N(G)-MONOMETHYL-L-ARGININE DOES NOT RESTORE LOSS OF HYPOXIC PULMONARY VASOCONSTRICTION INDUCED BY TNF-ALPHA

Tumor necrosis factor-alpha (TNF-alpha) causes systemic hypotension, pulmonary vasodilation, and loss of hypoxic pulmonary vasoconstriction. N(G)-monomethyl-L-arginine (L-NMMA) inhibits nitric oxide (NO) production and prevents some systemic manifestations of TNF-alpha. We tested using an isolated perfused canine lobe whether NO also mediates the pulmonary vascular effects of TNF-alpha. Total resistance (RT) was measured during control and hypoxic ventilation over a 90-min period in six control lobes, five lobes treated with TNF-alpha (250 mug), six lobes treated with L-NMMA (200 mg), and five lobes treated with L-NMMA (200 mg) + TNF-alpha (250 mug). In the control lobes RT increased (P < 0.02) from 0.0474 +/- 0.0105 to 0.0677 +/- 0.0133 cmH2O . ml-1 . min during normoxic and hypoxic ventilation, respectively. RT decreased (P < 0.05) from a baseline of 0.0593 +/- 0.0133 to 0.0449 +/- 0.0176 cmH2O . ml-1 . min 30 min after TNF-alpha administration and did not further change during hypoxic ventilation (0.0475 +/- 0.0107 cmH2O . ml-1 . min). L-NMMA pretreatment did not prevent the TNF-a-induced loss of hypoxic pulmonary vasoconstriction, with values of RT unchanged from normoxic (0.0541 +/- 0.0067 cmH2O . ml-1 . min) to hypoxic (0.0545 +/- 0.0078 cmH2O . ml-1 . min) ventilation (P > 0.10) in the L-NMMA+TNF-alpha group after TNF-alpha administration. We conclude that NO is not the mediator responsible for the acute pulmonary vascular effects of TNF-alpha.