Local amplification of platelet function by 8-Epi prostaglandin F2alpha is not mediated by thromboxane receptor isoforms.
8-epi-Prostaglandin (PG) F2alpha may be formed by cyclooxygenases 1 and 2 or by a free radical catalyzed process as an isoprostane. Concentrations of 8-epi-PGF2alpha in the range 1 nM to 1 microM induce a dose-dependent increase in platelet shape change, in calcium release from intracellular stores [Ca2+]iand in inositol phosphates; it also causes irreversible platelet aggregation, dependent on thromboxane generation, when incubated with subthreshold concentrations of ADP, thrombin, collagen, and arachidonic acid. Much higher concentrations of 8-epi-PGF2alpha (10-20 microM) alone induce weak, reversible aggregation. Although these effects are prevented by pharmacological thromboxane receptor antagonists, they are unlikely to be mediated by thromboxane receptors. Thus, 8-epi-PGF2alpha does not compete for binding at the stably expressed placental or endothelial isoforms of the thromboxane receptor or for binding of thromboxane ligands to human platelets. Furthermore, the response to 8-epi PGF2alpha exhibits structural specificity versus 8-epi PGF3alpha and PGF2alpha. Concentrations in the range that evoke its effects on platelets do not desensitize the aggregation response stimulated by thromboxane or PGH2 analogs. Unlike primary prostaglandins, which are rapidly metabolized to inactive products, 8-epi PGF2alpha circulates in plasma. However, the systemic concentrations found in healthy volunteers (median 48 pmol/liter) and in patients with hepatic cirrhosis (median 147 pmol/liter), a syndrome of oxidant stress in vivo, fall well below those which modulate platelet function. 8-Epi PGF2alpha may amplify the response to platelet agonists in syndromes where oxidant stress and platelet activation coincide. Despite blockade by thromboxane antagonists, 8-epi PGF2alpha does not activate either of the thromboxane receptor isoforms described in platelets. Activation of a distinct receptor would be consistent with the enzymatic formation of 8-epi PGF2alpha by cyclooxygenases. However, incidental activation of such a receptor by systemic concentrations of 8-epi PGF2alpha is unlikely to occur, even in syndromes of excessive free radical generation in vivo.
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Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Smyth
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EM
Violi
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FitzGerald
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D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000244:Adenosine Diphosphate / Q000494:pharmacology; D016718:Arachidonic Acid / Q000494:pharmacology; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003094:Collagen / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D028441:F2-Isoprostanes; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D007668:Kidney; D007700:Kinetics; D037342:Pertussis Toxin; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011869:Radioligand Assay; D017482:Receptors, Thromboxane / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D028441:F2-Isoprostanes; D005231:Fatty Acids, Unsaturated; D007295:Inositol Phosphates; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; C061750:7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid; C075750:8-epi-prostaglandin F2alpha; D016718:Arachidonic Acid; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003094:Collagen; D015237:Dinoprost; D037342:Pertussis Toxin; D013917:Thrombin; D002118:Calcium