title: Rapid regulation of platelet activation in vivo by nitric oxide.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäfer
authors.forename: Frank
authors.initials: F
authors.lastname: Wiesmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Neubauer
authors.forename: Martin
authors.initials: M
authors.lastname: Eigenthaler
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D008840:Microfilament Proteins; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D005996:Nitroglycerin / Q000494:pharmacology; D019007:P-Selectin / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D015539:Platelet Activation; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D060149:Tetraspanin 30; D019323:omega-N-Methylarginine / Q000494:pharmacology; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015703:Antigens, CD; C554586:CD63 protein, human; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D008840:Microfilament Proteins; D020030:Nitric Oxide Donors; D019007:P-Selectin; D010750:Phosphoproteins; D010980:Platelet Membrane Glycoproteins; D060149:Tetraspanin 30; D000098662:Vasodilator-Stimulated Phosphoprotein; D023201:CD40 Ligand; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D005340:Fibrinogen; D019001:Nitric Oxide Synthase; D005996:Nitroglycerin