The L-arginine nitric oxide pathway contributes to the acute release of tissue plasminogen activator in vivo in man

Objective: Effective endogenous fibrinolysis requires rapid release of endothelial tissue plasminogen activator (t-PA). Using the nitric oxide synthase inhibitor, L-N-G-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 mu g/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-I 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. (C) 1998 Elsevier Science B.V. All rights reserved.