Ticagrelor induces adenosine triphosphate release from human red blood cells.
BACKGROUND
The novel P2Y(12) antagonist ticagrelor inhibits ADP-induced platelet aggregation more rapidly and more potently than clopidogrel. Clinical trials have revealed dyspnea and asymptomatic ventricular pauses as side effects of ticagrelor. The mechanism behind these side effects is not known, but it is plausible that they are mediated by adenosine.


OBJECTIVE
Ticagrelor is known to increase adenosine concentrations by inhibiting red blood cell reuptake, but the potency of this effect may be too low to fully explain the adenosine related effects. The purpose of the present study was to determine whether ticagrelor has other effects on red blood cells (RBCs) that could contribute to explain the pleiotropic effects seen with ticagrelor treatment.


RESULTS
Using a luciferase-based bioluminescence assay, we studied ATP release in human blood. Human RBCs responded to ticagrelor in vitro by releasing substantial amounts of ATP in a dose-dependent manner (IC(50) 14μM). The rapid effect indicates release through membrane channels, which was supported by a depolarizing effect of ticagrelor and inhibition of ATP release by anion channel blockers.


CONCLUSIONS
In conclusion, our data show that, in vitro, ticagrelor can induce ATP release from human RBCs, which is subsequently degraded to adenosine. Further studies are warranted to determine what role this mechanism may play in the clinical effects of ticagrelor.
Department of Cardiology, Lund University, Lund, Sweden. Jenny.ohman@med.lu.se
Jenny
J
Ohman
Ramesh
R
Kudira
Sebastian
S
Albinsson
Björn
B
Olde
David
D
Erlinge
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D002478:Cells, Cultured; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D000077486:Ticagrelor
D058921:Purinergic P2Y Receptor Antagonists; D000255:Adenosine Triphosphate; D000077486:Ticagrelor; D000241:Adenosine