Adenosine Receptor Agonists Exhibit Anti-Platelet Effects and the Potential to Overcome Resistance to P2Y12 Receptor Antagonists.

Nina Wolska,Cezary Watala,Joanna Wzorek,Magdalena Gapinska,Tomasz Przygodzki,Dawid Polak,Marcin Rozalski,Magdalena Boncler

doi:10.3390/molecules25010130

Nina Wolska, Cezary Watala + Show 6 more

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https://doi.org/10.3390/molecules25010130

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Abstract

Large inter-individual variation in platelet response to endogenous agonists and pharmacological agents, including resistance to antiplatelet therapy, prompts a search for novel platelet inhibitors and development new antithrombotic strategies. The present in vitro study evaluates the beneficial effects of three adenosine receptor (AR) agonists (regadenoson, LUF 5835 and NECA), different in terms of their selectivity for platelet adenosine receptors, when used alone and in combination with P2Y12 inhibitors, such as cangrelor or prasugrel metabolite. The anti-platelet effects of AR agonists were evaluated in healthy subjects (in the whole group and after stratification of individuals into high- and low-responders to P2Y12 inhibitors), using whole blood techniques, under flow (thrombus formation) and static conditions (study of platelet activation and aggregation). Compared to P2Y12 antagonists, AR agonists were much less or not effective under static conditions, but demonstrated similar antiplatelet activity in flow. In most cases, AR agonists significantly enhanced the anti-platelet effect of P2Y12 antagonists, despite possessing different selectivity profiles and antiplatelet activities. Importantly, their inhibitory effects in combination with P2Y12 antagonists were similar in high- and low-responders to P2Y12 inhibitors. In conclusion, a combination of anti-platelet agents acting via the P1 and P2 purinergic receptors represents a promising alternative to existing antithrombotic therapy.

Highlights

The leading causes of morbidity and mortality in developed countries are cardiovascular disease and stroke, resulting predominantly from arterial thrombosis dependent on blood platelet hyperreactivity
We found that the use of Adenosine receptor (AR) agonists can lead to significantly higher inhibition of platelet function caused by P2Y12 antagonists and effect was on the same level in high- and low-responders to P2Y12 inhibitors, which suggests that AR agonists have the potential to overcome resistance to P2Y12 blockers
To ensure that AR agonists used in this work do not exhibit cytotoxic effects on blood platelets, which could influence the results of functional tests, platelet viability was measured

Summary

Introduction

The leading causes of morbidity and mortality in developed countries are cardiovascular disease and stroke, resulting predominantly from arterial thrombosis dependent on blood platelet hyperreactivity. ADP is one of the key mediators of both physiological haemostasis and thrombosis, being a direct agonist of platelets, and an important factor released from platelet intracellular structures, enhancing the platelet response initially induced by other activators. Platelets have two ADP receptors on their surface: the P2Y1 receptor initiates platelet aggregation, while the P2Y12 receptor enhances this process, eventually leading to the formation of a clot. Due to this fact, the P2Y12 receptor is the main therapeutic target in anti-platelet therapy targeted at the ADP-dependent activation pathway [5]. Thienopyridines are prodrugs: their short-lived active metabolites irreversibly inactivate the receptor and inhibit

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