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Combination of cyclic nucleotide modulators with P2Y 12 receptor antagonists as anti‐platelet therapy
Author(s) -
Armstrong Paul C.,
Ferreira Plinio M.,
Chan Melissa V.,
Lundberg Slingsby Martina H.,
Crescente Marilena,
Shih ChihChin,
Kirkby Nicholas S.,
Hobbs Adrian J.,
Warner Timothy D.
Publication year - 2020
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14826
Subject(s) - p2y12 , pharmacology , platelet , ex vivo , chemistry , prasugrel , platelet activation , in vivo , biochemistry , medicine , biology , in vitro , clopidogrel , aspirin , microbiology and biotechnology
Background Endothelium‐derived prostacyclin and nitric oxide elevate platelet cyclic nucleotide levels and maintain quiescence. We previously demonstrated that a synergistic relationship exists between cyclic nucleotides and P2Y 12 receptor inhibition. A number of clinically approved drug classes can modulate cyclic nucleotide tone in platelets including activators of NO‐sensitive guanylyl cyclase (GC) and phosphodiesterase (PDE) inhibitors. However, the doses required to inhibit platelets produce numerous side effects including headache. Objective We investigated using GC‐activators in combination with P2Y 12 receptor antagonists as a way to selectively amplify the anti‐thrombotic effect of both drugs. Methods In vitro light transmission aggregation and platelet adhesion under flow were performed on washed platelets and platelet rich plasma. Aggregation in whole blood and a ferric chloride‐induced arterial thrombosis model were also performed .Results The GC‐activator BAY‐70 potentiated the action of the P2Y 12 receptor inhibitor prasugrel active metabolite in aggregation and adhesion studies and was associated with raised intra‐platelet cyclic nucleotide levels. Furthermore, mice administered sub‐maximal doses of the GC activator cinaciguat together with the PDE inhibitor dipyridamole and prasugrel, showed significant inhibition of ex vivo platelet aggregation and significantly reduced in vivo arterial thrombosis in response to injury without alteration in basal carotid artery blood flow. Conclusions Using in vitro, ex vivo, and in vivo functional studies, we show that low dose GC activators synergize with P2Y 12 inhibition to produce powerful anti‐platelet effects without altering blood flow. Therefore, modulation of intra‐platelet cyclic nucleotide levels alongside P2Y 12 inhibition can provide a strong, focused anti‐thrombotic regimen while minimizing vasodilator side effects.