title: Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model.
abstract: OBJECTIVE
  A routine secondary pharmacology screen indicated that reversibly binding oral P2Y(12) receptor antagonist ticagrelor could inhibit adenosine uptake in human erythrocytes, suggesting that ticagrelor may potentiate adenosine-mediated responses in vivo. The aim of this study was to further characterize the adenosine uptake inhibition in vitro and study possible physiological consequences of adenosine uptake inhibition by ticagrelor in an anesthetized dog model of coronary blood flow compared to dipyridamole.
  
  
  RESULTS
  We measured [2-3H]adenosine uptake in purified human erythrocytes and several cell lines in the presence of ticagrelor or the known uptake inhibitor dipyridamole as a comparator. Using an open-chest dog model (beagles), we measured the left anterior descending (LAD) coronary artery blood flow during reactive hyperemia after 1 minute occlusion or intracoronary infusion of adenosine before and after administration of vehicle, ticagrelor, or dipyridamole (each n = 8). Ticagrelor concentration-dependently inhibited adenosine uptake in human erythrocytes and in cell lines of rat, canine, or human origin. In the dog model, ticagrelor and dipyridamole dose-dependently augmented reactive hyperemia after LAD occlusion, as assessed by percentage repayment of flow debt relative to control (both Ps < .05). Ticagrelor and dipyridamole also dose-dependently augmented intracoronary adenosine-induced increases in LAD blood flow relative to control (both Ps < .05).
  
  
  CONCLUSIONS
  Ticagrelor inhibits adenosine uptake in vitro and subsequently augments cardiac blood flow in a canine model of reactive hypoxia- or adenosine-induced blood flow increases. These findings suggest that ticagrelor may have additional benefits in patients with acute coronary syndrome beyond inhibition of platelet aggregation.
authors.affiliation: Department of BioScience, AstraZeneca R&D, Mölndal, Sweden. hans.vangiezen@astrazeneca.com
authors.forename: J J J
authors.initials: JJ
authors.lastname: van Giezen
authors.forename: James
authors.initials: J
authors.lastname: Sidaway
authors.forename: Philip
authors.initials: P
authors.lastname: Glaves
authors.forename: Ian
authors.initials: I
authors.lastname: Kirk
authors.forename: Jan-Arne
authors.initials: JA
authors.lastname: Björkman
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy / Q000503:physiopathology; D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D003326:Coronary Circulation / Q000187:drug effects*; D004176:Dipyridamole / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D006940:Hyperemia / Q000378:metabolism; D008297:Male; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D000077486:Ticagrelor
chemical_list: D058921:Purinergic P2Y Receptor Antagonists; D004176:Dipyridamole; D000077486:Ticagrelor; D000241:Adenosine