Determinants of nitric oxide in exhaled gas in the isolated rabbit lung.

Carlin, Robert E.; Ferrario, L; Boyd, J. T.; Camporesi, Enrico M.; McGraw, Daniel J.; Hakim, T. S.

doi:10.1164/ajrccm.155.3.9117027

Cited by 66 publications

(62 citation statements)

References 21 publications

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“…This is in contrast to other species, including rabbits, pigs, dogs, and humans, whereby similar manipulations result in a fall in eNO. 8,[31][32][33][34][35][36][37][38] Our findings are similar to those of other investigators, who have documented eNO concentrations of Ϸ1 to 5 ppb from intact rats and isolated rat lungs, in addition to insensitivity to NOS inhibition and excess NOS substrate (L-arginine). 39 -44 The lack of change in eNO is in contrast to the observed vascular effects seen with addition of free Hb to the perfusate ( Figure 2), NOS inhibition, and addition of GSNO to the perfusate.…”

Section: Exhaled No In the Rat Lungsupporting

confidence: 91%

Effects of S-Nitrosation and Cross-Linking of Hemoglobin on Hypoxic Pulmonary Vasoconstriction in Isolated Rat Lungs

Deem

Kim

Manjula

et al. 2002

Circulation Research

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Abstract-Free hemoglobin (Hb) and red blood cells augment hypoxic pulmonary vasoconstriction (HPV) by scavenging nitric oxide (NO). S-nitrosation of Hb (SNO-Hb) may confer vasodilatory properties by allowing release of NO during deoxygenation and/or by interaction with small-molecular weight thiols. Likewise, cross-linking of free Hb may limit its vasoconstrictive effect by preventing abluminal movement of the molecule. We compared the effects of free SNO-Hb and Hb intramolecularly cross-linked at the ␤-cysteine 93 residue [Bis(maleidophenyl)-polyethylene glycol2000HbA (Bis-Mal-PEGHb)] to those of free oxyHb on pulmonary artery pressure (PAP), HPV, and exhaled NO (eNO) in isolated, perfused rat lungs. Ventilation of lungs with anoxic gas for 5 minutes reduced perfusate PO 2 to 11Ϯ1.0 Torr. Addition of SNO-Hb or Bis-Mal-PEGHb (100 mol/L) to buffer perfusate increased normoxic PAP and augmented HPV in similar magnitude as free oxyHb, but had no effect on eNO. Addition of the allosteric modulator inositol hexaphosphate to increase Hb P50 and the thiol glutathione (GSH) to allow removal of NO from Hb via transnitrosation to the perfusate did not reduce augmentation of HPV by SNO-Hb or increase eNO. GSH resulted in an Ϸ50% reduction in perfusate [S-nitrosothiol] T he rapid oxidation of nitric oxide (NO) by oxyhemoglobin (oxyHb) to form methemoglobin (metHb) and nitrate acts to limit the magnitude and duration of the vasorelaxant effects of NO. 1 In the pulmonary circulation, this is manifest as increased pulmonary vascular resistance (PVR) and augmentation of hypoxic pulmonary vasoconstriction (HPV) by red blood cells (RBCs) and free Hb. [2][3][4][5][6][7][8] An additional reaction of NO with Hb is S-nitrosation at the ␤-cysteine 93 (␤-cys93) residue to form S-nitrosoHb (SNO-Hb). 9 This reaction is also reversible, particularly in the presence of low-molecular weight thiols such as glutathione (GSH), 9,10 and/or under the allosteric influence of deoxygenation. 9,11,12 This dynamic, oxygen-linked property of SNO-Hb has led to the theory that Hb may act as a carrier of NO from the lung to the peripheral circulation, where it is released on deoxygenation of Hb. That free and intraerythrocytic SNO-Hb results in systemic and cerebral vasodilation supports this hypothesis. 9,11 Recently, we showed that free SNO-Hb is a potent a vasoconstrictor in the pulmonary circulation. 6 In addition, we were unable to demonstrate an allosteric effect of deoxygenation on NO release from SNO-Hb, although this observation was limited by the low P 50 of free SNO-Hb and the inability to reduce perfusate PO 2 below Ϸ38 Torr despite ventilation with anoxic gas in this model.In the present work, we again studied the effects of SNO-Hb on PVR and HPV. However, we expanded on our previous work by using a different animal model (isolated, perfused rat lungs), which allowed a reduction in the perfusate PO 2 to Ϸ10 Torr during anoxic ventilation, a level that should promote deoxygenation of SNO-Hb. In addition, we studied both lower and higher conce...

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Section: Exhaled No In the Rat Lungsupporting

confidence: 91%

Effects of S-Nitrosation and Cross-Linking of Hemoglobin on Hypoxic Pulmonary Vasoconstriction in Isolated Rat Lungs

Deem

Kim

Manjula

et al. 2002

Circulation Research

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“…Dogs have very low baseline levels of exhaled NO compared to several other species [19]. Nevertheless, a statistically significant decline in exhaled NO levels was demonstrated in these five dogs under all experimental conditions.…”

Section: Critique Of Methodsmentioning

confidence: 68%

mentioning

confidence: 95%

“…In the guinea-pig, 6% CO 2 causes a reduction in exhaled NO of 60% [17] and, in the rabbit, of 30% [18]. In the isolated perfused rabbit lung, low concentrations of CO 2 cause a decrease in levels of exhaled NO [19] and NO metabolites measured in the perfusate [20].These experiments show that alterations in CO 2 concentration affect NO production in the lung, suggesting that inspired CO 2 might elicit its effects on V '/Q ' heterogeneity through changes in NO metabolism in the airways, nerves or vessels. It was hypothesized that inhibition of lung NOS should mimic the effect of inhaled CO 2 on V '/Q ' relationships in the lung and not further reduce V '/ Q ' heterogeneity when combined with CO 2 .…”

mentioning

confidence: 98%

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Pulmonary NO synthase inhibition and inspired CO2: effects on V ′/Q ′ and pulmonary blood flow distribution

Brogan¹,

Hedges²,

McKinney³

et al. 2000

Eur Respir J

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Inhaled carbon dioxide decreases ventilation/perfusion ratio (V '/Q ') heterogeneity in dogs. The aim of this study was to test whether inhaled CO 2 improves the V '/Q ' by inhibition of nitric oxide production and whether inhibition of endogenous NO production in the lung alters gas exchange and V '/Q ' matching.Eleven healthy dogs were anaesthetized and mechanically ventilated. The multiple inert gas elimination technique (MIGET) was used to measure V '/Q ' heterogeneity and regional pulmonary blood flow heterogeneity was assessed in five dogs using fluorescent microspheres. In a separate set of five dogs, exhaled NO levels were measured via chemiluminescence. All dogs were studied before and after 4.8% inspired CO 2 , and then given the NO synthase inhibitor N v -nitro-L-arginine methyl ester (L-NAME, 10 mg . kg -1 ) via nebulization, after which they were studied again with room air and inhaled CO 2 .CO 2 and L-NAME improved arterial and alveolar oxygen tension, but the improvements with L-NAME did not reach statistical significance. Improved V '/Q ' matching, as assessed by the MIGET, occurred under all experimental conditions. Exhaled NO levels were reduced by 40% with CO 2 and 70% with L-NAME. The standard deviation of regional pulmonary blood flow assessed via microspheres decreased only with inhaled CO 2 . Fractal analysis of pulmonary blood flow distributions revealed that regional blood flow was highly correlated with flow to neighbouring pieces of lung in all four conditions with no changes in the fractal dimension.Inspired carbon dioxide improves ventilation perfusion ratio matching and is associated with a more homogeneous distribution of pulmonary blood flow. Although inspired carbon dioxide causes a reduction in exhaled nitric oxide, the differences in pulmonary perfusion distributions found between carbon dioxide and N v -nitro-Larginine methyl ester suggest that the carbon dioxide effect is not mediated by a reduction in nitric oxide production. The improved ventilation perfusion ratio matching with inhibition of nitric oxide synthase suggests the intriguing possibility requiring further study that endogenous production of nitric oxide in the lung does not subserve ventilation perfusion ratio regulation. Eur Respir J 2000; 16: 288±295. Addition of low concentrations (2±5%) of carbon dioxide to inspired gas improves gas exchange and arterial oxygenation in normal lungs [1,2]. Using the multiple inert gas elimination technique (MIGET), it was demonstrated that inspired CO 2 reduces ventilation/perfusion ratio (V '/Q ') heterogeneity even with constant ventilation [3]. Although CO 2 has many effects on the lungs that may promote V '/Q ' matching [4,5], it remains unknown how and at what site(s) CO 2 decreases V '/Q ' heterogeneity.Changes in CO 2 concentration or the accompanying pH may affect airways, parenchyma or vessels directly or indirectly through modulation of effector substances such as prostaglandins [6] or calcium [7]. Of considerable interest, also, is nitric oxide, which is ...

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“…Also, perfusate accumulation of NO x was lower in chronic hypoxia than in controls [14]. Carlin and co-workers have also shown a dose-dependent decrease in exhaled NO in hypoxic rabbits [15]. Hyperoxia increases the level of exhaled NO, which indicates increased NO production.…”

Section: Discussionmentioning

confidence: 89%

Effects of Moderate Altitude on Exhaled Nitric Oxide, Erythrocytes Lipid Peroxidation and Superoxide Dismutase Levels.

Güzel

Sayan²,

Erbaş³

2000

JJP

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Physical exercise at high altitude has become common as one of the luxuries of modern life. Physical activities begin to be affected at about the elevation of 1,300 m due to reductions in ventilation. Endurance (aerobic) exercises are affected more by altitude than sprinting or anaerobic exercise. Training time for acclimatization needs to be longer as the altitude becomes higher [1].Several researchers have investigated the reactive oxygen species (ROS) production activity of circulating neutrophils after exercise and have reported conflicting findings including increases, decreases or no change in the response [2]. The variability in the findings could be attributable to the difference in the intensity and duration of exercise or the sampling point for the assesment. Hack et al. reported increased ROS after 1 d of exercise [3]. In many studies, ROSs' are found to be decreased after exercise [4]. Physical exercise at high altitude decreases the generation of free radical species and activity of superoxide dismutase (SOD) [5]. At high altitude, the decreased filterability of erythrocytes may be due to increased lipid peroxidation [6]. Radak et al. (1997) have shown that 4 weeks of exercise at an altitude of 4,000 m increased the activity of mitochondrial SOD in skeletal muscle [5]. Exhaled nitric oxide increases through exercise, but there is no information for high altitude. In this study, we aimed to determine the effect of high altitude on the oxidant-antioxidant mechanisms and NO x levels in trained subjects. MATERIALS AND METHODSThis study was performed using nine healthy male (mean age 19.3Ϯ3.7) and nine healthy female (mean age 18.3Ϯ2) cross-country skiers with at least 1 year of experience. They individually prepared themselves by endurance training daily for 1.5 h by skiing at low (856 m above sea level in Ankara) and moderate (2,300 m above sea level in Erciyes, PO 2 was 83 mm Hg) altitudes. The period of stay at the moderate altitude was 7 d. All of the blood measurements were performed before (12 h before moving to the moderate altitude), during (1st day and 7th day) and Japanese Journal of Physiology, 50, 187-190, 2000 Key words: nitric oxide, nitrite, superoxide dismutase, lipid peroxidation, altitude. Abstract:The purpose of this study was to investigate the effects of staying at a moderate altitude (2,300 m, 7 d) on the levels of plasma nitrite, exhaled nitric oxide (NO), malondialdehyde (MDA) and superoxide dismutase (SOD). Measurements were obtained from 9 female (mean age 18.3Ϯ2) and 9 male (mean age 19.3Ϯ3.7) cross-country volunteer skiers: before, during (1st day, 7th day) and after staying at a moderate altitude. Exhaled nitric oxide levels were measured only before and after staying at the altitude. Nitrite levels increased throughout the stay at the altitude, while MDA levels decreased. In parallel with the nitrite levels, SOD activities were also found to have increased. Exhaled NO values were decreased after the stay at the moderate altitude. These results show that altitude hypoxia ...

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Determinants of nitric oxide in exhaled gas in the isolated rabbit lung.

Cited by 66 publications

References 21 publications

Effects of S-Nitrosation and Cross-Linking of Hemoglobin on Hypoxic Pulmonary Vasoconstriction in Isolated Rat Lungs

Effects of S-Nitrosation and Cross-Linking of Hemoglobin on Hypoxic Pulmonary Vasoconstriction in Isolated Rat Lungs

Pulmonary NO synthase inhibition and inspired CO2: effects on V ′/Q ′ and pulmonary blood flow distribution

Effects of Moderate Altitude on Exhaled Nitric Oxide, Erythrocytes Lipid Peroxidation and Superoxide Dismutase Levels.

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