Ticagrelor Does Not Inhibit Adenosine Transport at Relevant Concentrations: A Randomized Cross-Over Study in Healthy Subjects In Vivo.

T N A Van Den Berg,G A Rongen,P H H Van Den Broek,A R T Donders,S El Messaoudi,A Bilos,N P Riksen,M E Gomes,Yoshihiro Fukumoto

doi:10.1371/journal.pone.0137560

Abstract

Background and PurposeIn patients with myocardial infarction, ticagrelor reduces cardiovascular and sepsis-related mortality, and can cause dyspnea. It is suggested that this is caused by adenosine receptor stimulation, because in preclinical studies, ticagrelor blocks the nucleoside transporter and increases cellular ATP release. We now investigated the effects of ticagrelor on the adenosine system in humans in vivo.Experimental ApproachIn a double-blinded, placebo-controlled cross-over trial in 14 healthy subjects, we have tested whether ticagrelor (180 mg) affects adenosine- and dipyridamole-induced forearm vasodilation, as surrogates of nucleoside uptake inhibition and adenosine formation, respectively. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was measured. Primary endpoint was adenosine-induced vasodilation.Key ResultsTicagrelor did not affect adenosine- or dipyridamole-induced forearm vasodilation. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was not affected by ticagrelor. In vitro, ticagrelor dose-dependently inhibited nucleoside uptake, but only at supra-physiological concentrations.Conclusion and ImplicationsIn conclusion, at relevant plasma concentration, ticagrelor does not affect adenosine transport, nor adenosine formation in healthy subjects. Therefore, it is unlikely that this mechanism is a relevant pleiotropic effect of ticagrelor.Trial RegistrationClinicalTrials.gov NCT01996735

Highlights

Ticagrelor is a novel direct-acting and reversibly binding P2Y12 receptor antagonist
We have previously demonstrated that dipyridamole potentiates the post-occlusive reactive hyperemia (PORH) response [8] and that statins potentiate the PORH by an increase of the extracellular adenosine formation [15]
The sample size calculation was based on the following assumptions: in previous studies from our own group, we found that the vasodilator response to the intrabrachial administration of adenosine averages 2.8±0.6, 4.4±1.0, 9.0±1.7 ml/min per dl of forearm volume for 0.5, 1.5, and 5.0 μg/min/dl, respectively

Summary

Introduction

Ticagrelor is a novel direct-acting and reversibly binding P2Y12 receptor antagonist. Dyspnea and asymptomatic ventricular pauses were reported more often in the ticagrelor treated patients. These finding have instigated the search for pleiotropic effects of ticagrelor over and above the classical antiplatelet effect. Inhibition of the hENT1 activity will increase the extracellular adenosine concentration, and this mechanism has been proposed to mediate the effects of ticagrelor observed in the PLATO study [3]. In patients with myocardial infarction, ticagrelor reduces cardiovascular and sepsis-related mortality, and can cause dyspnea. It is suggested that this is caused by adenosine receptor stimulation, because in preclinical studies, ticagrelor blocks the nucleoside transporter and increases cellular ATP release. We investigated the effects of ticagrelor on the adenosine system in humans in vivo.

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