Adenosine-Mediated Effects of Ticagrelor

Abstract

This review constitutes a critical evaluation of recent publications that have described an additional mode of action of the P2Y12 receptor antagonist ticagrelor. The effect is mediated by inhibition of the adenosine transporter ENT1 (type 1 equilibrative nucleoside transporter), which provides protection for adenosine from intracellular metabolism, thus increasing its concentration and biological activity, particularly at sites of ischemia and tissue injury where it is formed. Understanding the mode of action of ticagrelor is of particular interest given that its clinical profile, both in terms of efficacy and adverse events, differs from that of thienopyridine P2Y12 antagonists.

Ticagrelor Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

“…13,14 We have recently shown that 7-day oral pretreatment with ticagrelor, but not clopidogrel, limits myocardial infarct size (IS) in rats subjected to 30-minute coronary artery ligation followed by 24-hour reperfusion. 15 Importantly, the degree of platelet inhibition was comparable between the clopidogrel and ticagrelor arms indicating a P2Y 12 -and platelet-independent cardioprotective effect of ticagrelor. Indeed, the protective effect was mediated by adenosine receptor activation with downstream phosphorylation of protein kinase B (Akt), endothelial NO synthase, and activation of cyclooxygenase-2 (COX2).…”

“…The effect should be sustained as long as sufficient ticagrelor exposure is present. [9][10][11][12] In a previous study we showed that 7-day pretreatment with ticagrelor upregulated COX2 expression and activity. 15 The protective effect of ticagrelor pretreatment was blocked with specific COX2 inhibitors, as well as aspirin.…”

“…n patients with acute coronary syndromes (ACSs), P2Y 12 receptor antagonists reduce the incidence of cardiovascular events. 1 A combination of aspirin with P2Y 12 receptor antagonists is recommended by the guidelines for patients with ACS, including ST-segment-elevation myocardial infarction (STEMI).…”

“…7,8 Although the increased benefit was originally ascribed to better and more consistent platelet inhibition, ticagrelor, in addition to its P2Y 12 receptor-blocking properties, inhibits interstitial adenosine cell reuptake, via inhibition of the equilibrative nucleoside transporter 1, thereby increasing extracellular adenosine levels. [9][10][11][12] Adenosine is a major mediator of myocardial protection against ischemia-reperfusion injury and is essential for the myocardial protection by ischemic preconditioning and various pharmacological preconditioning. 13,14 We have recently shown that 7-day oral pretreatment with ticagrelor, but not clopidogrel, limits myocardial infarct size (IS) in rats subjected to 30-minute coronary artery ligation followed by 24-hour reperfusion.…”

Böbrekte İskemi-Reperfüzyon Hasarında Ticagrelor’un Etkisi: Pleiotropik Etki Geçerli Bir Faktör mü?

“…It is a direct-acting antagonist of P2Y 12 , which is a purinergic receptor for adenosine diphosphate (ADP) expressed by platelets. P2Y 12 plays an important role in thrombosis and homeostasis and defects in P2Y 12 to result in bleeding due to its role in ADP-induced platelet aggregation [4][5][6] . Due to these effects, ticagrelor is widely used to prevent stroke and acute coronary syndrome [7] .…”