© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
The L-arginine/nitric oxide pathway contributes to the acute release of tissue plasminogen activator in vivo in man
aClinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK
bDepartment of Cardiology, University of Edinburgh, Royal Infirmary, Lauriston Place, Edinburgh EH3 9YW, UK
cDepartment of Haematology, University of Edinburgh, Royal Infirmary, Lauriston Place, Edinburgh EH3 9YW, UK
* Corresponding author. Tel.: +44 (131) 332-1205; Fax: +44 (131) 343-6017; E-mail: d.e.newby@ed.ac.uk
Objective: Effective endogenous fibrinolysis requires rapid release of endothelial tissue plasminogen activator (t-PA). Using the nitric oxide synthase inhibitor, L-NG-monomethylarginine (L-NMMA), we examined the contribution of endogenous nitric oxide to substance P-induced t-PA release in vivo in man. Methods: Blood flow and plasma fibrinolytic and haemostatic factors were measured in both forearms of 8 healthy male volunteers who received unilateral brachial artery infusions of substance P (2–8 pmol/min) and L-NMMA (1–4 µg/min). Results: Substance P caused dose-dependent increases in blood flow (P<0.001) and plasma t-PA antigen (P=0.04) and activity (P<0.001) concentrations confined to the infused forearm, but had no effect on plasminogen activator inhibitor type 1 (PAI-1) or von Willebrand factor concentrations. In the presence of L-NMMA, substance P again caused significant increases in blood flow (P<0.001) and t-PA antigen (P=0.003) and activity (P<0.001) concentrations but these increases were significantly less than with substance P alone (P<0.001, P=0.05 and P<0.01, respectively). L-NMMA alone significantly reduced blood flow in the infused arm, but had no measurable effect on t-PA or PAI-1 concentrations. Conclusions: The L-arginine/nitric oxide pathway contributes to substance P-induced t-PA release in vivo in man. This provides an important potential mechanism whereby endothelial dysfunction increases the risk of atherothrombosis through a reduction in the acute fibrinolytic capacity.
KEYWORDS Thrombolysis; Endothelial factor; Nitric oxide; Blood flow; Endothelial function
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