Abstract 20532: Ticagrelor and Adenosine Reuptake Blockade

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Abstract

Introduction: Ticagrelor, a P2Y12 antagonist approved for the treatment of coronary disease, also blocks adenosine reuptake, and potentiation of adenosine actions may contribute to its unique pleiotropic beneficial effects (improved cardiovascular mortality) and side effects (dyspnea, asymptomatic ventricular pauses).

Hypothesis: Because the clinical relevance of this effect is unclear, we used the isolated forearm model to test the hypothesis that ticagrelor blocks adenosine reuptake, taking advantage of the fact that the vascular wall expresses high affinity nucleoside transporters that provide a barrier to transfer of adenosine from the intravascular compartment to the underlying interstitium.

Methods: We infused intrabrachial adenosine 0.125 mg/min and measured vasodilation (forearm blood flow, FBF) and dialysate concentrations of adenosine ([Ado]) from a microdialysis probe inserted in the underlying muscle, in 3 groups of normal subjects before and 2 hrs after oral administration of placebo, the adenosine reuptake blocker dipyridamole (200 mg), or ticagrelor (180 mg). Subjects’ assignment was randomized and the study double blind.

Results: Adenosine-induced vasodilation (increased FBF) was potentiated by dipyridamole (28.0±2.8 vs. 17.2±2 ml/100ml/min, p=0.008) and ticagrelor (17.9±3.4 vs. 13.1±2.6 ml/100ml/min, p=0.039). [Ado] increased during intravascular adenosine infusion only after dipyridamole (49.2±12 vs. 26.2±7.8 ng/ml, p=0.039) and ticagrelor administration (44.8±9.4 vs. 34.6±11.6 ng/ml, not significant), but not after placebo (39.6±7.7 vs. 44.3±8.9 ng/ml).

Conclusions: These results are consistent with a clinically relevant effect of ticagrelor in blocking adenosine reuptake and potentiating adenosine-induced vasodilation. Dipyridamole was more potent than ticagrelor in overcoming the vascular barrier to transport of adenosine from the intravascular to the interstitial compartment.

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