THE EFFECT OF TUMOR-NECROSIS-FACTOR ON VASCULAR SMOOTH-MUSCLE - INVITRO STUDIES USING RAT AORTIC RINGS

The mechanisms of vasodilation in septic shock have not been well elucidated. We used isolated rat aortic rings as an in vitro model of vascular reactivity to assess the acute, direct effects on vascular smooth muscle relaxation of four cytokines: interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (IL-6), and tumor necrosis factor (TNF). The rings were precontracted with catecholamines and then test cytokines were added. The changes in tension with IL-1 at 1,000 U/ml, IL-2 at 1,000 U/ml, and IL-6 at 500 U/ml differed from controls by -67 +/- 59, -5 +/- 42, and 8 +/- 56 mg/mg of tissue, respectively (for each, n = 10, p = NS). The change in tension with TNF at 1,000 U/ml differed from controls by -176 +/- 42 mg/mg of tissue (n = 20, p < 0.001). Chemical removal of the endothelium with deoxycholate diminished TNF-induced vasodilation to -62 +/- 14 mg/mg of tissue (p < 0.05). The relaxation with TNF occurred in a concentration-dependent fashion and was unaffected by indomethacin. This study demonstrates that TNF has an acute, concentration-dependent, cyclooxygenase-independent, vasodilatory effect on vascular smooth muscle. The effect of TNF was partially, but not fully, dependent on the presence of an intact endothelium, implying that TNF acts on both the endothelium and the smooth muscle. These findings suggest that TNF may play an important role in the vasodilation characteristic of septic shock.