ADMINISTRATION OF TUMOR-NECROSIS-FACTOR-ALPHA IN-VIVO DEPRESSES ENDOTHELIUM-DEPENDENT RELAXATION

Although depressed endothelium-dependent relaxation occurs during earl y sepsis, the precise mechanism responsible for this remains unknown. Because the elevated levels of plasma tumor necrosis factor (TNF) play a major role in the pathophysiology of sepsis, we investigated whethe r TNF-alpha administration alters endothehum-dependent relaxation. To study this, recombinant TNF-alpha (1.2 x 10(7) U/mg) was infused intra venously (0.25 mg/kg body wt) for 0.5 h in normal rats, and mean arter ial pressure was monitored. At 1 h after the completion of TNF-alpha o r vehicle infusion, the aorta and a pulmonary artery were isolated, cu t into 2.5-mm rings, and placed in organ chambers. Norepinephrine (2 x 10(-7) M) was applied to achieve near-maximal contraction, and dose r esponses for an endothelium-dependent vasodilator, acetylcholine, and an endothelium-independent vasodilator, nitroglycerine, were determine d. In additional studies, aortic rings from normal animals were incuba ted with TNF-alpha for 2 h in vitro, and vascular reactivity was deter mined. The results indicate that TNF-alpha administration significantl y reduced acetylcholine-induced vascular relaxation both in vivo and i n vitro. Such a reduction was sustained at least 80 min after the comp letion of 2-h incubation with TNF-alpha. In contrast, TNF did not alte r nitroglycerine-induced vascular relaxation. Thus TNF-alpha depresses endothelium-dependent relaxation in vitro as well as in vivo. Because TNF-alpha infusion increases plasma TNF levels without decreasing mea n arterial pressure, the depressed endothelium-dependent relaxation ob served during early sepsis may be due to the elevated circulating leve ls of TNF.