The effects of some salicylate analogues on human blood platelets: 1. Structure activity relationships and the inhibition of platelet aggregation

Mills, D. G.; Philp, Richard B.; Hirst, Maurice

doi:10.1016/0024-3205(74)90449-4

Cited by 23 publications

(6 citation statements)

References 23 publications

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“…Aggregation of human platelets by ADP and adrenaline occurs in the form of a double wave. The secondary wave of aggregation and the accompanying release reaction are inhibited by aspirin-like drugs (O'Brien, 1968;Mills et al, 1974) and accordingly, they are attributed to the formation of proaggregatory metabolites of arachidonate, TxA2 and prostaglandin endoperoxides (Holmsen, 1977;Lages & Weiss, 1980;and Meyers et al, 1979). The primary wave of aggregation by ADP persisted in the presence of alkaline phosphatase, but the secondary wave and the accompanying ATP secretion were abolished.…”

Section: Resultsmentioning

confidence: 99%

“…Reversibility also supports the concept that the sites of interaction of the platelet with the arachidonate metabolites and its mimetics involve the external surface of the cell. This antagonism to the effects of TxA2 should explain the interference of alkaline phosphatase with the second wave of ADP-induced aggregation, which is suppressed by thromboxane agonists and cyclo-oxygenase inhibitors (O'Brien, 1968;Mills et al, 1974;Armstrong et al, 1985). Those inhibitors are also effective against the second wave of adrenaline-induced aggregation (O'Brien, 1968;Armstrong et al, 1985), which was surprisingly not modified by alkaline phosphatase.…”

Section: Discussionmentioning

confidence: 97%

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Alkaline phosphatase prevents platelet stimulation by thromboxane‐mimetics

Hatmi

Haye

Gavaret

et al. 1991

British J Pharmacology

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1 The effects of alkaline phosphatase on platelet aggregation, secretion and thromboxane B2 (TxB2) generation induced by the full dose-range of common platelet agonists were studied in human platelet-rich plasma and washed platelets. 2 Platelet aggregation and adenosine 5'-triphosphate (ATP) secretion induced by threshold and supramaximal concentrations of arachidonate and stable TxA2 and prostaglandin endoperoxide-mimetics (compounds U46619 and EP171) were abolished in the presence of alkaline phosphatase (0.5-1 u ml 1), even though the synthesis of TxB2 persisted. In contrast, platelet aggregation by PAF-acether and by supramaximal concentrations of thrombin as well as the primary wave of aggregation by adenosine diphosphate (ADP) and adrenaline were unaffected by alkaline phosphatase under conditions where the secondary wave of aggregation by ADP was blocked. 3 Alkaline phosphatase, unlike prostacyclin, failed to raise the adenosine 3': 5'-cyclic monophosphate (cyclic AMP) content of the platelets. Also, the pretreatment of platelets by inorganic phosphate or by ATP plus creatine phosphate/creatine phosphokinase reversed the inhibitory effect of alkaline phosphatase.4 Experiments performed in the guinea-pig in vivo showed that alkaline phosphatase was effective on thrombocytopenia induced by arachidonate. 5 Our results provide the first direct evidence for a specific inhibitory effect of alkaline phosphatase at a site sensitive to TxA2 and prostaglandin endoperoxides and suggest that its phosphorylation/ dephosphorylation state may play an important role in modulating platelet activation. These results also suggest the presence of ecto-protein kinases on membrane platelets.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Alkaline phosphatase prevents platelet stimulation by thromboxane‐mimetics

Hatmi

Haye

Gavaret

et al. 1991

British J Pharmacology

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“…Excessive platelet accumulation and recruitment lead to vessel narrowing and occlusion has been considered as one of the factors leading to cardiovascular disease, stroke and sudden death (Flores 1996; Fuster et al 1992). A number of therapeutic reagents, such as aspirin and its analogues, have been used to decrease platelet aggregation (Abrahamsen et al 1974; Mills et al 1974); however, many of these drugs have overt side effects which sometimes make compliance difficult. Glycine is a natural, non-toxic amino acid circulating in the 100–200 µM range in blood under normal conditions.…”

Section: Discussionmentioning

confidence: 99%

Glycine reduces platelet aggregation

et al. 2012

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It has been demonstrated that a wide variety of white blood cells and macrophages (i.e. Kupffer cells, alveolar and peritoneal macrophages and neutrophils) contain glycine-gated chloride channels. Binding of glycine on the receptor stimulates Cl− influx causing membrane hyperpolarization that prevents agonist-induced influx of calcium. Since platelet-aggregation is calcium-dependent, this study was designed to test the hypothesis that glycine would inhibit platelet aggregation. Rats were fed diets rich of glycine for 5 days, while controls received isonitrogenous valine. The bleeding time and ADP- and collagen-induced platelet aggregation were measured. Dietary glycine significantly increased bleeding time about two fold compared to valine-treated controls. Furthermore, the amplitude of platelet aggregation stimulated with ADP or collagen was significantly decreased in whole blood drawn from rats fed 2.5 or 5 % dietary glycine by over 50 %. Addition of glycine in vitro (1–10 mM) also blunted rat platelet aggregation in a dose-dependent manner. Strychnine, a glycine receptor antagonist, abrogated the inhibitory effect of glycine on platelet-aggregation in vitro suggesting the glycine works via a glycine receptor. Glycine also blunted aggregation of human platelets. Further, the glycine receptor was detected in both rat and human platelets by western blotting. Based on these data, it is concluded that glycine prevents aggregation of platelets in a dose-dependent manner via mechanisms involving a glycine receptor.

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“…Aspirin, which is the most common nonsteroidal anti-inflammatory drug in use today, is of little value in hemostatic disorders because it induces long-lasting inhibition of platelet ag-gregation9. 16 philia. Although the bleeding time was prolonged 2 hr after drug ingestion in both groups, this was not physiologically significant and there was no change in the clinical management or transfusion requirements of the hemophiliac patients tested.…”

Section: Discussionmentioning

confidence: 99%

Effect of ibuprofen on platelet function in normal subjects and hemophiliac patients

McIntyre

Philp

Inwood

1978

Clin Pharma and Therapeutics

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New propionic acid derivatives are claimed to induce a lower incidence of gastrointestinal bleeding and hemostatic disturbance than older anti-inflammatory analgesics such as aspirin. One of these (ibuprofen, Motrin) was given (600 mg orally) to normal subjects and hemophiliac subjects on a random, double-blind basis (lactose placebo). Platelet adhesiveness, aggregation, platelet and red cell counts, percent packed cells, percent hemoglobin, serum ibuprofen levels, and modified Ivy bleeding time were measured before and 2 and 24 hr after drug. Predrug and 24-hr postdrug values were normal, but at 2 hr after drug, adenosine diphosphate, epinephrine, and collagen aggregations were inhibited and bleeding times were slightly but significantly prolonged in the ibuprofen-treated normal subjects. The other parameters tested remained unchanged. Similar results were obtained in the ibuprofen-treated hemophiliac patients, although bleeding time was not prolonged. The results suggest that ibuprofen may be given to hemophiliac subjects with greater safety than some of the older anti-inflammatory drugs.

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The effects of some salicylate analogues on human blood platelets: 1. Structure activity relationships and the inhibition of platelet aggregation

Cited by 23 publications

References 23 publications

Alkaline phosphatase prevents platelet stimulation by thromboxane‐mimetics

Alkaline phosphatase prevents platelet stimulation by thromboxane‐mimetics

Glycine reduces platelet aggregation

Effect of ibuprofen on platelet function in normal subjects and hemophiliac patients

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