Endotoxin results in a granulocyte mediated loss of hypoxic pulmonary vasoconstriction (HPV). Dapsone blocks the granulocyte respiratory burst and might, therefore, preserve HPV following endotoxin. Isolated-perfused canine lobes (n = 6) were pretreated with 18 mg/kg dapsone (dapsone group), and compared to six lobes which did not receive dapsone (control group). Total pulmonary vascular resistance (Rtot) and arterial, middle (Rm), and venous segmental resistances were calculated by a vascular occlusion technique. We then administered endotoxin (2 mg/kg) and repeated measurements at 5, 30, and 90 min. The increase in Rm during 3% O2 compared to 35% O2 ventilation was used to define the presence of HPV. In the control group, following endotoxin, values of Rm did not change (P > 0.05) during 3% O2 ventilation (0.011 +/- 0.006 cm H2O/ml/min) compared with 35% O2 ventilation (0.014 +/- 0.005 cm H2O/ml/min). In the dapsone group, following endotoxin, values of Rm increased (P < 0.05) during 3% O2 ventilation (0.06 +/- 0.026 cm H2O/ml/min) compared with 35% O2 ventilation (0.03 +/- 0.015 cm H2O/ml/min). Changes in 6-keto PGF1 alpha or thromboxane B2 do not explain these observations. We conclude that in this experimental preparation, pretreatment with dapsone prevents the loss of HPV associated with endotoxin.

A pulmonary injury of varying severity occurs routinely after cardiopulmonary bypass. We studied the pulmonary complications of partial cardiopulmonary bypass in four groups of dogs to better define the injury and to evaluate the efficacy of two interventions (addition of a leukocyte filter or cyclooxygenase inhibition) on preservation of systemic oxygenation. All animals received a standard anesthetic (pentobarbital, morphine, and vecuronium) and, after sternotomy, three groups of animals received 3 hours of partial cardiopulmonary bypass. The animals were randomized to receive partial bypass alone (n = 6), indomethacin and bypass (n = 5), or a leukocyte filter and bypass (n = 5). A fourth group (n = 5) did not receive bypass and served as a time control. We measured blood gases and also obtained histologic samples to assess the degree of lung injury. We found that bypass alone caused a significant reduction (p < 0.05) in arterial oxygen tension 1 hour after the conclusion of bypass (175 +/- 53 mm Hg) compared with prebypass values (357 +/- 41 mm Hg). Pretreatment with indomethacin ameliorated the decrease in arterial oxygen tension from prebypass to postbypass values (477 +/- 50 mm Hg versus 339 +/- 57 mm Hg, respectively). Similarly use of a leukocyte filter reduced the decline in arterial oxygen tension from prebypass to postbypass values (440 +/- 71 mm Hg versus 311 +/- 73 mm Hg, respectively). We believe that indomethacin ameliorates the decline in systemic oxygenation associated with bypass by augmentation of hypoxic pulmonary vasoconstriction and that the leukocyte filter acted to reduce pulmonary edema and thereby minimized intrapulmonary shunt.

Purpose: The lazaroids are a new class of potent free-radical scavengers. We tested whether U-74389G, a lazaroid, could attenuate some of the adverse cardiopulmonary effects of sepsis.Methods: Dogs were randomized to receive either 10 mg/kg U-74389G (n = 10), or a saline control (n = 11). After baseline measurements of hemodynamics and gas exchange, they were then randomized to receive either 0.2 mg/kg endotoxin or a saline infusion. Measurements of hemodynamics and gas exchange were repeated. The study was concluded 70 minutes after endotoxin infusion and the lungs were then removed for histologic evaluation.Results: In endotoxin-treated control animals. PO2 decreased (278 +/- 123 mm Hg to 67 +/- 13 mm Hg, P < .05) and intrapulmonary shunt increased (12.9% +/- 1.1% to 28.2% +/- 11.4%. P < .05) after endotoxin. Pretreatment with U-74389G attenuated the decrease in PO2 (476 +/- 61 mm Hg to 226 +/- 143) and the increase in intrapulmonary shunt (12.6% +/- 6.1% to 14.3% +/- 6.8%) observed after endotoxin. The extent of lung injury and systemic hemodynamics were similar between control or U-74389G-treated dogs.Conclusions: A free-radical-scavenger can attenuate the gas exchange defect commonly associated with endotoxin but it does not improve the derangement of systemic hemodynamics. Copyright (C) 1994 by W.B. Saunders Company

Tumor necrosis factor-alpha (TNF-alpha) causes systemic hypotension, pulmonary vasodilation, and loss of hypoxic pulmonary vasoconstriction. NG-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 micrograms), six lobes treated with L-NMMA (200 mg), and five lobes treated with L-NMMA (200 mg) + TNF-alpha (250 micrograms). In the control lobes RT increased (P < 0.02) from 0.0474 +/- 0.0105 to 0.0677 +/- 0.0133 cmH2O.ml-1 x 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 x min 30 min after TNF-alpha administration and did not further change during hypoxic ventilation (0.0475 +/- 0.0107 cmH2O.ml-1 x min). L-NMMA pretreatment did not prevent the TNF-alpha-induced loss of hypoxic pulmonary vasoconstriction, with values of RT unchanged from normoxic (0.0541 +/- 0.0067 cmH2O.ml-1 x 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.