Mac-1 inhibitor affects certain hemostatic parameters during myocardial stunning in swine.
Myocardial stunning (MS) is a transient contractile dysfunction occurring subsequent to an episode of ischemia followed by reperfusion. NPC 15669 is a leumedin, which inhibits leukocyte adhesion to the endothelium by blocking Mac-1 upregulation. The effect of NPC 15669 supplementation on the hemostasis during MS is unknown. We linked the potential changes in the hemostasis with NPC 15669 therapy during mild MS. Twelve Yorkshire swine underwent coronary artery occlusion for 8 min followed by 90 min of reperfusion. NP 15669 (10 mg/kg loading dose followed by constant infusion a 6 mg kg-1 h-1) was administered to 6 of the animals; another swine received saline and served as the controls. Concentrations of antithrombin III (AT-III), protein C, total protein S, fibronectin, endothelin 1 (ET-1) and the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto-PGF1 alpha) were measured in the systemic circulation. NPC 15669 therapy was associated with diminished ET-1 (37.4%) and 6-keto-PGF1 alpha (47.1%) levels and increased fibronectin (77.6%) concentrations during MS. There were no changes in the plasma concentrations of TxB2, total protein S, protein C and AT-III in the NPC 15669 group when compared with controls. Mild MS in associated with substantial changes in the hemostatic profile. NPC 15669 administration in a swine model of MS affects certain hemostatic parameters. These data provide support for the involvement of cellular mechanisms in the pathogenesis of MS. The ability of leumedins to modulate hemostasis may have implications for their use in cardiovascular disease.
Heart Associates Research and Education Foundation, Union Memorial Hospital, Baltimore, MD 21218, USA.
V L
VL
Serebruany
S R
SR
Solomon
L R
LR
Edenbaum
W R
WR
Herzog
P A
PA
Gurbel
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000990:Antithrombin III / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006487:Hemostasis / Q000187:drug effects; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016177:Macrophage-1 Antigen / Q000187:drug effects*; D017682:Myocardial Stunning / Q000188:drug therapy* / Q000503:physiopathology; D011486:Protein C / Q000378:metabolism; D017293:Protein S / Q000378:metabolism; D015427:Reperfusion Injury / Q000503:physiopathology*; D013552:Swine; D013929:Thromboxane B2 / Q000097:blood; D015854:Up-Regulation / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001798:Blood Proteins; D019332:Endothelin-1; D005353:Fibronectins; D016177:Macrophage-1 Antigen; D011486:Protein C; D017293:Protein S; C071244:N-(9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl)leucine; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D000990:Antithrombin III; D007930:Leucine