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A review and discussion of platelet nitric oxide and nitric oxide synthase: do blood platelets produce nitric oxide from l-arginine or nitrite?

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Abstract

The NO/sGC/cGMP/PKG system is one of the most powerful mechanisms responsible for platelet inhibition. In numerous publications, expression of functional NO synthase (NOS) in human and mouse platelets has been reported. Constitutive and inducible NOS isoforms convert l-arginine to NO and l-citrulline. The importance of this pathway in platelets and in endothelial cells for the regulation of platelet function is discussed since decades. However, there are serious doubts in the literature concerning both expression and functionality of NOS in platelets. In this review, we aim to present and critically evaluate recent data concerning NOS expression and function in platelets, and to especially emphasise potential pitfalls of detection of NOS proteins and measurement of NOS activity. Prevailing analytical problems are probably the main sources of contradictory data on occurrence, activity and function of NOS in platelets. In this review we also address issues of how these problems can be resolved. NO donors including organic nitrites (RONO) and organic nitrate (RONO2) are inhibitors of platelet activation. Endogenous inorganic nitrite (NO2 −), the product of NO autoxidation, and exogenous inorganic nitrite are increasingly investigated as NO donors in the circulation. The role of platelets in the generation of NO from nitrite is also discussed.

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Abbreviations

CA:

Carbonic anhydrase

DAF:

Diaminofluorescein

DAN:

Diaminonaphthalene

ECNICI:

Electron-capture negative-ion chemical ionization

EI:

Electron ionization

GC:

Gas chromatography

sGC:

Soluble guanylyl cyclase

cGMP:

Cyclic guanosine monophosphate

IP:

Immunoprecipitation

LOD:

(Lower) limit of detection

LOQ:

(Lower) limit of quantitation

MS:

Mass spectrometry

NAT:

Naphthotriazol

NO:

Nitric oxide

NOS:

Nitric oxide synthase

eNOS:

Endothelial NOS

iNOS:

Inducible NOS

nNOS:

Neuronal NOS

PDE:

Phosphodiesterase

PFB:

Pentafluorobenzyl

PFB-Br:

Pentafluorobenzyl bromide

PKG:

cGMP-dependent protein kinase

RSD:

Relative standard deviation

SIM:

Selected-ion monitoring

VASP:

Vasodilator stimulated phosphoprotein

WF/R:

von Wildebrandt factor/ristocetin

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Acknowledgments

Financial support was granted to SG (Russian Fund of Fundamental Research 15-04-02438) and to DT (TS 60/4-1) from the Deutsche Forschungsgemeinschaft (Germany). We thank the reviewers for their useful comments and suggestions which helped improve our manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The studies reported in this article were approved by the Ethics Committee of the Hannover Medical School.

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Authors and Affiliations

  1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 44 Thorez Prosp, St. Petersburg, 194223, Russia

    Stepan Gambaryan

  2. Centre of Pharmacology and Toxicology, Bioanalytical Laboratory for Nitric Oxide, Oxidative Stress and Eicosanoids (BIOFORNOX20), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Dimitrios Tsikas

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Correspondence to Stepan Gambaryan or Dimitrios Tsikas.

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Gambaryan, S., Tsikas, D. A review and discussion of platelet nitric oxide and nitric oxide synthase: do blood platelets produce nitric oxide from l-arginine or nitrite?. Amino Acids 47, 1779–1793 (2015). https://doi.org/10.1007/s00726-015-1986-1

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