Endothelial modulation of pH-dependent pressor response in isolated perfused rabbit lungs

Yamaguchi, Kazuhiro; Takasugi, Tomoaki; Fujita, Hiroto; Mori, Masaaki; Oyamada, Yoshitaka; Suzuki, Katsutoshi; Miyata, Atsushi; Aoki, Takuya; Suzuki, Yukio

doi:10.1152/ajpheart.1996.270.1.h252

Cited by 19 publications

(22 citation statements)

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“…Interestingly, the nuclear effect of pH on eNOS was not in line with L-citrulline production with acidification, although it fits in the case of alkalization. Although this result contrasts with a previous study from Yamaguchi et al (31) of isolated perfused rabbit lungs, in which hypercapnic acidosis elevated vascular tone and perfusate nitrite/nitrate, it would appear that acidification can stimulate another unidentified subcellular molecular mechanism in the pretranscriptional phase of eNOS. A recent study relevantly reports that acidosis induced by HCl or hypercapnia increased eNOS mRNA in pig and rat brain vessels (21), although the precise mechanism was not elucidated.…”

Section: Discussioncontrasting

confidence: 99%

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Alkalosis stimulates endothelial nitric oxide synthase in cultured human pulmonary arterial endothelial cells

Mizuno

Demura

Ameshima

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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To investigate the effect of extracellular pH on endothelial nitric oxide synthase (eNOS) in human pulmonary arteries, we measured eNOS activity and expression as well as some ion channels in human pulmonary arterial endothelial cells (HPAEC) exposed to various pH levels (6.6–8.0). eNOS activity was found to increase with alkalization and decrease with acidification, while Ca2+ uptake into HPAEC increased with alkalization. The addition of 3′,4′-dichlorobenzamil hydrochloride, an inhibitor of the Na+/Ca2+ exchanger (NCX), prevented the increase of eNOS activity with alkalosis. Exposure to alkalosis and acidosis increased eNOS and NCX mRNA levels. These results suggest that an elevation of extracellular pH activates eNOS via the influx of extracellular Ca2+ and that NCX also regulates eNOS activity during alkalosis. Furthermore, NCX may have a tight interaction with eNOS at the level of transcription and might affect pulmonary circulation during alkalosis and acidosis.

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Section: Discussioncontrasting

confidence: 99%

“…Effect of extracellular pH on intracellular pH in HPAEC. Adhering HPAEC were incubated in media (pH from 6.6 to 8.0), and intracellular pH was measured by the method previously described (31). The range of intracellular pH exposed to the media was from 7.115 Ϯ 0.046 to 7.653 Ϯ 0.098.…”

Section: Discussionmentioning

confidence: 99%

Alkalosis stimulates endothelial nitric oxide synthase in cultured human pulmonary arterial endothelial cells

Mizuno

Demura

Ameshima

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…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 .…”

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confidence: 96%

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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“…The vascular reactivity of pulmonary microvessels, especially acinar microvessels, in response to acidosis induced by either alveolar hypercapnia (hypercapnic acidosis (HA)) or metabolic disturbance (isocapnic acidosis (IA)) is one of the major modulators regulating the distribution of pulmonary blood flow [1][2][3][4]. An exact knowledge of acinar microvessel behaviour in acidosis is absolutely necessary when treating patients with diseased lungs using controlled ventilation with permissive hypercapnia, which has increasingly assumed an important place in managing acute lung injury [5,6].…”

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confidence: 99%

NOS and COX isoforms and abnormal microvessel responses to CO₂and H⁺in hyperoxia-injured lungs

Naoki¹,

Kudo²,

Suzuki³

et al. 2002

Eur Respir J

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The aim of the present study was to compare microvessel responses to hypercapnic and isocapnic acidosis in hyperoxia-injured lungs and to assess the role of constitutive and inducible forms of nitric oxide synthase (NOS) and cyclo-oxygenase (COX).Real-time confocal luminescence microscopy was used to measure changes in the diameter of acinar arterioles, venules and capillaries in response to stimulation with hypercapnic and isocapnic acidosis in isolated rat lungs injured by 90% oxygen exposure for 48 h. Observations were made with and without inhibition of constitutive (endothelial constitutive NOS (ecNOS) and COX-1) and inducible isoforms (iNOS and COX-2) of NOS and COX. Upregulation of NOS was assessed by measuring enzyme levels in lung homogenates by Western blot analysis and enhancement of the COX-related pathway was judged from perfusate concentrations of 6-ketoprostaglandin F 1a .ecNOS and COX-1, but not iNOS and COX-2, were upregulated in hyperoxiainjured lungs. The nitric oxide produced by ecNOS attenuated COX-1 activity in injured arterioles and venules, but carbon dioxide enhanced it, leading to paradoxical dilatation of these microvessels under hypercapnic conditions with ecNOS inhibition. Although a high hydrogen ion concentration was unnecessary for excitation of COX-1, venule constriction in response to H z was enhanced by COX-1 inhibition. Constitutive, but not inducible, isoforms of cyclo-oxygenase and nitric oxide synthase play an important role in abnormal microvessel responses to carbon dioxide and hydrogen ions in hyperoxia-injured lungs. Eur Respir J 2002; 20: 43-51.

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Endothelial modulation of pH-dependent pressor response in isolated perfused rabbit lungs

Cited by 19 publications

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Alkalosis stimulates endothelial nitric oxide synthase in cultured human pulmonary arterial endothelial cells

Alkalosis stimulates endothelial nitric oxide synthase in cultured human pulmonary arterial endothelial cells

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

NOS and COX isoforms and abnormal microvessel responses to CO₂and H⁺in hyperoxia-injured lungs

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Endothelial modulation of pH-dependent pressor response in isolated perfused rabbit lungs

Cited by 19 publications

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Alkalosis stimulates endothelial nitric oxide synthase in cultured human pulmonary arterial endothelial cells

Alkalosis stimulates endothelial nitric oxide synthase in cultured human pulmonary arterial endothelial cells

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

NOS and COX isoforms and abnormal microvessel responses to CO2and H+in hyperoxia-injured lungs

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NOS and COX isoforms and abnormal microvessel responses to CO₂and H⁺in hyperoxia-injured lungs