On the Interrelationship of Prostaglandin Endoperoxide G<sub>2</sub> and Cyclic Nucleotides in Platelet Function

Claesson, Hans‐Erik; Malmsten, Curt

doi:10.1111/j.1432-1033.1977.tb11593.x

Cited by 46 publications

(5 citation statements)

References 26 publications

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“…The other effects of oADP and oATP on the response to arachidonic acid ( Fig.6 and 7) appear consistent with the proposal that this response results both from a direct effect of thromboxane A2 and/or the endoperoxides on the platelet [8] as well as from a response to ADP secreted as a consequence of stimulation by these metabolites [36]. Thus the effect of oATP on the rate and extent of the aggregation response to a given arachidonate concentration (Fig.…”

Section: Discussionsupporting

confidence: 85%

Factors Influencing the Response of Human Blood Platelets to Analogues of ADP Which May Act as Partial Agonists at the ADP Receptor

Egan

Fisher

Scrutton

1979

European Journal of Biochemistry

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1. The prior addition of non-aggregating concentrations of the divalent cation ionophore, A-23187, causes human platelets to aggregate in response to a subsequent addition of the 2',3'-dialdehyde and 2',3'-dialcohol derivatives of ADP (oADP and orADP). Previous studies [Pearce et al. (1978) Eur. J. Biochem. 88,5551 have shown that these derivatives act as partial agonists at the platelet ADP receptor inducing only the transition from discoid to globular morphology ('shape change'). A secretion response is also observed on addition of a low concentration of ionophore A-23187 prior to orADP. These responses are not observed if ionophore A-23187 is added prior to the 2',3'-dialdehyde and 2',3'-dialcohol derivatives of ATP (oATP and orATP) and are markedly inhibited by prior addition of the ADP antagonist, adenosine 5'-[b,y-methylene]triphosphate.2. The aggregation response to oADP in the presence of ionophore A-23187 is reduced but not eliminated by addition of 3 mM EGTA when studies are performed in heparinised platelet-rich plasma. Additions of 3 mM EGTA in citrated platelet-rich plasma, or of 4 mM EDTA in either system completely inhibits this response. Inhibitors which are reported to elevate the intracellular concentration of adenosine 3':5'-monophosphate (cyclic AMP) or to prevent Ca2+ movement also inhibit the aggregation response to oADP which is observed in the presence of ionophore A-23187.3. Prior addition of inhibitors of adenylate cyclase fails to cause an aggregation response to subsequent addition of oADP or orADP. Certain of these inhibitors enhance and prolong the shape change response to oADP or orADP but only at concentrations an order of magnitude in excess of those required to antagonise inhibition by agents such as prostaglandin El, which act by increasing the concentration of cyclic AMP.4. The concentration of prostaglandin El, adenosine or papaverine required to inhibit shape change induced by oADP is one to two orders of magnitude lower than that required to inhibit shape change induced by ADP.5. Prior addition of oADP decreases the lag phase in the response of human platelets to arachidonate while also increasing the concentration required to observe half-maximal response, and causing a decrease in the extent of that response. Prior addition of oATP also diminishes the extent of this response and increases the concentration of arachidonate required but has no effect on the lag phase.6. The data suggest that oADP and orADP are capable only of acting as partial agonists at the ADP receptor because of a defective ability to increase cytosolic Ca2+ concentration. This defect is rectified by the presence of low concentrations of ionophore A-23 187, which promotes mobilisation of Ca2+ from an intracellular store. The results do not appear consistent with the thesis that a decrease in platelet cyclic AMP is an initiating event in aggregation induced by ADP, but do support a model which implicates cyclic AMP in depletion of cytosolic Ca2+.

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Section: Discussionsupporting

confidence: 85%

Factors Influencing the Response of Human Blood Platelets to Analogues of ADP Which May Act as Partial Agonists at the ADP Receptor

Egan

Fisher

Scrutton

1979

European Journal of Biochemistry

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“…The role of ADP in thromboxane A 2 -induced platelet aggregation has been investigated using enzymes that deplete released ADP. This work suggested that the aggregation response is mediated by the secretion of platelet ADP (45)(46)(47)(48)(49). It was concluded that U46619-induced platelet aggregation depends on the release of stored ADP.…”

Section: Discussionmentioning

confidence: 97%

Molecular Mechanism of Thromboxane A2-induced Platelet Aggregation

Paul

Jin

Kunapuli

1999

Journal of Biological Chemistry

259

201

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Thromboxane A 2 is a positive feedback lipid mediator produced following platelet activation. The G q -coupled thromboxane A 2 receptor subtype, TP␣, and G i -coupled TP␤ subtype have been shown in human platelets. ADPinduced platelet aggregation requires concomitant signaling from two P2 receptor subtypes, P2Y1 and P2T AC , coupled to G q and G i , respectively. We investigated whether the stable thromboxane A 2 mimetic, (15S)-hydroxy-9,11-epoxymethanoprosta-5Z,13E-dienoic acid (U46619), also causes platelet aggregation by concomitant signaling through G q and G i , through co-activation of TP␣ and TP␤ receptor subtypes. Here we report that secretion blockade with Ro 31-8220, a protein kinase C inhibitor, completely inhibited U46619-induced, but not ADP-or thrombin-induced, platelet aggregation. Ro 31-8220 had no effect on U46619-induced intracellular calcium mobilization or platelet shape change. Furthermore, U46619-induced intracellular calcium mobilization and shape change were unaffected by A3P5P, a P2Y1 receptor-selective antagonist, and/or cyproheptadine, a 5-hydroxytryptamine subtype 2A receptor antagonist. Either Ro 31-8220 or AR-C66096, a P2T AC receptor selective antagonist, abolished U46619-induced inhibition of adenylyl cyclase. In addition, AR-C66096 drastically inhibited U46619-mediated platelet aggregation, which was further inhibited by yohimbine, an ␣ 2A -adrenergic receptor antagonist. Furthermore, inhibition of U46619-induced platelet aggregation by Ro 31-8220 was relieved by activation of the G i pathway by selective activation of either the P2T AC receptor or the ␣ 2A -adrenergic receptor. We conclude that whereas thromboxane A 2 causes intracellular calcium mobilization and shape change independently, thromboxane A 2 -induced inhibition of adenylyl cyclase and platelet aggregation depends exclusively upon secretion of other agonists that stimulate G i -coupled receptors.Upon exposure to activating agonists (e.g. thrombin, ADP, and collagen), platelets liberate arachidonic acid stored as phospholipid in the platelet plasma membrane that is converted into thromboxane A 2 by sequential oxygenation of arachidonic acid by cycloxygenase and thromboxane A 2 synthase (1). The released thromboxane A 2 acts as a positive feedback mediator in the activation and recruitment of more platelets to the primary hemostatic plug (2). Thromboxane A 2 exerts its actions via specific G protein-coupled receptors and has been described as either a potent platelet agonist (2, 3) or as a weak agonist with an important role in amplifying the response of platelets to more potent agonists (4).Pharmacological studies indicate the presence of two potential thromboxane A 2 receptor (TP receptor) 1 subtypes on human platelets (5, 6). The TP receptor gene has been cloned and encodes two subtypes of the TP receptor that result from alternative splicing of the primary transcript (7). The subtypes share the identical first 293 amino acids but possess different carboxyl-terminal domains. A complete cDNA of the 343 amino acid T...

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“…These experiments suggested that contact between platelet membranes was required for activation of guanylate cyclase and that increases in platelet cyclic GMP were more likely to be an effect than a cause of aggregation. Although one group has reported that exogenous cyclic GMP and derivatives can potentiate the platelet release reaction (Chiang et al 1976), others have not been able to reproduce this effect (Claesson andMalmsten 1977, Haslam 1978). In view of these considerations, it is conceivable that cyclic GMP is a feedback inhibitor of platelet responses rather than a mediator of platelet activation.…”

Section: Cyclic Gmpmentioning

confidence: 99%

Cyclic Nucleotides in Platelet Function

et al. 1978

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SummaryInhibition of adenylate cyclase in intact platelets by addition of compounds such as 2’, 5’- dideoxyadenosine prevented the inhibition of platelet aggregation by PGE1 but did not affect the responses of platelets to aggregating agents in the absence of PGE1. This confirms that cyclic AMP mediates the effects of PGE1 but indicates that the level of cyclic AMP in unstimulated platelets is too low to affect the actions of aggregating agents. Studies on the phosphorylation of proteins in intact 32P-labelled platelets showed that PGE1 increased the phosphorylation of a membrane-bound polypeptide (P24) and prevented the increased phosphorylation of other polypeptides (P47 and P20) that occurred on addition of inducers of the release reaction. It is suggested that the cyclic AMP-dependent phosphorylation of P24 stimulates the active transport of Ca2+ out of the platelet cytosol, so preventing phosphorylation of P47 and P20, reactions which may be involved in the release mechanism. As increases in platelet cyclic GMP could be dissociated from both platelet aggregation and the release reaction, it is proposed that the bidirectional regulation of platelet function is achieved primarily by the opposing actions of increases in the concentrations of Ca2+ and cyclic AMP.

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On the Interrelationship of Prostaglandin Endoperoxide G₂ and Cyclic Nucleotides in Platelet Function

Cited by 46 publications

References 26 publications

Factors Influencing the Response of Human Blood Platelets to Analogues of ADP Which May Act as Partial Agonists at the ADP Receptor

Factors Influencing the Response of Human Blood Platelets to Analogues of ADP Which May Act as Partial Agonists at the ADP Receptor

Molecular Mechanism of Thromboxane A2-induced Platelet Aggregation

Cyclic Nucleotides in Platelet Function

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On the Interrelationship of Prostaglandin Endoperoxide G2 and Cyclic Nucleotides in Platelet Function

Cited by 46 publications

References 26 publications

Factors Influencing the Response of Human Blood Platelets to Analogues of ADP Which May Act as Partial Agonists at the ADP Receptor

Factors Influencing the Response of Human Blood Platelets to Analogues of ADP Which May Act as Partial Agonists at the ADP Receptor

Molecular Mechanism of Thromboxane A2-induced Platelet Aggregation

Cyclic Nucleotides in Platelet Function

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On the Interrelationship of Prostaglandin Endoperoxide G₂ and Cyclic Nucleotides in Platelet Function