{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:55:06Z","timestamp":1790787306769,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/11\/75\/29105"],"award-info":[{"award-number":["PG\/11\/75\/29105"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/12\/68\/29779"],"award-info":[{"award-number":["PG\/12\/68\/29779"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014226","name":"William Harvey Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>P2Y<jats:sub>12<\/jats:sub> receptor antagonists reduce platelet aggregation and the incidence of arterial thrombosis. Adenosine signalling in platelets directly affects cyclic nucleotide tone, which we have shown to have a synergistic relationship with P2Y<jats:sub>12<\/jats:sub> inhibition. Several studies suggest that ticagrelor inhibits erythrocyte uptake of adenosine and that this could also contribute to its antiplatelet effects. We therefore examined the effects on platelet activation of adenosine signalling activators in combination with the P2Y<jats:sub>12<\/jats:sub> receptor antagonists ticagrelor and prasugrel.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Human washed platelets, platelet\u2010rich plasma and whole blood were used to test the interactions between ticagrelor or prasugrel and adenosine or 5\u2032\u2010<jats:italic>N<\/jats:italic>\u2010ethylcarboxamidoadenosine (NECA). Platelet reactivity to thrombin, protease\u2010activated receptor 1 (PAR\u20101) activation or collagen was assessed by a combination of 96\u2010well plate aggregometry, light transmission aggregometry, whole blood aggregometry, ATP release assay and levels of cAMP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The inhibitory effects of ticagrelor and prasugrel on platelet aggregation and ATP release were enhanced in the presence of adenosine or NECA. Isobolographic analysis indicated a powerful synergy between P2Y<jats:sub>12<\/jats:sub> receptor inhibition and adenosine signalling activators. Increased levels of cAMP in platelets were also observed. In all cases, ticagrelor showed similar synergistic effects on platelet inhibition as prasugrel in the presence of adenosine or NECA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>These results indicate that P2Y<jats:sub>12<\/jats:sub> antagonists have a synergistic relationship with adenosine signalling and that their efficacy may depend partly upon the presence of endogenous adenosine. This effect was common for prasugrel and ticagrelor despite reports of differences in their effects upon adenosine reuptake.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15659","type":"journal-article","created":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T20:58:36Z","timestamp":1628801916000},"page":"4758-4771","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Platelet inhibition by P2Y<sub>12<\/sub> antagonists is potentiated by adenosine signalling activators"],"prefix":"10.1111","volume":"178","author":[{"given":"Chih\u2010Chin","family":"Shih","sequence":"first","affiliation":[{"name":"Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London  London UK"},{"name":"Department of Pharmacology National Defense Medical Center  Taipei R.O.C., 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