期刊
VASCULAR PHARMACOLOGY
卷 113, 期 -, 页码 47-56出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.vph.2018.11.005
关键词
Platelet; Adenosine receptor; P2Y(12) antagonist; Dual anti-platelet therapy; Aggregation
资金
- Foundation for Polish Science - European Union under the European Regional Development Fund [TEAM/2016-1/8]
- Medical University [502-03/6-020-01/502-64-127-18]
Several adenosine receptor (AR) agonists have been shown in the past to possess anti-platelet potential; however, the adjunctive role of AR agonists in anti-platelet therapy with the use of P2Y(12) receptor inhibitors has not been elucidated so far. This in vitro aggregation-based study investigates whether the inhibition of platelet function mediated by cangrelor or prasugrel metabolite can be potentiated by AR agonists. It evaluates the effect of non-selective (2-chloroadenosine), A(2A)-selective (UK 432097, MRE 0094, PSB 0777) and A(2B)-selective AR agonists (BAY 60-6583) on platelet function in relation to their toxicity, specificity towards adenosine receptor subtypes, structure and solubility. UK 432097, 2-chloroadenosine, MRE 0094 and PSB 0777 were found to be more or less potent inhibitors of ADP-induced platelet aggregation when acting alone, and that they remained non-cytotoxic to the cells. These AR agonists were also effective in the potentiation of the effects exerted by P2Y(12) antagonists. Considering the estimated IC50 value, UK 432097, showing a relatively high binding affinity to the A(2A) adenosine receptor, has been identified as the most potent anti-aggregatory agent. This compound diminished platelet aggregation at nanomolar concentrations and further augmented platelet inhibition by P2Y(12) antagonists by approx. 60% (P < .01). Our results indicate the importance of adenosine receptors as therapeutic targets and point out challenges and potential benefits of therapeutic use of a combined therapy of P2Y(12) antagonist and AR agonist in cardioprotection. Our comparative analysis of the effects of AR agonists on platelet response in plasma and whole blood may indirectly suggest that other blood morphology elements contribute little to the inhibition of platelet function by AR agonists.
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