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 (0.0 3, 0.1 mg kg(-1) intravenously [iv]) and metoclopramide (0.1, 0.3 mg k g(-1) iv) alone or in combination. The animal model chosen for this st udy involved the generation of cyclic flow variations (CFV) in the cir cumflex coronary artery of anaesthetized dogs as a result of a critica l coronary stenosis associated with a controlled arterial lesion at th e site of stenosis. Subsequent regular CFV represent sequential thromb us formation and embolization in the damaged vessel. Neither aspirin n or metoclopramide alone demonstrated antithrombotic properties at the doses tested. However, the combination of aspirin 0.1 mg kg(-1) iv and metoclopramide 0.3 mg kg(-1) iv 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 bl ood 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 antithromb otic influence of metoclopramide could be due to its 5HT(2)-antagonist or alpha(2)-antagonist properties, both of which would inhibit platel et aggregation. This demonstration of a synergistic antithrombotic act ion of the combination of aspirin and metoclopramide is of interest si nce these two agents are often combined in clinical use. Its therapeut ic relevance, however, remains to be established.