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

Abstract

Background and purpose: 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 now investigated the effects of ticagrelor on the adenosine system in humans in vivo.

Experimental approach: In 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 results: Ticagrelor 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 implications: In 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 registration: ClinicalTrials.gov NCT01996735.

Conflict of interest statement

Competing Interests: The study is conducted with financial support from AstraZeneca. NPR and MEG have served on a scientific advisory board of AstraZeneca. GAR has served on a scientific advisory board of Novartis. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Study Flow chart.

Fig 2. Schematic flow chart of the experiment.

Fig 3. Forearm blood flow measurements.

FBF values in the experimental forearm (triangle) and non-experimental forearm (circle) after ticagrelor treatment (black symbols) or placebo treatment (open symbols, dashed line) during intrabrachial administration of adenosine (A), after five (B) and two (C) minutes of forearm ischemia, and during intrabrachial administration of dipyridamole (D). P-values represent the effect of ticagrelor on the FBF-values.

Fig 4. The correlation between the plasma ticagrelor concentration and the area under the curve (AUC) of adenosine-induced forearm vasodilation.

Fig 5. Ex vivo uptake of adenosine (A) and uridine (B) in red blood cells isolated from the subjects before (pre-tica) and two hours after intake of ticagrelor (post-tica).

In A, the adenosine concentration in the supernatant is expressed as the percentage of the baseline adenosine concentration (n = 13; P >0.1). In B, the uridine uptake is expressed for each individual subjects before and after intake of ticagrelor (n = 13, P = 0.056 for comparison between before and after).

Fig 6. In vitro uptake of uridine in isolated red blood cells from healthy subjects.

The cells were pre-incubated with ticagrelor either after isolation (A; n = 3) of in whole blood before isolation of the red blood cells (B; n = 3). In C, the adenosine disappearance in whole blood from healthy volunteers is expressed as the percentage of the baseline concentration in the presence of ticagrelor in the concentrations 10−6 M (squares), 10−5 M (triangles), and 10−4 M (reversed triangles or in the presence of vehicle (circles, dashed line) (n = 2).