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.

Abstract

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.

Ridogrel Inhibits Systemic and Renal Formation of Thromboxane A2 and Antagonizes Platelet Thromboxane A2/Prostaglandin Endoperoxide Receptors upon Chronic Administration to Man

“…However, such a low grade antagonism of TXA 2 /PG endoperoxide receptors when superimposed on a strong reduction of TXA 2 synthase activity may produce substantial functional effects. That possibility is corroborated by the anti-platelet activity of ridogrel at dual acting doses, stronger than that of either single TXA 2 synthase or TXA 2 /PG endoperoxide receptor antagonism, in preventing coronary thrombosis, speeding up rt-PA thrombolysis and preventing re-occlusion after successful lysis in animal models (7,21,47,49).…”

“…However, specific inhibition of the TXA 2 synthase produces an accumulation of PG endoperoxides, activating platelet and vascular TXA 2 /PG endoperoxide receptors and attenuating the inhibitory effects of PGI 2 and PGD 2 . Therefore, a combination of TXA 2 synthase inhibition and of TXA 2 /PG endoperoxide receptor antagonism has been advocated as an improved pharmacological maneuver against platelet-dependent thrombus formation (7,14,16,(18)(19)(20)(21)(22).…”

Acadesine Reduces the Frequency of Coronary Artery Reocclusion Following rt-PA Induced Thrombolysis in the Dog

“…While this hypothesis remains to be studied directly, similar conclusions were reached by Vandeplassche el al. (28), who demonstrated that prevention of arterial occlusion following deep vascular injury required a higher dose of ridogrel (a thromboxane synthase inhibilor/receplor antagonist) than that needed for prevention of platelet-dependent cyclic coronary flow reductions. These investigators suggested that the higher dose of ridogrel would be expected to result in greater platelet concentrations of cAMP and, hence, antithrombotic activity.…”

Effects of U-46619 on Pulmonary Hemodynamics Before and After Administration of BM-573, a Novel Thromboxane A2 Inhibitor

“…However, specific inhibitors of TXA 2 synthase are also responsible for increasing generation of prostanoids such as prostaglandin I 2 , which can be beneficial by attenuating platelet activation and decreasing vascular resistance. Therefore, efforts to modulate the actions of TXA 2 focused on agents able to block biosynthesis of TXA 2 and to antagonize both PGH 2 and TXA 2 at their common receptor (Oates et al, 1988;Vandeplassche et al, 1991;Vandeplassche et al, 1993).…”