title: Chronic treatment with ticagrelor limits myocardial infarct size: an adenosine and cyclooxygenase-2-dependent effect.
abstract: OBJECTIVE
  In a phase III clinical trial (PLATelet inhibition and patient Outcomes, PLATO), ticagrelor provided better clinical outcomes than clopidogrel in patients with acute coronary syndromes. In addition to P2Y12-receptor antagonism, ticagrelor prevents cell uptake of adenosine and has proven able to augment adenosine effects. Adenosine protects the heart against ischemia-reperfusion injury. We compared the effects of clopidogrel and ticagrelor on myocardial infarct size (IS).
  
  
  RESULTS
  Rats received oral ticagrelor (0, 75, 150, or 300 mg/kg/d) or clopidogrel (30 or 90 mg/kg/d) for 7 days and underwent 30-minute coronary artery ligation and 24-hour reperfusion. Area at risk was assessed by blue dye and IS by 2,3,5-triphenyl-tetrazolium-chloride. Cyclooxygenase-2 (COX2) enzyme activity was assessed by ELISA and expression by real-time polymerase chain reaction. Mechanism responsible was explored using adenosine-receptor antagonist (CGS15943, an A2A/A1 antagonist) or cyclooxygenase inhibition by either aspirin (5, 10, or 25 mg/kg) or specific cyclooxygenase-1 (SC560) or COX2 (SC5815) inhibitors. Ticagrelor, dose-dependently, reduced IS, whereas clopidogrel had no effect. Adenosine-receptor antagonism blocked the ticagrelor effect and COX2 inhibition by SC5815, or high-dose aspirin attenuated the IS-limiting effect of ticagrelor, whereas cyclooxygenase-1 inhibition or low-dose aspirin had no effect. Ticagrelor, but not clopidogrel, upregulated COX2 expression and activity. Also this effect was blocked by adenosine-receptor antagonism. Ticagrelor, but not clopidogrel, increased Akt and endothelial nitric oxide synthase phosphorylation.
  
  
  CONCLUSIONS
  Ticagrelor, but not clopidogrel, reduces myocardial IS. The protective effect of ticagrelor was dependent on adenosine-receptor activation with downstream upregulation of endothelial nitric oxide synthase and COX2 activity.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston (M.K.N., S.L., M.K., Y.Y., Y.B.); State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China (S.L.); AstraZeneca R&D, Mölndal, Sweden (S.N.); and Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX (Y.B.).
authors.forename: Manjyot K
authors.initials: MK
authors.lastname: Nanhwan
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston (M.K.N., S.L., M.K., Y.Y., Y.B.); State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China (S.L.); AstraZeneca R&D, Mölndal, Sweden (S.N.); and Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX (Y.B.).
authors.forename: Shukuan
authors.initials: S
authors.lastname: Ling
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston (M.K.N., S.L., M.K., Y.Y., Y.B.); State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China (S.L.); AstraZeneca R&D, Mölndal, Sweden (S.N.); and Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX (Y.B.).
authors.forename: Monica
authors.initials: M
authors.lastname: Kodakandla
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston (M.K.N., S.L., M.K., Y.Y., Y.B.); State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China (S.L.); AstraZeneca R&D, Mölndal, Sweden (S.N.); and Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX (Y.B.).
authors.forename: Sven
authors.initials: S
authors.lastname: Nylander
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston (M.K.N., S.L., M.K., Y.Y., Y.B.); State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China (S.L.); AstraZeneca R&D, Mölndal, Sweden (S.N.); and Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX (Y.B.).
authors.forename: Yumei
authors.initials: Y
authors.lastname: Ye
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston (M.K.N., S.L., M.K., Y.Y., Y.B.); State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China (S.L.); AstraZeneca R&D, Mölndal, Sweden (S.N.); and Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX (Y.B.). ybirnbau@bcm.edu.
authors.forename: Yochai
authors.initials: Y
authors.lastname: Birnbaum
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000077144:Clopidogrel; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction / Q000187:drug effects; D044045:Lipoxins / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000502:physiology; D043705:Receptor, Adenosine A2A / Q000502:physiology; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D014230:Triazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D002316:Cardiotonic Agents; D052246:Cyclooxygenase 2 Inhibitors; D044045:Lipoxins; D011720:Pyrazoles; D011799:Quinazolines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; C115461:SC 560; D014230:Triazoles; C040527:lipoxin A4; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D015121:6-Ketoprostaglandin F1 alpha; D000077144:Clopidogrel; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine; D001241:Aspirin; C052410:9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine
keywords: adenosine; aspirin; cyclooxygenase; platelet aggregation inhibitors