Combination of cyclic nucleotide modulators with P2Y12 receptor antagonists as anti‐platelet therapy

Abstract

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Platelet inhibition by P2Y12 antagonists is potentiated by adenosine signalling activators

“…In this way, when platelet cyclic nucleotide levels are elevated, as may well be the case within the circulation where platelets are bathed in NO and PGI 2 , the antiplatelet effects of P2Y 12 inhibition are greatly potentiated. This synergistic relationship holds clear clinical relevance as a therapeutic target, as we have recently demonstrated by coupling the P2Y 12 antagonist prasugrel with sGC stimulators (Armstrong et al, 2020).…”

“…We have previously shown that P2Y 12 receptor antagonists in vitro only weakly inhibit thrombin-or collagen-induced platelet aggregation (Armstrong et al, 2011;Kirkby et al, 2013), however, their effect is strongly related to cyclic nucleotide levels in platelets (Knowles & Warner, 2019). In this way, when platelet cyclic nucleotide levels are elevated, as may well be the case within the circulation where (Armstrong et al, 2020).…”

“…We have previously demonstrated a synergistic relationship between the actions of PGI 2 and NO and anti-thrombotic blockade of platelet P2Y 12 receptors (Chan et al, 2016;Kirkby et al, 2013). Following on from this work, we also reported that coupling prasugrel with soluble GC (sGC) stimulators can produce powerful antiplatelet effects (Armstrong et al, 2020). Considering the potential downstream action of adenosine on intraplatelet cAMP levels, we hypothesized that adenosine may also amplify P2Y 12 receptor antagonism.…”