title: Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y12 antagonism.
abstract: BACKGROUND
  Ticagrelor, a P2Y12 antagonist, is an antiplatelet agent approved for the treatment of acute coronary syndromes; it also inhibits adenosine uptake by erythrocytes and other cells.
  
  
  OBJECTIVE
  To test whether ticagrelor inhibits platelet aggregation (PA) in whole blood (WB) by increasing the extracellular levels of adenosine, which inhibits PA via the A2A receptor.
  
  
  METHODS
  Collagen-induced PA was measured in WB or platelet-rich plasma (PRP) from 50 healthy subjects and two patients with inherited P2Y12 deficiency, in presence/absence of adenosine concentrations that by themselves marginally affected PA in WB, and ZM241385 (A2A antagonist). The effects of ticagrelor, the active metabolite of prasugrel (PAM) (P2Y12 antagonist), and dipyridamole (adenosine uptake inhibitor) on PA and on adenosine clearance in WB were compared.
  
  
  RESULTS
  For PA in WB, adenosine contributed to drug-induced inhibition of PA; the adenosine contribution was similar for dipyridamole and ticagrelor but was significantly greater for ticagrelor than for PAM (P < 0.01). For PA in PRP (no adenosine uptake by erythrocytes), adenosine contributed to inhibition of PA in the presence/absence of all tested drugs. ZM241385 reversed the inhibition by adenosine in WB and PRP. Similar results were obtained with WB and PRP from P2Y12 -deficient patients. Adenosine (7.1 μmol L(-1) ) added to WB, was detectable for 0.5 min in the presence of vehicle or PAM, for 3-6 min in the presence of ticagrelor, and for > 60 min in the presence of dipyridamole.
  
  
  CONCLUSIONS
  This study provides the first evidence of an additional antiplatelet mechanism by ticagrelor, mediated by the induced increase of adenosine levels.
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Nylander
authors.forename: E A
authors.initials: EA
authors.lastname: Femia
authors.forename: M
authors.initials: M
authors.lastname: Scavone
authors.forename: P
authors.initials: P
authors.lastname: Berntsson
authors.forename: A-K
authors.initials: AK
authors.lastname: Asztély
authors.forename: K
authors.initials: K
authors.lastname: Nelander
authors.forename: L
authors.initials: L
authors.lastname: Löfgren
authors.forename: R G
authors.initials: RG
authors.lastname: Nilsson
authors.forename: M
authors.initials: M
authors.lastname: Cattaneo
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D019271:Hypoxanthine / Q000097:blood; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D000077486:Ticagrelor; D055815:Young Adult
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D019271:Hypoxanthine; D000077486:Ticagrelor; D000241:Adenosine
keywords: adenosine; adenosine A2A receptor; equilibrative nucleoside transporter 1; platelet aggregation; receptors, purinergic P2Y12; ticagrelor