TY - JOUR
T1 - Regulation of local tissue-type plasminogen activator release by endothelium-dependent and endothelium-independent agonists in human vasculature
AU - Stein, C. Michael
AU - Brown, Nancy
AU - Vaughan, Douglas E.
AU - Lang, Chim C.
AU - Wood, Alastair J j
N1 - Funding Information:
This study was supported by a Grant-in-Aid from the American Heart Association, Dallas, Texas and by USPHS Grants GM 46622, HL 56251, HL 51387 and GM 5M01-RR00095 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Dr. Stein is the recipient of a Pharmaceutical Manufacturers of America (Washington, D.C.) Faculty Development Award in Clinical Pharmacology. Dr. Lang was supported by a Merck Sharp and Dohme (Rahway, New Jersey) International Fellowship in Clinical Pharmacology. Dr. Vaughan is the recipient of a Clinical Investigator Award from the Department of Veterans Affairs Research Service, Washington, D.C.
PY - 1998/7
Y1 - 1998/7
N2 - Objectives. 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 μg/min) and sodium nitroprusside (SNP) (8 μg/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.
AB - Objectives. 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 μg/min) and sodium nitroprusside (SNP) (8 μg/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.
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U2 - 10.1016/S0735-1097(98)00210-1
DO - 10.1016/S0735-1097(98)00210-1
M3 - Article
C2 - 9669258
AN - SCOPUS:0032127738
SN - 0735-1097
VL - 32
SP - 117
EP - 122
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 1
ER -
