Prostaglandin E2: Effects on aggregation, shape change and cyclic AMP of rat platelets

Shio, Hideo; Ramwell, Peter W.; Jessup, Sheila J.

doi:10.1016/0090-6980(72)90063-9

Cited by 34 publications

(9 citation statements)

References 14 publications

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“…Previous experiments have demonstrated that PGE 2 is able to either promote or inhibit platelet aggregation in experiments performed in vitro depending on the precise experimental conditions used [1][2][3][4][5][6][7][8][9][10][11][12][13][14], and when we started the current experiments it was believed that overall promotion or inhibition of platelet aggregation by PGE 2 is the consequence of effects of PGE 2 at EP3 receptors (causing potentiation via G i and inhibition of adenylyl cyclase) and IP receptors (causing inhibition via G s and stimulation of adenylyl cyclase). It was within this context that we looked at the effects of the IP antagonist CAY10441 to explore the role of the IP receptor, the EP3 antagonist DG-041 to explore the role of the EP3 receptor, and the EP4 antagonist ONO-AE3-208 to explore the role of the EP4 receptor in determining the effects of PGE 2 on platelet function.…”

Section: Discussionmentioning

confidence: 99%

“…The results of numerous previous investigations performed on human, mouse and rat platelets suggest that the effects of prostaglandin E 2 (PGE 2 ) represent a balance between enhancement and inhibition of platelet function via interaction with different receptors for PGE 2 on the platelet surface [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. There is good evidence that potentiation of platelet function is via effects at EP3 receptors linked to G i and inhibition of adenylyl cyclase [7,10,11,[13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

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The role of prostanoid receptors in mediating the effects of PGE₂on human platelet function

et al. 2010

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The effects of prostaglandin E(2) (PGE(2)) on platelet function are believed to be the result of opposing mechanisms that lead to both enhancement and inhibition of platelet function. Enhancement of platelet function is known to be via EP3 receptors linked to G(i) and inhibition of adenylyl cyclase. However, the receptors involved in inhibition of platelet function have not been fully defined. Here we have used measurements of platelet aggregation, calcium signaling and P-selectin expression to assess platelet function induced by platelet activating factor (PAF), thrombin receptor activating peptide (TRAP-6) and the thromboxane A(2) mimetic U46619 respectively, to determine the effects of PGE(2) and of selective prostanoid receptor agonists on platelet function. Their effects on vasodilator-stimulated phosphoprotein (VASP) phosphorylation were also determined. We also assessed the ability of selective prostanoid receptor antagonists to modify the effects of PGE(2). The agonists and antagonists used were iloprost (IP agonist), ONO-DI-004 (EP1 agonist), ONO-AE1-259 (EP2 agonist), sulprostone (EP3 agonist), ONO-AE1-329 (EP4 agonist), CAY10441 (IP antagonist), ONO-8713 (EP1 antagonist), DG-041 (EP3 antagonist) and ONO-AE3-208 (EP4 antagonist). Using the agonists available to us we demonstrated that EP3, EP4 and IP receptors elicit functional responses in platelets. The EP3 receptor agonist promoted platelet aggregation, calcium signaling and P-selectin expression and this was associated with a reduction in VASP phosphorylation. Conversely agonists acting at IP and EP4 receptors inhibited platelet function and this was associated with an increase in VASP phosphorylation. The effects on platelet function and VASP phosphorylation of the selective prostanoid receptor antagonists used in conjunction with PGE(2) were consistent with PGE(2) interacting with EP3 receptors to enhance platelet function and with EP4 receptors (but not IP receptors) to inhibit platelet function. This is the first demonstration of the involvement of EP4 receptors in platelet responses to PGE(2).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The role of prostanoid receptors in mediating the effects of PGE₂on human platelet function

et al. 2010

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“…PGE 2 has long been known to attenuate platelet aggregation at high concentrations, ie, in the micromolar range; at lower concentrations, however, PGE 2 is promoting aggregatory responses induced by platelet activators, such as ADP or collagen. 6,7,9,10,32 Therefore, the primary action of PGE 2 was suggested to be proaggregatory. The EP3 receptor was subsequently characterized as the receptor that mediates the PGE 2 -induced augmentation of platelet aggregation, and EP3 receptor antagonists are currently under consideration as potential novel antithrombotic treatment.…”

Section: Discussionmentioning

confidence: 99%

The Prostaglandin E ₂ Receptor EP4 Is Expressed by Human Platelets and Potently Inhibits Platelet Aggregation and Thrombus Formation

Philipose

Kónya

Sreckovic

et al. 2010

ATVB

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Objective-Low concentrations of prostaglandin (PG) E 2 enhance platelet aggregation, whereas high concentrations inhibit it. The effects of PGE 2 are mediated through 4 G protein-coupled receptors, termed E-type prostaglindin (EP) receptor EP1, EP2, EP3, and EP4. The platelet-stimulating effect of PGE 2 has been suggested to involve EP3 receptors. Here we analyzed the receptor usage relating to the inhibitory effect of PGE 2 . Methods and Results-Using flow cytometry, we found that human platelets expressed EP4 receptor protein. A selective EP4 agonist (ONO AE1-329) potently inhibited the platelet aggregation as induced by ADP or collagen. This effect could be completely reversed by an EP4 antagonist, but not by PGI 2 , PGD 2 , and thromboxane receptor antagonists or cyclooxygenase inhibition. Moreover, an EP4 antagonist enhanced the PGE 2 -induced stimulation of platelet aggregation, indicating a physiological antiaggregatory activity of EP4 receptors. The inhibitory effect of the EP4 agonist was accompanied by attenuated Ca 2ϩ flux, inhibition of glycoprotein IIb/IIIa, and downregulation of P-selectin. Most importantly, adhesion of platelets to fibrinogen under flow and in vitro thrombus formation were effectively prevented by the EP4 agonist. In this respect, the EP4 agonist synergized with acetylsalicylic acid. Key Words: aspirin Ⅲ pharmacology Ⅲ platelet receptor blockers Ⅲ platelets Ⅲ prostacyclin Ⅲ prostaglandins Ⅲ thromboxanes S ubjects with increased platelet reactivity are at increased prospective risk for coronary events and death. A number of pathophysiological states, such as atherosclerosis, diabetes, and metabolic syndrome, are associated with increased platelet reactivity and thrombogenic potential. Under inflammatory conditions, the synthesis of prostanoids in endothelial cells and smooth muscle cells is highly increased. Predominantly, the biosynthesis of prostaglandin (PG) E 2 is enhanced in vascular smooth muscle cells 1 and macrophages 2,3 by inflammatory mediators. Conclusion-TheseProstanoids are involved in hemostasis by differentially influencing platelet aggregation. Although thromboxane (TX) A 2 , produced in platelets, and PGH 2 , released untransformed from activated/dysfunctional endothelium, are potent stimulators of platelet aggregation, 4 PGI 2 and PGD 2 are known to inhibit platelet aggregation. 5 PGE 2 shows a biphasic, concentration-dependent effect on platelet aggregation. Although high concentrations inhibit platelet aggregation, lower concentrations enhance it. 6 -11 PGE 2 binds and activates 4 G protein-coupled receptors, EP1, EP2, EP3, and EP4. Each of these receptors has a distinct pharmacological signature and intracellular signal transduction. 12,13,14 Stimulation of the EP3 receptors results in elevation of free intracellular Ca 2ϩ levels, whereas stimulation of the EP2 and EP4 receptors usually increases intracellular cAMP levels through activation of G s protein, 12 resulting in a decrease of intracellular Ca 2ϩ levels. Human platelets contain mRNA for EP1 receptors,...

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“…[17, 18] Studies in the early 1970s noted that the effect of PGE 2 on platelets was either inhibitory or stimulatory depending on its concentration and the species of animal examined. [19-22] Bruno et al reported that low doses of PGE 2 did not potentiate aggregation induced by either ADP or collagen, but higher (supraphysiological) doses (>1 μM) inhibited aggregation. [19] Others have observed potentiation of ADP- or collagen-induced aggregation at low doses (10-100 nM PGE 2 ) and inhibition at high doses (10 μM PGE 2 ), similar to the data from mice.…”

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confidence: 99%

PGE2 decreases reactivity of human platelets by activating EP2 and EP4

Smith

Haddad

Downey

et al. 2010

Thrombosis Research

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Prostaglandin E2: Effects on aggregation, shape change and cyclic AMP of rat platelets

Cited by 34 publications

References 14 publications

The role of prostanoid receptors in mediating the effects of PGE₂on human platelet function

The role of prostanoid receptors in mediating the effects of PGE₂on human platelet function

The Prostaglandin E ₂ Receptor EP4 Is Expressed by Human Platelets and Potently Inhibits Platelet Aggregation and Thrombus Formation

PGE2 decreases reactivity of human platelets by activating EP2 and EP4

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Prostaglandin E2: Effects on aggregation, shape change and cyclic AMP of rat platelets

Cited by 34 publications

References 14 publications

The role of prostanoid receptors in mediating the effects of PGE2on human platelet function

The role of prostanoid receptors in mediating the effects of PGE2on human platelet function

The Prostaglandin E 2 Receptor EP4 Is Expressed by Human Platelets and Potently Inhibits Platelet Aggregation and Thrombus Formation

PGE2 decreases reactivity of human platelets by activating EP2 and EP4

Contact Info

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The role of prostanoid receptors in mediating the effects of PGE₂on human platelet function

The role of prostanoid receptors in mediating the effects of PGE₂on human platelet function

The Prostaglandin E ₂ Receptor EP4 Is Expressed by Human Platelets and Potently Inhibits Platelet Aggregation and Thrombus Formation