L-NAME aggravates pulmonary oxygen toxicity in rats

Capellier, Gilles; Maupoil, Véronique; Boillot, A.; Jp, Kantelip; Rochette, Luc; Régnard, Jean-François; Barale, F

doi:10.1183/09031936.96.09122531

Cited by 28 publications

(15 citation statements)

References 31 publications

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“…We found that the treatment with L‐NAME of newborn rats reduced lung oedema. This is similar to the experiments with adult rats exposed to hyperoxia that showed that inhibition of NOS decreased water content in lungs (Capellier et al , 1996). The treatment of rat pups with L‐NAME also led to reduction of hyperoxia‐induced epithelial proliferation.…”

Section: Discussionsupporting

confidence: 89%

The role of nitric oxide and metalloproteinases in the pathogenesis of hyperoxia‐induced lung injury in newborn rats

Radomski

Sawicki

Olson

et al. 1998

British J Pharmacology

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1 The eects of nitric oxide (NO) and metalloproteinases (MMP-2 and MMP-9) in the pathogenesis of hyperoxia-induced lung damage in newborn rats were examined. 2 Three-day-old rat pups were subjected to hyperoxia (595% O 2 ) or room air for 7 and 14 days. 3 Some animals were treated with N G -L-nitro-L-arginine methyl ester (L-NAME, 10 mg kg 71 , s.c., daily). 4 Histology, morphometry, oedema, Ca 2+ -dependent and -independent NO synthase (NOS) activities, expression of NOS isoforms and the activities of MMP-2 and MMP-9 were measured in lungs of hyperoxic and control animals. 5 Exposure of rats to hyperoxia for 7 days resulted in alveolar sac injury characterized by the presence of cellular debris, red cell extravasation and in¯ammatory in®ltration with mononuclear cells. Lung water content, epithelial, smooth muscle layers and total airway thickness was similar to controls. 6 In contrast, exposure of rats to hyperoxia for 14 days resulted in lung oedema, in¯ammation and epithelial proliferation. 7 Hyperoxia caused a decrease in Ca 2+ -dependent NOS activity, an eect that was associated with increased expression of eNOS protein.8 In control rats, Ca 2+ -dependent NOS activity and expression of eNOS were reduced at 14 days. 9 Hyperoxia caused 10 fold increase in the activity of Ca 2+ -independent NOS that remained signi®cantly elevated after 14 days of exposure to hyperoxia. The activity of this enzyme was unchanged in control rats. 10 In lungs of hyperoxic rats, the immunoblot showed time-dependent, biphasic expression (peak at 7 days) of iNOS. The pro®le of expression of iNOS in control rats was similar. 11 The activities of MMPs were increased in lungs of hyperoxic animals. 12 The L-NAME treatment of hyperoxic animals reduced lung oedema and epithelial proliferation, but enhanced the activities of MMPs. L-NAME exerted no signi®cant eects in control rats. 13 It is concluded that increased generation of NO contributes to the pathogenesis of hyperoxiainduced lung damage in newborn rats.

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Section: Discussionsupporting

confidence: 89%

The role of nitric oxide and metalloproteinases in the pathogenesis of hyperoxia‐induced lung injury in newborn rats

Radomski

Sawicki

Olson

et al. 1998

British J Pharmacology

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“…significantly attenuated the O 2 -mediated injury to lung endothelium and alveolar epithelium in rats exposed to 60 h of hyperoxia (Mcelroy et al, 1997). Similarly, L-NAME increased the mortality rate in rats exposed to 60 h of hyperoxia from 22% (saline controls) to 57% (Capellier et al, 1996). These studies support the view that ambient O 2 environment plays a critical role in the response to NO synthase inhibition.…”

Section: Discussionsupporting

confidence: 74%

The effects of hyperoxia on the biosynthesis of cyclooxygenase products and haemodynamic response to nitric oxide synthase inhibition with L‐NAME in endotoxaemic pigs

Hellyer

Wright

Mallinckrodt

et al. 1998

Vet Pharm & Therapeutics

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The interaction between constitutive nitric oxide and oxygen may depend on the degree of tissue oxygenation and may play a critical role in the pathophysiological response to endotoxaemia. We investigated if hyperoxia (100% O2) attenuated the systemic and pulmonary vasoconstriction and increased biosynthesis of thromboxane B2 (TXB2) and 6-keto-prostaglandin (PG) F1alpha induced by inhibition of nitric oxide synthase with NG-nitro-L-arginine-methyl-ester (L-NAME) in a porcine model of endotoxaemia. Twenty-two domestic, random source pigs, weighing 15.4 +/- 2.7 kg (mean +/- standard deviation) were the subjects of this study. Pigs were anaesthetized with isoflurane in 100% O2, orotracheally intubated and ventilated to maintain normocapnia, and then instrumented for haemodynamic monitoring. Following instrumentation, pigs were maintained at an end-tidal isoflurane concentration of 2%. Pigs were randomly assigned to treatment groups: saline + 30% O2 (Control, n = 6); Escherichia coli lipopolysaccharide (5 microg/kg/h from 1 to 2 h followed by 2 microg/kg/h from 2 to 5 h) + 30% O2 (LPS, n = 4); L-NAME (0.5 mg/kg/h, from 0 to 5 h) + LPS + 100% O2 (n = 6); and L-NAME + LPS + 30% O2 (n = 6). L-NAME and endotoxin significantly (P < 0.05) increased mean arterial pressure, mean pulmonary arterial pressure, and systemic and pulmonary vascular resistance index beginning at 90 min. When results were pooled across all time periods, mean arterial pressure and mean pulmonary arterial pressure were significantly higher in the L-NAME + LPS + 30% O2 group than all other groups, reflecting pulmonary and systemic vasoconstriction. Hyperoxia attenuated the L-NAME + LPS-induced increases in TXB2 and 6-keto-PGF1alpha concentrations at 90 and 120 min and 120 min, respectively, although the differences were not statistically significant. These results support the observation that nitric oxide synthase inhibition with L-NAME has deleterious haemodynamic effects in this model of endotoxaemia. The temporal attenuation of L-NAME-induced pulmonary and systemic vasoconstriction by hyperoxia suggested that the haemodynamic effects of acute endotoxaemia were in part influenced by the relative amounts of nitric oxide and oxygen present.

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“…Adult rats exposed to hyperoxia, in the presence of L-NAME (nonspecific NOS inhibitor) and aminoguanidine (specific NOS2 inhibitor), had significantly increased mortality and HALI (32,33). In 6-to 8-week-old mice (FVBN strain), hyperoxia exposure did not impact on NOS2 expression or activity, but decreased NOS3 activity (6).…”

Section: Discussionmentioning

confidence: 99%

Increased Hyperoxia-Induced Lung Injury in Nitric Oxide Synthase 2 Null Mice Is Mediated via Angiopoietin 2

Bhandari

Choo-Wing

Harijith

et al. 2012

Am J Respir Cell Mol Biol

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Supplemental oxygen is frequently prescribed. However, prolonged exposure to high concentrations of oxygen causes hyperoxic acute lung injury (HALI), which manifests as acute respiratory distress syndrome in adults and leads to bronchopulmonary dysplasia in newborns (NBs). Nitric oxide (NO), NO synthases (NOSs), and angiopoietin (Ang) 2 have been implicated in the pathogenesis of HALI. However, the mechanisms of the contributions of NOS/NO and the relationship(s) between NOS/NO and Ang2 have not been addressed. In addition, the relevance of these moieties in adults and NBs has not been evaluated. To address these issues, we compared the responses in hyperoxia of wild-type (NOS [1/1]) and NOS null (2/2) young adult and NB mice. When compared with NOS21/1 adult controls, NOS2 2/2 animals manifest exaggerated alveolar-capillary protein leak and premature death. These responses were associated with enhanced levels of structural cell death, enhanced expression of proapoptotic regulatory proteins, and Ang2. Importantly, silencing RNA knockdown of Ang2 decreased the levels of cell death and the expression of proapoptotic mediators. These effects were at least partially NOS2 specific, and were development dependent, because survival was similar in adult NOS3 1/1 and NOS3 2/2 mice and NB NOS2 1/1 and NOS2 2/2 mice, respectively. These studies demonstrate that NOS2 plays an important protective role in HALI in adult animals. They also demonstrate that this response is mediated, at least in part, by the ability of NOS2 to inhibit hyperoxia-induced Ang2 production and thereby decrease Ang2-induced tissue injury.Keywords: cytokines; hyperoxia; lung Supplemental oxygen is commonly employed to counteract tissue hypoxemia. Although this is lifesaving in most circumstances, prolonged exposure to high concentrations of oxygen can lead to untoward effects. In the lung, exposure to hyperoxia is characterized by an inflammatory response (mediated by cytokines) and breakdown of the alveolar-capillary barrier, leading to pulmonary edema and endothelial and epithelial cell injury/ death (1). In adults, hyperoxic acute lung injury (HALI) causes acute respiratory distress syndrome (2). In neonates, HALI has been shown to lead to a pulmonary phenotype suggestive of bronchopulmonary dysplasia (3). Hence, HALI is a major cause of morbidity and mortality in both adult (2) and neonatal (3,4) populations.In addition, nitric oxide (NO) is known to have oxidant effects (5), and has been implicated in the pathogenesis of HALI. NO is generated via the action of NO synthases (NOSs). The inflammatory response in HALI is initiated and propagated, to a large extent, by the release of cytokines (1), which are known to induce NOS (6, 7). Most data suggest that hyperoxia exposure up-regulates inducible NOS (NOS2) and endothelial NOS (NOS3) expression in adult (8-16) and neonatal (7,(16)(17)(18)(19) lungs. In ALI and cell death, the endogenous production of NO is said to be mostly contributed by up-regulation of NOS2 in the lung (20)(21)(22).Previous work...

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L-NAME aggravates pulmonary oxygen toxicity in rats

Cited by 28 publications

References 31 publications

The role of nitric oxide and metalloproteinases in the pathogenesis of hyperoxia‐induced lung injury in newborn rats

The role of nitric oxide and metalloproteinases in the pathogenesis of hyperoxia‐induced lung injury in newborn rats

The effects of hyperoxia on the biosynthesis of cyclooxygenase products and haemodynamic response to nitric oxide synthase inhibition with L‐NAME in endotoxaemic pigs

Increased Hyperoxia-Induced Lung Injury in Nitric Oxide Synthase 2 Null Mice Is Mediated via Angiopoietin 2

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