Combined ADP and thromboxane A2 antagonism prevents cyclic flow variations in stenosed and endothelium-injured arteries in nonhuman primates.

BACKGROUND: This study was designed to test the hypothesis that clopidogrel, a potent inhibitor of platelet aggregation, can eliminate cyclic flow variations in stenosed and endothelium-injured coronary and femoral arteries in nonhuman primates. METHODS AND RESULTS: We studied five anesthetized, open-chest baboons. Blood flow velocity in the coronary and femoral arteries was monitored by pulsed Doppler flow probes placed around the arteries. Cyclic flow variations were established by mechanically injuring the endothelium of the arteries and by narrowing the arteries with external constrictors. Clopidogrel (10 to 20 mg/kg i.v. bolus plus 2.5 mg.kg-1 x h-1 continuous infusion) was administered 60 minutes after cyclic flow variations were established. Clopidogrel abolished cyclic flow variations in the coronary and femoral arteries of 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 micrograms.kg-1 x min-1 i.v.). Epinephrine did not restore cyclic flow variations in the coronary or femoral arteries of any baboon. Before treatment with clopidogrel, ADP, collagen, and U46619, a thromboxane A2 mimetic, induced dose-dependent platelet aggregation in vitro. Serotonin, however, did not induce platelet aggregation in vitro. Clopidogrel given in vivo completely inhibited ADP-induced platelet aggregation and significantly diminished collagen- and U46619-induced platelet aggregation in vitro. CONCLUSIONS: Clopidogrel eliminates cyclic flow variations in stenosed and endothelium-injured coronary and femoral arteries of nonhuman primates at least in part by antagonizing the platelet proaggregatory effects of ADP and thromboxane A2.