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

D E Newby, R A Wright, P Dawson, C A Ludlam, N A Boon, K A Fox, D J Webb

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)485-92
Number of pages8
JournalCardiovascular Research
Volume38
Issue number2
DOIs
Publication statusPublished - 1 May 1998

Keywords

  • Adult
  • Analysis of Variance
  • Area Under Curve
  • Dose-Response Relationship, Drug
  • Forearm
  • Humans
  • Male
  • Nitric Oxide Synthase
  • Plasminogen Activator Inhibitor 1
  • Plethysmography
  • Regional Blood Flow
  • Substance P
  • Tissue Plasminogen Activator
  • omega-N-Methylarginine

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