NDLI: Synergistic Inhibition of Both P2Y$ _{1}$ and P2Y$ _{12}$ Adenosine Diphosphate Receptors As Novel Approach to Rapidly Attenuate Platelet-Mediated Thrombosis

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Synergistic Inhibition of Both P2Y$ _{1}$ and P2Y$ _{12}$ Adenosine Diphosphate Receptors As Novel Approach to Rapidly Attenuate Platelet-Mediated Thrombosis

Content Provider	Scilit
Author	Andrew, L. Frelinger I. I. I. Gremmel, Thomas Yanachkov, Ivan B. Yanachkova, Milka I. Wright, George E. Wider, Joseph Undyala, Vishnu V. R. Michelson, Alan D. Przyklenk, Karin
Copyright Year	2016
Description	Journal: Arteriosclerosis, thrombosis, and vascular biology Objective—: Unlike currently approved adenosine diphosphate receptor antagonists, the new diadenosine tetraphosphate derivative GLS-409 targets not only P2Y$ _{12}$ but also the second human platelet adenosine diphosphate receptor P2Y$ _{1}$ and may, therefore, be a promising antiplatelet drug candidate. The current study is the first to investigate the in vivo antithrombotic effects of GLS-409. Approach and Results—: We studied (1) the in vivo effects of GLS-409 on agonist-stimulated platelet aggregation in anesthetized rats, (2) the antithrombotic activity of GLS-409 and the associated effect on the bleeding time in a canine model of platelet-mediated coronary artery thrombosis, and (3) the inhibition of agonist-stimulated platelet aggregation by GLS-409 versus selective P2Y$ _{1}$ and P2Y$ _{12}$ inhibition in vitro in samples from healthy human subjects before and 2 hours after aspirin intake. In vivo treatment with GLS-409 significantly inhibited adenosine diphosphate- and collagen-stimulated platelet aggregation in rats. Further, GLS-409 attenuated cyclic flow variation, that is, platelet-mediated thrombosis, in vivo in our canine model of unstable angina. The improvement in coronary patency was accompanied by a nonsignificant 30% increase in bleeding time. Of note, GLS-409 exerted its effects without affecting rat and canine hemodynamics. Finally, in vitro treatment with GLS-409 showed effects similar to that of cangrelor and the combination of cangrelor with the selective P2Y$ _{1}$ inhibitor MRS 2179 on agonist-stimulated platelet aggregation in human platelet-rich plasma and whole blood before and 2 hours after aspirin intake. Conclusions—: Synergistic inhibition of both P2Y$ _{1}$ and P2Y$ _{12}$ adenosine diphosphate receptors by GLS-409 immediately attenuates platelet-mediated thrombosis and effectively blocks agonist-stimulated platelet aggregation irrespective of concomitant aspirin therapy.
Related Links	https://www.ahajournals.org/doi/pdf/10.1161/ATVBAHA.115.306885 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767596/pdf https://www.ahajournals.org/doi/reader/10.1161/ATVBAHA.115.306885
Ending Page	509
Page Count	9
Starting Page	501
ISSN	10795642
e-ISSN	15244636
DOI	10.1161/atvbaha.115.306885
Journal	Arteriosclerosis, thrombosis, and vascular biology
Issue Number	3
Volume Number	36
Language	English
Publisher	Ovid Technologies (Wolters Kluwer Health)
Publisher Date	2016-03-01
Access Restriction	Open
Subject Keyword	Journal: Arteriosclerosis, thrombosis, and vascular biology Peripheral Vascular Disease Antiplatelet Therapy Adenosine Diphosphate
Content Type	Text
Resource Type	Article
Subject	Cardiology and Cardiovascular Medicine

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