In open-chest dogs, cyclic flow reductions (CFRs, 5.1-6.6/hr in controls; n = 24) caused by platelet deposition/dislodgment at sites of endothelial cell injury in critically stenosed left anterior descending coronary arteries (59% flow reduction) were attenuated to the same extent either by single
thromboxane A2 (TXA2) synthase inhibition (0.31 mg/kg i.v.
ridogrel; CFR, 0.16 +/- 0.16/hr; n = 6; p less than 0.05) or by a comparatively modest degree of TXA2/
prostaglandin endoperoxide receptor antagonism on top of TXA2 synthase inhibition (5 mg/kg i.v.
ridogrel; CFR, 0.22 +/- 0.1/hr; n = 10; p less than 0.05). By contrast, occlusive
thrombosis on deep vascular damage elicited by intraluminal stimulation (150-microA anodal constant current) in nonpreconstricted canine coronary arteries (time to occlusion, 237.1 +/- 13.9 minutes; n = 7; incidence of occlusion within 300 minutes, six of seven experiments) was not affected by platelet
cyclooxygenase inhibition (5 mg/kg i.v.
acetylsalicylic acid; n = 7), single TXA2 synthase inhibition (1.25 mg/kg i.v.
ridogrel; n = 7), or single TXA2/
prostaglandin endoperoxide receptor antagonism (10 mg/kg + 10 mg/kg/hr i.v.
sulotroban for 300 minutes; n = 5). However, such an occlusive
thrombus formation was significantly reduced by combined TXA2
synthase/prostaglandin endoperoxide receptor inhibition (5 mg/kg i.v.
ridogrel; time to occlusion greater than 300 minutes, n = 7; incidence of occlusion within 300 minutes, one of seven experiments; p less than 0.05). This study reveals 1) a differential efficacy of TXA2 synthase inhibition, singly or combined with TXA2/
prostaglandin endoperoxide receptor antagonism, depending on the extent of the vessel wall lesion triggering
thrombosis and the size of the
thrombus required to obstruct the vascular lumen and 2) a significant synergism in preventing occlusive
thrombosis of extensively damaged coronary arteries between strong TXA2 synthase inhibition and comparatively modest TXA2/
prostaglandin endoperoxide receptor antagonism with
ridogrel.