An Enzymatic Mechanism for the Antithrombotic and Antihemostatic Actions of Aspirin

Willis, A.L.

doi:10.1126/science.183.4122.325

Cited by 110 publications

(51 citation statements)

References 18 publications

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“…1. reducible with stannous chloride to PGF2a during aggregation induced by various agents also supported this view (9,10). Arachidonic acid induces aggregation when added to human platelets (11,12) and aggregating material is formed from this acid when it is incubated with preparations of sheep vesicular gland (13). The latter material has not been conclusively identified but might, in view of the work described above (9), be a mixture of PGG2 and PGH2 (14).…”

mentioning

confidence: 77%

Physiological role of an endoperoxide in human platelets: hemostatic defect due to platelet cyclo-oxygenase deficiency.

Malmsten¹,

Hámberg²,

Svensson³

et al. 1975

Proc. Natl. Acad. Sci. U.S.A.

262

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The endoperoxide prostaglandin G2 (PGG2) induced platelet aggregation as well as the platelet release reaction (release of ADP and serotonin) when added to human platelet-rich plasma. Formation of a metabolite of PGG2 [8-(1-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid] and a lipoxygenase product [12L-hydroxy-5,8,10,14-eicosatetraenoic acid] accompanied the release reaction caused by aggregating agents such as collagen, ADP, epinephrine, and thrombin. Indomethacin inhibited the release reaction and PGG2 formation induced by these agents but had no effect on PGG2-induced release reaction. The aggregating effect of PGG2 was abolished by furosemide, which is a competitive inhibitor of ADP-induced primary aggregation. These data indicate that the aggregating effect of PGG2 is due to release of ADP and that PGG2 synthesis is required for induction of the release reaction by various aggregating agents.A subject with a hemostatic defect due to abnormal release mechanism [decreased aggregation with epinephrine (second wave) and collagen and normal platelet ADP] had a deficiency of the cyclo-oxygenase that catalyzes formation of PGG2. Normal aggregation and release reaction were obtained with added PGG2.It is concluded that the endoperoxide (PGG2) is essential in normal hemostasis because of its role in initiating the release reaction required for aggregation by collagen and the second wave of aggregation caused by, e.g., ADP.

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mentioning

confidence: 77%

Physiological role of an endoperoxide in human platelets: hemostatic defect due to platelet cyclo-oxygenase deficiency.

Malmsten¹,

Hámberg²,

Svensson³

et al. 1975

Proc. Natl. Acad. Sci. U.S.A.

262

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“…The extensive transformation of added arachidonic acid into the potent aggregating agent PGG2 (2) and its metabolites provides a biochemical explanation for earlier observations on platelet aggregation induced by arachidonic acid (14,28) and appearance of an unidentified factor with aggregating properties (29,30).…”

mentioning

confidence: 82%

Prostaglandin Endoperoxides. Novel Transformations of Arachidonic Acid in Human Platelets

Hámberg

Samuelsson

1974

Proc. Natl. Acad. Sci. U.S.A.

1,207

359

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Arachidonic acid incubated with human platelets was converted into three compounds, 12L-hydroxy-5,8,10,14-eicosatetraenoic acid, 12L-hydroxy-5,8,-10-beptadecatrienoic acid, and the hemiacetal derivative of 8-(1-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid. The formation of the two latter compounds from arachidonic acid proceeded by pathways involving the enzyme, fatty acid cyclo-oxygenase, in the initial step and with the prostaglandin endoperoxide, PGG2, as an intermediate. The first mentioned compound was formed from 12L-hydroperoxy-5,8,10,14-eicosatetraenoic acid, which in turn was formed from arachidonic acid by the action of a novel lipoxygenase. Aspirin and indomethacin inhibited the fatty acid cyclo-oxygenase but not the lipoxygenase, whereas 5,8,11,14-eicosatetraynoic acid inhibited both enzymes. The almost exclusive transformation of the endoperoxide structure into nonprostaglandin derivatives supports the hypothesis that the endoperoxides can participate directly and not by way of the classical prostaglandins in regulation of cell functions. The observed transformations of arachidonic acid in platelets also explain the aggregating effect of this acid.Prostaglandins (PG) E2 and F2a are formed and released by human platelets during aggregation induced by various agents (3,4). This biosynthetic capacity has also been demonstrated with labeled precursors (5, 6).Recent work in our laboratory led to the isolation (1) of an earlier postulated (7) endoperoxide intermediate in prostaglandin biosynthesis. This finding was confirmed and extended in subsequent studies in which an additional endoperoxide derivative, carrying a hydroperoxy group at C-15, was isolated (2,8). Studies of the aggregation of human platelets also demonstrated that the biosynthetic process can stop at the endoperoxide stage resulting in release of the intermediates (PGG2 and/or PGH2) (2). Since the endoperoxides were found to be potent aggregating agents and since blockade of their formation is accompanied by inhibition of the second wave of aggregation, it was suggested that they play a physiological role in this process (2).In connection with these and other studies it became of particular interest to further investigate the transformation of arachidonic acid by human platelets. The present work demonstrates that arachidonic acid is oxygenated in this system both by the cyclo-oxygenase involved in prostaglandin [5,6,8,9,11,12,14,Arachidonic acid was prepared as described (10). 12-Hydroxyeicosanoic acid was prepared by anodic coupling of 10-acetoxyoctadecanoic acid [80 mg, prepared by acetylation of lO-hydroxyoctadecanoic acid (11)1 and methyl hydrogen succinate (300 mg). The product was hydrolyzed and subjected to silicic acid chromatography and preparative thin-layer chromatography, giving 30 mg (39%) of pure 12-hydroxyeicosanoic acid. Thin-layer chromatography of the methyl ester showed a single spot with RF = 0.57. Gasliquid chromatographic analysis of the methyl ester showed a single peak with equivalent c...

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“…In particular, they have identified a cyclic endoperoxide intermediate (prostaglandin G2) of prostaglandin synthesis in human platelets (9). The endoperoxide has been implicated as a mediator of the platelet release reaction induced by ADP and collagen (8,9). In addition, the enzyme (cyclo-oxygenase) responsible for the synthesis of prostaglandin Gs is located in the particulate fraction of human platelets (24) and is inhibited "permanently" by low concentrations (approximately 50 *rM) of aspirin (6,7,25).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies indicate that prostaglandin G2 production is stimulated by thrombin and that isolated prostaglandin G2 will cause platelet aggregation and the release reaction (8,9).…”

Section: Introductionmentioning

confidence: 99%

The mechanism of the effect of aspirin on human platelets. I. Acetylation of a particulate fraction protein.

Roth¹,

Majerus²

1975

J. Clin. Invest.

812

268

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A B S T R A C T Aspirin (acetylsalicylic acid) inhibits platelet prostaglandin synthesis and the ADP-and collagen-induced platelet release reaction. [acetyl-'H]aspirin radioactivity paralleled that of platelet turnover. Therefore, in addition to its saturability, acetylation of the particulate fraction protein by aspirin was permanent.In two respects, the inhibition of platelet function by aspirin correlates well with the aspirin-mediated acetylation of the particulate fraction protein. Both per-

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An Enzymatic Mechanism for the Antithrombotic and Antihemostatic Actions of Aspirin

Cited by 110 publications

References 18 publications

Physiological role of an endoperoxide in human platelets: hemostatic defect due to platelet cyclo-oxygenase deficiency.

Physiological role of an endoperoxide in human platelets: hemostatic defect due to platelet cyclo-oxygenase deficiency.

Prostaglandin Endoperoxides. Novel Transformations of Arachidonic Acid in Human Platelets

The mechanism of the effect of aspirin on human platelets. I. Acetylation of a particulate fraction protein.

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