EFFECTS OF TNF-ALPHA ON HEMODYNAMIC-CHANGES AND CIRCULATING ENDOTHELIUM-DERIVED VASOACTIVE FACTORS IN DOGS

To elucidate the relation of tumor necrosis factor-alpha (TNF-alpha)-induced hemodynamic change to endothelium-derived vasoactive factors, we simultaneously measured hemodynamic parameters and circulating endothelin (ET)-1, ET-3, nitrite/nitrate (NOx), and 6-ketoprostaglandin F-1 alpha (6-keto-PGF(1 alpha)) in anesthetized dogs following administration of TNF-alpha with or without N-G-nitro-L-arginine (L-NNA), a nitric oxide (NO) synthase inhibitor, and indomethacin, a cyclooxygenase inhibitor. Natural human TNF-alpha (10 mu g/kg, n = 5) with or without L-NNA(1 mg/kg, n = 5) or indomethacin (2 mg/kg, n = 5) was administered intravenously as a bolus, while administration of vehicle served as control (n = 5). After administration of TNF-(alpha), mean arterial pressure and cardiac index significantly decreased, whereas systemic (SVRI) and pulmonary (PVRI) vascular resistance index increased. Plasma levels of ET-1, ET-3, NOx, and 6-keto-PGF(1 alpha) significantly (P < 0.01) increased at 1 h. L-NNA or indomethacin blocked TNF-alpha-induced hypotension and remarkably increased SVRI but did not affect decreased cardiac index. Our data suggest that endogenous ET-1 may partly contribute to TNF-alpha-induced increases in SVRI and PVRI, against which ET-3, NO, and prostacyclin may function as compensatory vasodilators.