Increased thromboxane biosynthesis in a human preparation of platelet activation: biochemical and functional consequences of selective inhibition of thromboxane synthase.

Abstract

Although thromboxane A2 is a potent platelet agonist and vasoconstrictor in vitro, our knowledge of its pathophysiologic importance in human disease is limited. To facilitate the elucidation of its role in vivo, we sought to define a human syndrome in which pharmacologic interventions designed to inhibit the biosynthesis or biologic actions of thromboxane A2 might be appropriately assessed. Patients with severe peripheral vascular disease were selected on the basis of elevated plasma ,8-thromboglobulin and circulating platelet aggregates and compared with healthy, age-matched control subjects. In addition to the platelet indexes, their bleeding time was shorter and excretion of 2,3-dinor-thromboxane B2, a noninvasive index of thromboxane formation in vivo, and 2,3-dinor-6-ketoprostaglandin F,a, the major urinary metabolite of prostacyclin, was markely increased. A selective inhibitor of thromboxane synthase, imidazo (1,5-2) pyridine-5-hexanoic acid, was administered to these patients under randomized, double-blind, controlled conditions. Platelet aggregation ex vivo, the circulating platelet aggregate ratio, and the bleeding time were all unaltered, despite almost maximal inhibition of platelet thromboxane formation 1 hr after dosing. By contrast, pronounced inhibition of aggregation was observed when platelet cyclooxygenase was inhibited by aspirin. During long-term dosing with the synthase inhibitor, inhibition of thromboxane biosynthesis was incomplete, which would permit continued thromboxane-dependent platelet aggregation to occur. However, the failure of enzyme blockade to influence platelet function at the time of maximal drug action, despite efficient inhibition of serum thromboxane B2, suggests that accumulation of proaggregatory endoperoxides is also likely to have contributed to the persistence of platelet activation. We have characterized a human preparation in which platelet activation coexists with increased thromboxane biosynthesis. In this setting, platelet activation persists despite long-term administration of a thromboxane synthase inhibitor in a dosing regimen representative of that employed in clinical trials. Prolongation of drug action and combination with antagonists of the shared endoperoxide/thromboxane A2 receptor may be necessary to assess the potential of selective inhibition of thromboxane synthase as a therapeutic strategy in man.Circulation 73, No. 6, 1300No. 6, -1309No. 6, , 1986 IN VIEW OF the potential importance of the proaggregatory platelet eicosanoid thromboxane A2 in the mediation of vascular occlusive events in vivo, there has been considerable interest in the effects of selective From the

Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice

“…PGI 2 biosynthesis also increased in the mice as they developed atherosclerosis. Again, this is consistent with observations in human atherosclerosis (11,13) and probably reflects a homeostatic response to accelerated platelet-vessel-wall interactions. The biochemically selective dose of nimesulide suppressed excretion of the PGI metabolite by approximately 60%, suggesting that COX-2 was a prominent source of the increase in PGI 2 biosynthesis.…”

“…Urinary Tx biosynthesis, as reflected by metabolite excretion in urine, increased in the LDLR-KO mice as they developed atherosclerosis. Thus, despite the resistance of atherosclerotic mice to plaque fissure and thrombosis, they develop biochemical evidence of increased platelet activation, as is the case in atherosclerotic patients (11,13). Nimesulide had no effect on endogenous Tx biosynthesis, again consistent with observations with selective doses of COX-2 inhibition in humans (48).…”

“…Therefore, such studies do not address the possibility that platelets activated in the circulation of patients with atherosclerosis (11) might release products that modulate lesion progression, and controlled clinical trials of antiplatelet agents on plaque progression have not been performed. Similarly, mouse models of atherosclerosis seem quite resistant to spontaneous thrombosis (12), and it is unknown whether their development of vascular lesions alone results in platelet activation in vivo, as is the case in human atherosclerosis (11,13).The efficacy of low-dose aspirin in platelet-dependent vascular occlusion (3-5) is consistent with the role of platelet-derived thromboxane (Tx) A 2 as an amplifying signal for activation by more potent primary platelet agonists such as thrombin (14).Platelet Tx is formed via prostaglandin endoperoxide intermediates (15) by cyclooxygenase (COX)-1 (16). An alternative source of Tx formation by macrophages and smooth-muscle cells in the vessel wall is COX-2 (17, 18).…”

“…Therefore, such studies do not address the possibility that platelets activated in the circulation of patients with atherosclerosis (11) might release products that modulate lesion progression, and controlled clinical trials of antiplatelet agents on plaque progression have not been performed. Similarly, mouse models of atherosclerosis seem quite resistant to spontaneous thrombosis (12), and it is unknown whether their development of vascular lesions alone results in platelet activation in vivo, as is the case in human atherosclerosis (11,13).…”

Vascular responses to platelet activation in normal and atherosclerotic primates in vivo.

“…33 Vasodilator responses to ADP, which are mediated through release of endothelium-derived relaxing factor, are attenuated in atherosclerotic arteries. 7 We have demonstrated previously that constrictor responses to serotonin and TxA 2 are augmented in atherosclerotic vessels in vivo.…”