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 receivedunilateral 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.
RCT Entities:
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.
Authors: Tracy Baynard; Helena M Jacobs; Craig M Kessler; Jill A Kanaley; Bo Fernhall Journal: Eur J Appl Physiol Date: 2007-08-04 Impact factor: 3.078
Authors: D E Newby; F N Witherow; R A Wright; P Bloomfield; C A Ludlam; N A Boon; K A A Fox; D J Webb Journal: Heart Date: 2002-01 Impact factor: 5.994
Authors: Amanda L Hunter; Jon Unosson; Jenny A Bosson; Jeremy P Langrish; Jamshid Pourazar; Jennifer B Raftis; Mark R Miller; Andrew J Lucking; Christoffer Boman; Robin Nyström; Kenneth Donaldson; Andrew D Flapan; Anoop S V Shah; Louis Pung; Ioannis Sadiktsis; Silvia Masala; Roger Westerholm; Thomas Sandström; Anders Blomberg; David E Newby; Nicholas L Mills Journal: Part Fibre Toxicol Date: 2014-12-09 Impact factor: 9.400