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(Circulation. 2004;109:1819-1822.)
© 2004 American Heart Association, Inc.

Brief Rapid Communications

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; 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.

Correspondence to Professor Dr Keith M. Channon, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail keith.channon{at}cardiov.ox.ac.uk

Received July 28, 2003; revision received January 22, 2004; accepted March 1, 2004.

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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