Regulation of local tissue-type plasminogen activator release by endothelium-dependent and endothelium-independent agonists in human vasculature.
OBJECTIVE
This study sought to define the local regulation of vascular tissue-type plasminogen activator (t-PA) release.


BACKGROUND
The vascular endothelium, through the production of t-PA and plasminogen activator inhibitor (PAI-1), is an important regulator of fibrinolysis. Plasma t-PA levels increase in response to adrenergic stimulation; however, it is unclear whether this increase is the result of systemic reflex responses or direct effects on the vascular endothelium.


METHODS
Forearm blood flow dose responses were generated to low doses of agonist infused directly into the brachial artery in 15 normotensive men (mean [+/-SE] age 28.9 +/- 2.2 years). Simultaneous arterial and venous blood samples were drawn at baseline and in response to the intraarterial administration of isoproterenol (400 ng/min), methacholine (8 microg/min) and sodium nitroprusside (SNP) (8 microg/min). PAI-1 and t-PA antigen levels were measured by enzyme-linked immunosorbent assay, and the net release across the forearm was calculated.


RESULTS
Forearm plasma flow increased significantly from baseline (1.4 +/- 0.2 ml/100 ml per min) after administration of isoproterenol, methacholine and SNP (9.7 +/- 1.9, 8.7 +/- 1.9 and 6.7 +/- 1.1 ml/100 ml per min, respectively) (p < 0.001 by analysis of variance). Baseline net t-PA release (0.7 +/- 0.3 ng/100 ml per min) increased significantly after administration of isoproterenol (26.2 +/- 11.6 ng/100 ml per min, p = 0.005) and methacholine (15.3 +/- 5.5 ng/100 ml per min, p = 0.001) but not after administration of SNP (1.8 +/- 2.2 ng/100 ml per min, p = 0.84). There was no net release of PAI-1 across the vascular bed.


CONCLUSIONS
Marked, rapid local t-PA release occurred in response to isoproterenol, a beta-adrenoceptor agonist, and methacholine, an endothelium-dependent nitric oxide agonist, in the human forearm. This effect was selective and independent of the effects of shear stress due to increased flow because SNP induced similar increases in forearm blood flow without affecting t-PA release. Vascular t-PA release may be a potentially valuable tool for evaluating endothelial function in diseases associated with increased risk of thrombosis.
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. michael.stein@mcmail.vanderbilt.edu
C M
CM
Stein
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Brown
D E
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Vaughan
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CC
Lang
A J
AJ
Wood
D000328:Adult; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology*; D009569:Nitric Oxide / Q000819:agonists; D009599:Nitroprusside / Q000494:pharmacology*; D010277:Parasympathomimetics / Q000494:pharmacology*; D015849:Plasminogen Inactivators / Q000097:blood; D017534:Radial Artery / Q000187:drug effects / Q000502:physiology; D013566:Sympathomimetics / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000097:blood*; D014665:Vasodilator Agents / Q000494:pharmacology*
D010277:Parasympathomimetics; D015849:Plasminogen Inactivators; D013566:Sympathomimetics; D014665:Vasodilator Agents; D016210:Methacholine Chloride; D009599:Nitroprusside; D009569:Nitric Oxide; D010959:Tissue Plasminogen Activator; D007545:Isoproterenol