The Pulmonary Effect of Nitric Oxide Synthase Inhibition Following Endotoxemia in a Swine Model

Abstract

FObjective: To evaluate the pulmonary effect of treatMain Outcome Measures: Cardiopulmonary variment with N-nitro-L-arginine methyl ester (NAME) with ables and blood gases were measured serially. The muland without inhaled nitric oxide (NO) in a swine model tiple inert gas elimination technique was performed at 3 of endotoxemia.hours. The wet-to-dry lung weight ratio was measured following necropsy. Design: Randomized controlled trial.Results: Administration of LPS resulted in pulmonary Setting: Laboratory.arterial hypertension, pulmonary edema, and hypoxemia with increased ventilation perfusion ratio misInterventions: Following a 20-minute intravenous inmatching. None of these changes were attenuated by fusion of Escherichia coli lipopolysaccharide (LPS) (200 NAME treatment alone but all were significantly pLg/kg), animals were resuscitated with saline solution improved by the simultaneous administration of (1 mL/kg per minute) and observed for 3 hours while meinhaled NO. chanically ventilated (fraction of inspired oxygen [Fio,], 0.6; tidal volume, 12 mLikg; positive end-expiratory presConclusions: Systemic NO synthase inhibition failed to sure, 5 cm HRO). Group 1 (LPS, n=6) received no addirestore hypoxic pulmonary vasoconstriction following LPS tional treatment; group 2 (NAME, n=5) received NAME administration. The deleterious effects of endotoxemia (3 mg/kg per hour) for the last 2 hours; group 3 (NO, on pulmonary function can be improved by inhaled NO n=6) received NAME (3 mg/kg per hour) and inhaled NO but not by systemic inhibition of NO synthase. (40 ppm) for the last 2 hours; and group 4 (control, n=5) received only saline solution without LPS.(Arch Surg. 1994;129:1233-1239 S EPSIS RESULTS in a systemic in-lowing sepsis is a significant comorbid facflammatory response that is tor, therapy aimed at attenuating this mediated by various cytodeleterious process may exert a benefikines and activated leukocial effect on outcome. cytes. Systemic vasodilation Hypoxic pulmonary vasoconstricand hypotension characteristic of sepsis tion is a mechanism that modulates pulhave been hypothesized to occur secondmonary gas exchange by matching the disarily to endogenous overproduction of nitribution of blood flow to ventilation. 7 ,8 tric oxide (NO).',' In contrast to the sysHowever, the cellular mechanisms that initemic vasodilatory response, pulmonary tiate and maintain HPV remain poorly un-

Effects ofl-arginine andN-nitro-l-arginine treatment on hemodynamics, DO2, VO2, and extravascular lung water in a dog endotoxin shock model

“…Similar findings were noted following single-dose and continuous infusion of L-NAME administration in a sheep and swine model during continuous infusion of E. coli endotoxin [21,22]. Meadow et al [13] oh-served that L-NNA preferentially constricted the pulmonary circulation to a greater extent than it did the systemic circulation.…”

“…In vivo measurements of EVLW did not demonstrate any significant differences between two control groups and one with inhaled nitric oxide [22]. This suggests that the primary effect of inhaled nitric oxide consists of controlling vasomotion rather than causing any changes in the permeability of the alveolar-capillary membrane.…”

Hypoxic Pulmonary Vasoconstriction

“…Most patients have mild to moderate pulmonary hypertension and normal cardiac outputs. Similar changes occurred in animal models, such as intravenous infusion of oleic acid in dogs (329, 1555,1557,1738), endotoxemia in pigs (1213,1414,1415), repeated lung lavage in pigs (389, 391), and prolonged hyperoxia in baboons (821).…”

“…These results are consistent with potentiation of HPV in shunt regions and enhanced diversion of perfusion to ventilated lung. In animal models of ALI/ARDS, these effects of almitrine were shared by antagonists of cyclooxygenase (33, 1058,1060,1738) but not by antagonists of NOS (1058,1415,1555,1668), which increased PVR but did not alter P a O 2 or shunt. These results suggest that endogenous production of vasodilator prostaglandins such as PGI 2 , and thus their inhibition of HPV and other vasoconstrictor mechanisms, may have been greater in more injured nonventilated lung than in less injured ventilated lung, whereas endogenous production of NO and NO-dependent inhibition of vasoconstriction was similar in ventilated and nonventilated lung.…”

Nitric oxide inhalation inhibits pulmonary apoptosis but not inflammatory injury in porcine meconium aspiration

“…Inhaled NO has been proposed to decrease inflammatory reactions in neonatal and adult lungs (5,8). Although exogenous NO may reduce the endothelial expression of adhesion molecules and proinflammatory cytokines in vitro (15), meconium-instilled piglet lungs did not show any attenuation in neutrophil accumulation after NO treatment, similar to the findings in some, but not all, experimental models of acute lung injury in adults (8,16). In contrast, low-dose (5 ppm) NO inhalation treatment decreases early neutrophil accumulation in experimental hyaline membrane disease in premature lambs (5).…”