COMBINED ADP AND THROMBOXANE A(2) ANTAGONISM PREVENTS CYCLIC FLOW VARIATIONS IN STENOSED AND ENDOTHELIUM-INJURED ARTERIES IN NONHUMAN-PRIMATES

Background. This study was designed to test the hypothesis that clopid ogrel, a potent inhibitor of platelet aggregation, can eliminate cycli c Bow variations in stenosed and endothelium-injured coronary and femo ral arteries in nonhuman primates. Methods and Results. We studied fiv e anesthetized, open-chest baboons. Blood flow velocity in the coronar y and femoral arteries was monitored by pulsed Doppler Bow probes plac ed around the arteries. Cyclic flow variations were established by mec hanically injuring the endothelium of the arteries and by narrowing th e arteries with external constrictors. Clopidogrel (10 to 20 mg/kg IV bolus plus 2.5 mg.kg(-1).h(-1) continuous infusion) was administered 6 0 minutes after cyclic flow variations were established. Clopidogrel a bolished cyclic flow variations in the coronary and femoral arteries o f all five baboons (frequency of cyclic flow variations, 0/h versus 14 /h at baseline, P<.001). Then epinephrine was infused (maximum average dose, 2.2 mu g.kg(-1). min(-1) IV). Epinephrine did not restore cycli c flow variations in the coronary or femoral arteries of any baboon. B efore treatment with clopidogrel, ADP, collagen, and U46619, a thrombo xane Az mimetic, induced dose-dependent platelet aggregation in vitro. Serotonin, however, did not induce platelet aggregation in vitro. Clo pidogrel given in vivo completely inhibited ADP-induced platelet aggre gation and significantly diminished collagen- and U46619-induced plate let aggregation in vitro. Conclusions. Clopidogrel eliminates cyclic f low variations in stenosed and endothelium-injured coronary and femora l arteries of nonhuman primates at least in part by antagonizing the p latelet proaggregatory effects of ADP and thromboxane Az.