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 micrograms, TNF62; n = 7), high-dose TNF-alpha (> or = 250 micrograms, 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 micrograms/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 < or = 0.08) baseline pulmonary arterial pressure in TNF250 rats and decreased (P < or = 0.05) hypoxia- and ANG II-induced constrictions in TNF62 and TNF250 rats. Whereas nitro-L-arginine potentiated (P < or = 0.05) pressure responses in control rats, it had no effect on hypoxic responses in TNF-alpha-treated rats. Nitro-L-arginine increased (P < or = 0.05) ANG II-induced vasoconstriction in TNF-alpha-treated rats, but the pulmonary arterial pressure response was still lower (P < or = 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.
Department of Physiology, Colorado State University, Fort Collins 80523.
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Stevens
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Morris
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McMurtry
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Zamora
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Tucker
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D000860:Hypoxia / Q000503:physiopathology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology; D019335:Nitroarginine; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine