Pretreatment with an inhibitor of mac-1 alters regional and systemic platelet function during ischemia-reperfusion in swine.
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.
Gurbel
P A
PA
Union Memorial Hospital, Baltimore, Md 21218, USA.
Serebruany
V L
VL
Komiathy
S F
SF
Collins
M E
ME
Bittar
G D
GD
Schlossberg
M L
ML
Mergner
W
W
D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D003327:Coronary Disease / Q000188:drug therapy / Q000517:prevention & control; D004195:Disease Models, Animal; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology*; D013552:Swine; D015854:Up-Regulation / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016177:Macrophage-1 Antigen; C071244:N-(9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl)leucine; D007930:Leucine