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-15 669, 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 loa ding dose over 12 min at the rate of 5 ml/min at the onset of left-ant erior descending coronary artery occlusion, followed by constant infus ion at 6 mg kg(-1) h(-1) during 90 min of reperfusion), Regional plate let aggregation (response to 5 mu M ADP) increased after 15 min occlus ion (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 r eperfusion, both p < 0.001 compared to control), Systemic platelet fun ction was not affected by NPC-15669 after 15 min occlusion (102% of ba seline vs, 96% of baseline for control, p NS), At 90 min of reperfusio n platelet function was increased in controls (131% of baseline) and n ot affected by NPC-156S9 (126% of baseline, p = NS), Myocardial neutro phil accumulation did not differ between the control and treatment gro ups, Inhibition of Mac-1 upregulation by NPC-15669 attenuates the incr eased regional platelet aggregability resulting from myocardial ischem ia-reperfusion, with a less marked effect on the systemic response, Th e data suggest that Mac-1 may modulate regional platelet responses ind uced 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 arteria l occlusion by platelet thrombi.