Increased circulating concentrations of tumour necrosis factor-α (TNF-α) are seen in several pathological conditions associated with vascular disease. TNF-α 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-α are elevated. The details of the interaction between ET-1 and TNF-α 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-α 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 6h infusion of TNF-α into the brachial artery. Forearm blood flow was significantly greater than baseline during exposure to TNF-α [median (lower quartile, upper quartile): baseline, 2.6 (2.1,2.8) ml·min-1·100ml-1; TNF-α, 4.6 (4.5,5.1) ml·min-1·100ml-1; P<0.05]. The rate of release of ET-1 was significantly greater than baseline after 30 and 260min of TNF-α infusion [median (lower quartile, upper quartile): baseline, 0.8 (0.6,1.1)pg·min-1·100ml-1; 30min, 2.4 (1.9,3.2)pg·min-1·100ml-1; 260min, 4.1 (3.1,4.2)pg·min-1·100ml-1; P<0.05]. The vasodilatory response to acetylcholine was diminished during TNF-α infusion, whereas the response to sodium nitroprusside remained unchanged. We thus demonstrate for the first time that local TNF-α increases ET-1 spillover from the human forearm and impairs endothelium-dependent vasodilatation. In spite of this action, TNF-α has a vasodilatory effect, resulting in an increase in forearm blood flow.

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