ROLE OF LIPID-DERIVED MEDIATORS IN TUMOR NECROSIS FACTOR-INDUCED ENDOTHELIN-1 RELEASE IN-VIVO

We hypothesized that endothelin (ET) may be released in response to tu mor necrosis factor-alpha (TNF) and that platelet-activating factor (P AF) and cyclooxygenase products modulate TNF-induced ET-I release in v ivo. Anesthetized and instrumented pigs were randomly assigned to rece ive: 1) saline + TNF (n = 8); 2) saline + heat-inactivated TNF (contro l group, n = 5); 3) WEB 2086 (PAF receptor antagonist) + TNF (n = 7); or 4) indomethacin + TNF (n = 6). infusion of TNF was associated with increases in mean aortic, mean pulmonary artery, and intratracheal pre ssures, increases in systemic and pulmonary vascular resistances, and elevated plasma thromboxane B-2 concentration. Plasma ET-1 concentrati ons were unchanged in controls and significantly increased in TNF-trea ted pigs at 2 to 4 h. WEB 2086 did not modify plasma levels of ET-I du ring exogenous infusion of TNF. In contrast, the cyclooxygenase inhibi tor, indomethacin, mildly, but not significantly, reduced plasma ET-1 levels. In addition, indomethacin (but not WEB 2086) blocked or attenu ated the TNF-induced increases in mean aortic pressure, systemic vascu lar resistance, mean pulmonary artery pressure, pulmonary vascular res istance, and intratracheal pressure. We conclude that in the pig, cycl ooxygenase products modulate some of the cardiovascular responses to T NF and may mildly affect ET-1 biosynthesis. On the other hand, PAF nei ther significantly influences TNF-induced biosynthesis of ET-1 nor its associated cardiovascular responses.