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-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 micrograms/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 I (PAI-I) 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.
Newby
D E
DE
Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, UK. d.e.newby@ed.ac.uk
Wright
R A
RA
Dawson
P
P
Ludlam
C A
CA
Boon
N A
NA
Fox
K A
KA
Webb
D J
DJ
D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D010991:Plethysmography; D012039:Regional Blood Flow / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000097:blood / Q000378:metabolism*; D019323:omega-N-Methylarginine / Q000494:pharmacology*
D017395:Plasminogen Activator Inhibitor 1; D019323:omega-N-Methylarginine; D013373:Substance P; D019001:Nitric Oxide Synthase; D010959:Tissue Plasminogen Activator