Published Online
on April 5, 2004

A more recent version of this article appeared on April 20, 2004

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Submitted on July 28, 2003
Revised on January 22, 2004
Accepted on March 1, 2004

Rapid Regulation of Platelet Activation In Vivo by Nitric Oxide

Andreas Schäfer MD, Frank Wiesmann MD, Stefan Neubauer MD, FRCP, Martin Eigenthaler MD, Johann Bauersachs MD, and Keith M. Channon MD, FRCP^*

From the Department of Cardiovascular Medicine, University of Oxford, UK (A.S., F.W., S.N., K.M.C.), and Medizinische Klinik (A.S., F.W., J.B.) and Institut für Klinische Biochemie und Pathobiochemie (M.E.), Julius-Maximilians-Universität Würzburg, Würzburg, Germany.

^* To whom correspondence should be addressed. E-mail: keith.channon{at}cardiov.ox.ac.uk.

Background--Platelet activation is a feature of many cardiovascular diseases characterized by endothelial dysfunction. The mechanistic relationship between impaired systemic nitric oxide (NO) bioavailability and platelet activation in vivo remains unclear. We investigated whether acute inhibition of NO production in humans modulates platelet activation in vivo and whether exogenous NO would counteract such an effect.

Methods and Results--Intravenous injection of the NO synthase inhibitor N^G-monomethyl-L-arginine in healthy volunteers resulted in NO synthase inhibition as detected by increased blood pressure and by significantly reduced phosphorylation of platelet vasodilator-stimulated phosphoprotein, an indicator of NO signaling. NO synthase inhibition increased platelet activation as determined by enhanced platelet binding of fibrinogen and surface expression of P-selectin, glycoprotein 53, and CD40 ligand, demonstrating tonic inhibition of platelet activation by NO production in vivo. Sublingual administration of the NO donor glyceryl trinitrate normalized platelet VASP phosphorylation and restored markers of platelet activation to baseline levels.

Conclusions--Acute inhibition of endogenous NO production in humans causes rapid platelet activation in vivo, which is reversed by exogenous NO, demonstrating that platelet function in vivo is rapidly regulated by NO bioavailability.

Key words: glycoproteins • nitric oxide • P-selectin • phosphoproteins • platelets

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