@article{Apostoli:2014:10.1111/jth.12711,
author = {Apostoli, GL and Solomon, A and Smallwood, MJ and Winyard, PG and Emerson, M},
doi = {10.1111/jth.12711},
journal = {Journal of Thrombosis and Haemostasis},
pages = {1880--1889},
title = {Role of inorganic nitrate and nitrite in driving nitric oxide-GMP-mediated inhibition of platelet aggregation in vitro and in vivo},
url = {http://dx.doi.org/10.1111/jth.12711},
volume = {12},
year = {2014}
}

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TY  - JOUR
AB  - BackgroundNitric oxide (NO) is a critical negative regulator of platelets that is implicated in the pathology of thrombotic diseases. Platelets generate NO, but the presence and functional significance of NO synthase (NOS) in platelets is unclear. Inorganic nitrate/nitrite is increasingly being recognized as a source of bioactive NO, although its role in modulating platelets during health and vascular dysfunction is incompletely understood.MethodsWe investigated the functional significance and upstream sources of NO–cGMP signaling events in platelets by using established methods for assessing in vitro and in vivo platelet aggregation, and assessed the bioconversion of inorganic nitrate to nitrite during deficiency of endothelial NOS (eNOS).ResultsThe phosphodiesterase 5 (PDE5) inhibitor sildenafil inhibited human platelet aggregation in vitro. This inhibitory effect was abolished by a guanylyl cyclase inhibitor and NO scavengers, but unaffected by NOS inhibition. Inorganic nitrite drove cGMP-mediated inhibition of human platelet aggregation in vitro and nitrate inhibited platelet function in eNOS−/− mice in vivo in a model of thromboembolic radiolabeled platelet aggregation associated with an enhanced plasma nitrite concentration as compared with wild-type mice.ConclusionsPlatelets generate transient, endogenous cGMP signals downstream of NO that are primarily independent of NOS and may be enhanced by inhibition of PDE5. Furthermore, nitrite can generate transient NO–cGMP signals in platelets. The absence of eNOS leads to enhanced plasma nitrite levels following nitrate administration in vivo, which negatively impacts on platelet function. Our data suggest that inorganic nitrate exerts an antiplatelet effect during eNOS deficiency, and, potentially, that dietary nitrate may reduce platelet hyperactivity during endothelial dysfunction.
AU  - Apostoli,GL
AU  - Solomon,A
AU  - Smallwood,MJ
AU  - Winyard,PG
AU  - Emerson,M
DO  - 10.1111/jth.12711
EP  - 1889
PY  - 2014///
SN  - 1538-7933
SP  - 1880
TI  - Role of inorganic nitrate and nitrite in driving nitric oxide-GMP-mediated inhibition of platelet aggregation in vitro and in vivo
T2  - Journal of Thrombosis and Haemostasis
UR  - http://dx.doi.org/10.1111/jth.12711
UR  - http://hdl.handle.net/10044/1/25847
VL  - 12
ER  - 

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