PULMONARY AND SYSTEMIC VASCULAR RESPONSIVENESS TO TNF-ALPHA IN CONSCIOUS RATS

Endotoxin decreases pulmonary vascular reactivity. Because tumor necrosis factor-alpha (TNF-alpha) is a primary mediator of endotoxemia, we tested whether TNF-alpha altered pulmonary vascular reactivity in conscious adult female rats. Osmotic pumps were implanted intraperitoneally, and low-dose TNF-alpha (62 mug, TNF62,; n = 7), high-dose TNF-alpha (greater-than-or-equal-to 250 mug, TNF250; n = 5), or saline (n = 5) was administered for 2 wk. Pulmonary pressor responses to 14% O2 and angiotensin II (ANG II, 0.0206 mug/min for 10 min) were measured without (day 13) or after (day 14) administration of nitro-L-arginine (4.4 mg/kg iv), an inhibitor of endothelium-derived relaxing factor (EDRF). TNF-alpha administration slightly decreased (P less-than-or-equal-to 0.08) baseline pulmonary arterial pressure in TNF250 rats and decreased (P less-than-or-equal-to 0.05) hypoxia- and ANG II-induced constrictions in TNF62 and TNF250 rats. Whereas nitro-L-arginine potentiated (P less-than-or-equal-to 0.05) pressor responses in control rats, it had no effect on hypoxic responses in TNF-alpha-treated rats. Nitro-L-arginine increased (P less-than-or-equal-to 0.05) ANG II-induced vasoconstriction in TNF-alpha-treated rats, but the pulmonary arterial pressure response was still lower (P less-than-or-equal-to 0.05) in TNF250 than in control and TNF62 rats. These results suggest that chronic TNF-alpha decreases 1) pulmonary vascular reactivity in the intact rat, 2) hypoxic pulmonary vasoconstriction by a mechanism that is independent of EDRF, and 3) ANG II-induced constriction by a mechanism that is partly EDRF dependent.