Rapid regulation of platelet activation in vivo by nitric oxide.
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.
Schäfer
Andreas
A
Department of Cardiovascular Medicine, University of Oxford, UK.
Wiesmann
Frank
F
Neubauer
Stefan
S
Eigenthaler
Martin
M
Bauersachs
Johann
J
Channon
Keith M
KM
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
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