Effect of adenosine A2 receptor stimulation on platelet activation-aggregation: Differences between canine and human models

Matthew D. Linden, Marc R. Barnard, A. L. Frelinger, Alan D. Michelson, Karin Przyklenk

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Introduction: Adenosine A2 agonists improve arterial patency in experimental models of recurrent thrombosis, an effect purportedly triggered by stimulation of platelet A2 receptors and subsequent down-regulation of platelet function. However: (i) there is no direct evidence to substantiate this premise; and (ii) given the recognized differences among species in platelet signaling, it is possible that the mechanisms of A2 receptor stimulation may be model-dependent. Accordingly, we applied an integrated in vivo and in vitro approach, using both canine and human models, to test the hypothesis that the anti-thrombotic effects of A2 agonist treatment are due in part to inhibition of platelet activation. Methods: In Protocol 1, recurrent coronary thrombosis was triggered in anesthetized dogs by application of a stenosis at a site of arterial injury. Coronary patency and flow cytometric indices of platelet activation (P-selectin expression; formation of heterotypic aggregates) were compared in dogs pre-treated with the A2 agonist CGS 21680 versus controls. In Protocols 2 and 3, blood samples were obtained from dogs and human volunteers. In vitro aggregation and platelet activation (assessed by impedance aggregometry and flow cytometry, respectively) were quantified in paired aliquots pre-incubated with CGS versus vehicle. Results: In the canine models, CGS improved in vivo coronary patency and attenuated in vitro aggregation but, contrary to our hypothesis, did not evoke a down-regulation in platelet activation. In contrast, in human blood samples, CGS attenuated both in vitro aggregation and flow cytometric markers of platelet activation-aggregation. Conclusion: The mechanisms contributing to the anti-thrombotic effect of A2 agonist treatment are species-dependent: adenosine A2 receptor stimulation inhibits platelet activation in human, but not canine, models.

Original languageEnglish
Pages (from-to)689-698
Number of pages10
JournalThrombosis Research
Volume121
Issue number5
DOIs
StatePublished - 2008

Keywords

  • Adenosine
  • Fibrinogen
  • Heterotypic aggregates
  • P-selectin
  • Platelets
  • Thrombosis

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