Role of tumor necrosis factor-α in small intestinal microcirculation. Discussion

The systemic manifestations of sepsis are associated with increased cardiac output, peripheral vasodilatation, and mesenteric vasoconstriction. Our objective was to determine whether tumor necrosis factor (TNF)-α regulates small intestinal microcirculatory changes observed during sepsis. An intact loop of terminal ileum of an anesthetized rat was exteriorized into modified Krebs solution and then topically suffused with varying concentrations of TNF-α (10 -4 ng/ml to 10 2 ng/ml), norepinephrine (10 -4 M), and sodium nitroprusside (10 -5 M). Videomicroscopy was used to measure arteriolar (A 1 , A 2 , A 3 ) and venular (V 1 , V 2 ) diameter changes in response to topical TNF-α. First order vessel diameters did not change in response to TNF-α. However, second and third order arterioles dilated maximally by 35 ± 16 and 52 ± 12 per cent, respectively, in a dose dependent manner in response to TNF-α. Higher order vessels were more sensitive to TNF-α than lower order vessels. Norepinephrine (10 -4 M) produced vasoconstriction in all vessels tested (A2 18 ± 3 per cent, p < 0.05; A3 6 ± 6 per cent; V2 13 ± 4 per cent, p < 0.05). Topical TNF-α caused dilation in preconstricted vessels as in the nonpreconstricted vessels. TNF-α induced vasodilation was prolonged and not reversed by removal of TNF-α. These data demonstrate statistically significant dilation in response to TNF-α in second and third order arterioles and venules of the small intestine. Persistent vasodilation suggests an induced mechanism of vasodilation in response to TNF-α that remains active even after removal of exogenous TNF-α. We, therefore, conclude that TNF-α causes persistent vasodilatation beyond the period of actual exposure to TNF-α in the small intestinal microcirculation. This effect is not altered by the presence of norepinephrine. These data suggest that small intestinal vasoconstriction observed during clinical conditions such as sepsis is unlikely to be mediated by TNF-α.