Patel J N, Jager A, Schalkwijk C, Corder R, Douthwaite J A, Yudkin J S, Coppack S W, Stehouwer C D A
Department of Medicine, Royal Free and University College London School of Medicine, Whittington Campus, London N19 3UA, UK.
Clin Sci (Lond). 2002 Oct;103(4):409-15. doi: 10.1042/cs1030409.
Increased circulating concentrations of tumour necrosis factor-alpha (TNF-alpha) are seen in several pathological conditions associated with vascular disease. TNF-alpha induces the synthesis of endothelin-1 (ET-1), a potent vasoconstictor, by the endothelium. However, there is profound vasodilatation in sepsis, where circulating levels of both ET-1 and TNF-alpha are elevated. The details of the interaction between ET-1 and TNF-alpha and the predominant resulting haemodynamic effect in healthy humans are unclear. The aim of the present study was to determine the effects of intra-arterial TNF-alpha on ET-1 spillover, vascular tone and endothelial function in the healthy human forearm. Brachial arterial and deep venous blood samples, forearm plasma flow measurements and blood flow responses to acetylcholine and sodium nitroprusside were obtained in six healthy subjects before and during a 6 h infusion of TNF-alpha into the brachial artery. Forearm blood flow was significantly greater than baseline during exposure to TNF-alpha [median (lower quartile, upper quartile): baseline, 2.6 (2.1, 2.8) ml.min(-1).100 ml(-1); TNF-alpha, 4.6 (4.5, 5.1) ml.min(-1).100 ml(-1); P <0.05]. The rate of release of ET-1 was significantly greater than baseline after 30 and 260 min of TNF-alpha infusion [median (lower quartile, upper quartile): baseline, 0.8 (0.6, 1.1) pg.min(-1).100 ml(-1); 30 min, 2.4 (1.9, 3.2) pg.min(-1).100 ml(-1); 260 min, 4.1 (3.1, 4.2) pg.min(-1).100 ml(-1); P <0.05]. The vasodilatory response to acetylcholine was diminished during TNF-alpha infusion, whereas the response to sodium nitroprusside remained unchanged. We thus demonstrate for the first time that local TNF-alpha increases ET-1 spillover from the human forearm and impairs endothelium-dependent vasodilatation. In spite of this action, TNF-alpha has a vasodilatory effect, resulting in an increase in forearm blood flow.
在一些与血管疾病相关的病理状况下，可观察到循环中肿瘤坏死因子-α（TNF-α）浓度升高。TNF-α可诱导内皮细胞合成内皮素-1（ET-1），一种强效血管收缩剂。然而，在脓毒症中存在显著的血管舒张，此时ET-1和TNF-α的循环水平均升高。ET-1与TNF-α之间相互作用的细节以及在健康人体内主要产生的血流动力学效应尚不清楚。本研究的目的是确定动脉内注射TNF-α对健康人前臂ET-1溢出、血管张力和内皮功能的影响。在6名健康受试者向肱动脉内输注TNF-α 6小时之前和期间，采集肱动脉和深静脉血样，测量前臂血浆流量以及对乙酰胆碱和硝普钠的血流反应。在接触TNF-α期间，前臂血流量显著高于基线水平[中位数（下四分位数，上四分位数）：基线水平，2.6（2.1，2.8）ml·min⁻¹·100 ml⁻¹；TNF-α，4.6（4.5，5.1）ml·min⁻¹·100 ml⁻¹；P<0.05]。在输注TNF-α 30分钟和260分钟后，ET-1的释放速率显著高于基线水平[中位数（下四分位数，上四分位数）：基线水平，0.8（0.6，1.1）pg·min⁻¹·100 ml⁻¹；30分钟，2.4（1.9，3.2）pg·min⁻¹·100 ml⁻¹；260分钟，4.1（3.1，4.2）pg·min⁻¹·100 ml⁻¹；P<0.05]。在输注TNF-α期间，对乙酰胆碱的血管舒张反应减弱，而对硝普钠的反应保持不变。因此，我们首次证明局部TNF-α可增加人前臂ET-1的溢出并损害内皮依赖性血管舒张。尽管有此作用，TNF-α仍具有血管舒张作用，导致前臂血流量增加。
