Combination of aspirin and metoclopramide produces a synergistic antithrombotic effect in a canine model of coronary artery thrombosis

We compared the antithrombotic properties of low doses of aspirin (0.03, 0.1 mg kg-1 intravenously [iv]) and metoclopramide (0.1, 0.3 mg kg-1 iv) alone or in combination. The animal model chosen for this study involved the generation of cyclic flow variations (CFV) in the circumflex coronary artery of anaesthetized dogs as a result of a critical coronary stenosis associated with a controlled arterial lesion at the site of stenosis. Subsequent regular CFV represent sequential thrombus formation and embolization in the damaged vessel. Neither aspirin nor metoclopramide alone demonstrated antithrombotic properties at the doses tested. However, the combination of aspirin 0.1 mg kg-1 i.v. and metoclopramide 0.3 mg kg-1 i.v. produced a significant antithrombotic effect, reducing the frequency of large CFV from 6.7 +/- 0.5 to 0.8 +/- 0.4 cycles h-1 (P < 0.01) and increasing minimum mean coronary blood flow from 5.0 +/- 1.1 to 23.7 +/- 2.6 mL min-1 (P < 0.01). This result apparently reflects an antithrombotic synergism between aspirin and metoclopramide since the effects of the combination were greater than the combined effects of the individual treatments. The antithrombotic influence of metoclopramide could be due to its 5HT2-antagonist or alpha 2-antagonist properties, both of which would inhibit platelet aggregation. This demonstration of a synergistic antithrombotic action of the combination of aspirin and metoclopramide is of interest since these two agents are often combined in clinical use. Its therapeutic relevance, however, remains to be established.