Stein C M, Brown N, Vaughan D E, Lang C C, Wood A J
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
J Am Coll Cardiol. 1998 Jul;32(1):117-22. doi: 10.1016/s0735-1097(98)00210-1.
This study sought to define the local regulation of vascular tissue-type plasminogen activator (t-PA) release.
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.
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.
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.
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.
本研究旨在确定血管组织型纤溶酶原激活剂（t-PA）释放的局部调节机制。
血管内皮通过产生t-PA和纤溶酶原激活剂抑制剂（PAI-1），是纤维蛋白溶解的重要调节因子。血浆t-PA水平在肾上腺素能刺激下会升高；然而，尚不清楚这种升高是全身反射反应的结果还是对血管内皮的直接作用。
对15名血压正常的男性（平均[±标准误]年龄28.9±2.2岁），将低剂量激动剂直接注入肱动脉，生成前臂血流剂量反应。在基线时以及动脉内给予异丙肾上腺素（400 ng/min）、乙酰甲胆碱（8 μg/min）和硝普钠（SNP）（8 μg/min）后，同时采集动脉和静脉血样。通过酶联免疫吸附测定法测量PAI-1和t-PA抗原水平，并计算前臂的净释放量。
给予异丙肾上腺素、乙酰甲胆碱和SNP后，前臂血浆流量较基线（1.4±0.2 ml/100 ml每分钟）显著增加（分别为9.7±1.9、8.7±1.9和6.7±1.1 ml/100 ml每分钟）（方差分析，p<0.001）。基线时t-PA净释放量（0.7±0.3 ng/100 ml每分钟）在给予异丙肾上腺素（26.2±11.6 ng/100 ml每分钟，p = 0.005）和乙酰甲胆碱（15.3±5.5 ng/100 ml每分钟，p = 0.001）后显著增加，但给予SNP后未增加（1.8±2.2 ng/100 ml每分钟，p = 0.84）。血管床无PAI-1的净释放。
在人类前臂中，β-肾上腺素能受体激动剂异丙肾上腺素和内皮依赖性一氧化氮激动剂乙酰甲胆碱可引起明显、快速的局部t-PA释放。这种作用具有选择性，且与因血流增加导致的剪切应力作用无关，因为SNP可引起前臂血流类似增加，但不影响t-PA释放。血管t-PA释放可能是评估与血栓形成风险增加相关疾病中内皮功能的潜在有价值工具。
