 6-keto-PGF(1a) (favoring antithrombosis), and decrease in endothelin-l and TxB(2) levels (favoring vasodilatation), following NPC 15669 may explain the reduction in infarct size previously reported with th is agent.