Evidence for the dependence of arterial haemostasis on ADP

1988 ◽  
Vol 234 (1276) ◽  
pp. 255-262 ◽  
Keyword(s):  
Platelet Aggregation ◽  
Vascular Injury ◽  
Adenosine Diphosphate ◽  
Mesenteric Arteries ◽  
Receptor Antagonists ◽  
Arterial Blood ◽  
Anaesthetized Rats ◽  
Adp Receptor ◽  
Adp Receptor Antagonists ◽  
Local Release

The possible involvement of adenosine diphosphate (ADP) in haemostatic platelet aggregation was investigated by determining the duration of primary haemorrhage as standardized bleeding times from punctures of small mesenteric arteries in anaesthetized rats. The bleeding times were highly significantly increased by infusing into the mesenteric arterial blood flowing towards the punctures either the nucleotidedephosphorylating enzyme apyrase or the ADP-receptor antagonists ATP, adenosine 5'-(β,γ-methylene)triphosphonate (AMP-PCP) or 2-methylthioadenosine 5'-(β,γ-methylene)triphosphonate (2-MeS-AMP-PCP). The increases in bleeding times could not be accounted for by local vasodilator effects of the agents. It is concluded that the presence of ADP through local release and/or formation at sites of vascular injury contributes significantly to haemostasis, presumably by accelerating platelet aggregation.

Glycoprotein Ibα inhibition and ADP receptor antagonists, but not aspirin, reduce platelet thrombus formation in flowing blood exposed to atherosclerotic plaques

2007 ◽  
Vol 97 (03) ◽  
pp. 435-443 ◽  
Author(s):  
Sandra Penz ◽  
Armin Reininger ◽  
Orsolya Toth ◽  
Hans Deckmyn ◽  
Richard Brandi ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Thrombus Formation ◽  
Arterial Flow ◽  
Atherosclerotic Plaques ◽  
Aggregate Formation ◽  
Receptor Antagonists ◽  
P2y12 Antagonists ◽  
Platelet Thrombus ◽  
Adp Receptor ◽  
Adp Receptor Antagonists

SummaryAnti-platelet drugs are used to prevent intra-arterial thrombus formation after rupture of atherosclerotic plaques. Until now, the inhibitory effect of present and future anti-platelet drugs such as aspirin, ADP receptor P2Y1/P2Y12 antagonists and glycoprotein (GP) Ibα inhibitors on the interaction of platelets with human plaques is not known. To study those effects we obtained human atherosclerotic plaques by surgical endarterectomy. Plaques induced maximal platelet aggregation in hirudinized platelet-rich plasma (PRP) and blood that was effectively inhibited by aspirin, the P2Y1 antagonist MRS2179 and the P2Y12 antagonist AR-C69931 MX, but not by GPIbα blockade with the mAB 6B4. Inhibition of platelet aggregation by MRS2179 was 74 ± 37% and 68 ± 20%, by AR-C69931 MX 94 ± 7% and 80 ± 6%, and by aspirin 88 ± 19% and 64 ± 28%, in PRP and blood, respectively (mean ± SD; n6–12 with plaques from 6 patients). The combination of both ADP receptor antagonists completely inhibited plaque-induced platelet aggregation in hirudinized PRP and blood. Under arterial flow conditions (1,500s-1), blockade of platelet GPIbα– resulted in a strong decrease of plaque-stimulated platelet adhesion/aggregate formation of 77 ± 5% (mean ± SD; n=4). Furthermore, MRS2I79, AR-C6993IMX and their combination reduced plaque-dependent platelet aggregate formation by 35 ± 14%, 32 ± 13% and 58 ± 12% (mean ± SD; n=5), respectively. Aspirin was without significant effect. In conclusion, a GPIbα-blocking antibody, as well as P2Y1 and P2Y12 receptor antagonists, alone or in combination, reduce in contrast to aspirin human plaque-induced platelet thrombus formation under arterial flow. Although these new anti-platelet agents inhibit platelet thrombus formation after plaque rupture, more efficient platelet blockers are required.

Revival of PFA-100 – how far is it useful for the monitoring of ADP receptor antagonists?

2013 ◽  
Vol 109 (03) ◽  
pp. 564-565
Author(s):  
Kamila Syska ◽  
Cezary Watala ◽  
Jacek Golanski
Keyword(s):  
Receptor Antagonists ◽  
Adp Receptor ◽  
Adp Receptor Antagonists

Mode of action of P2Y12 antagonists as inhibitors of platelet function

2011 ◽  
Vol 105 (01) ◽  
pp. 96-106 ◽  
Author(s):  
Jackie Glenn ◽  
Ann White ◽  
Sue Fox ◽  
Hans van Giezen ◽  
Sven Nylander ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
G Protein ◽  
Platelet Function ◽  
Adenosine Diphosphate ◽  
P2y12 Receptor ◽  
Receptor Antagonists ◽  
Receptor Agonists ◽  
P2y12 Antagonists ◽  
Induced Aggregation ◽  
G Protein Coupled

SummaryP2Y12 receptor antagonists are antithrombotic agents that inhibit platelet function by blocking the effects of adenosine diphosphate (ADP) at P2Y12 receptors. However, some P2Y12 receptor antagonists may affect platelet function through additional mechanisms. It was the objective of this study to investigate the possibility that P2Y12 antagonists inhibit platelet function through interaction with G-protein-coupled receptors other than P2Y12 receptors. We compared the effects of cangrelor, ticagrelor and the prasugrel active metabolite on platelet aggregation and on phosphorylation of vasodilator-stimulated phosphoprotein (VASP). We compared their effects with those of selective IP, EP4 and A2A agonists, which act at Gs-coupled receptors. All three P2Y12 antagonists were strong inhibitors of ADP-induced platelet aggregation but only partial inhibitors of aggregation induced by thrombin receptor activating peptide (TRAP) or the thromboxane A2 mimetic U46619. Further, after removing ADP and its metabolites using apyrase and adenosine deaminase, the P2Y12 antagonists produced only minor additional inhibition of TRAP or U46619-induced aggregation. Conversely, the Gs-coupled receptor agonists always produced strong inhibition of aggregation irrespective of whether ADP was removed. Other experiments using selective receptor agonists and antagonists provided no evidence of any of the P2Y12 antagonists acting through PAR1, TP, IP, EP4, A2A or EP3 receptors. All three P2Y12 antagonists enhanced VASPphosphorylation to a small and equal extent but the effects were much smaller than those of the IP, EP4 and A2A agonists. The effects of cangrelor, ticagrelor and prasugrel on platelet function are mediated mainly through P2Y12 receptors and not through another G-protein-coupled receptor.

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