Differential effects of thromboxane A2 synthase inhibition, singly or combined with thromboxane A2/prostaglandin endoperoxide receptor antagonism, on occlusive thrombosis elicited by endothelial cell injury or by deep vascular damage in canine coronary arteries.
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.
Vandeplassche
G
G
Department of Cardiovascular Pharmacology, Janssen Research Foundation, Beerse, Belgium.
Hemans
C
C
Van de Water
A
A
Xhonneux
R
R
Wouters
L
L
Van Ammel
K
K
De Clerck
F
F
D000818:Animals; D003328:Coronary Thrombosis / Q000209:etiology* / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology; D004285:Dogs; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D006439:Hemodynamics; D066298:In Vitro Techniques; D008297:Male; D010421:Pentanoic Acids / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane; D013449:Sulfonamides / Q000494:pharmacology; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D010421:Pentanoic Acids; D011725:Pyridines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; C055662:prostaglandin endoperoxide receptor; D013928:Thromboxane A2; C040624:sulotroban; D013930:Thromboxane-A Synthase; C060219:ridogrel