Anti-EDRF effect of tumor necrosis factor in isolated, perfused cat carotid arteries

Cat carotid arteries that have an intact endothelium were isolated and perfused with Krebs-Henseleit solution containing recombinant human tumor necrosis factor (rhTNF). Perfused arteries were preconstricted with KCl and then dilated with acetylcholine (ACh) or acidified NaNO2. After perfusion with TNF (4 micrograms/ml) for 120 min, the ACh-induced vasodilator response was markedly blunted, but the NaNO2 vasodilator response was not significantly affected. Arteries perfused with 2 micrograms/ml TNF for 60-120 min or with 4 micrograms/ml for 60 min did not develop a significantly impaired relaxation to ACh. Moreover, perfusion with 20-100 micrograms/ml cycloheximide, an inhibitor of protein synthesis, blocked the TNF-induced impairment of the relaxation to ACh. On the other hand, the vasodilator response to acidified NaNO2 did not change in any perfused carotid arteries. These results suggest that TNF promotes the synthesis of proteins that contribute to the damage of endothelial cells directly, probably by inhibiting endothelium-derived relaxing factor release.