Role of Nitric Oxide in the Pathogenesis of Chronic Pulmonary Hypertension

Hampl, Václav; Herget, J

doi:10.1152/physrev.2000.80.4.1337

Cited by 224 publications

(182 citation statements)

References 376 publications

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“…It was concluded that abnormal extension of smooth muscle to peripheral arteries did not increase the reactivity of the pulmonary arteries to NO. Many studies show a decrease in endothelium-dependent relaxation and in endothelium-independent relaxation in the pulmonary arteries of chronically hypoxic rats [15]. Conversely, DINH-XUAN et al [16] and ORTON et al [17] demonstrated that endothelium-independent vasodilator response to sodium nitroprusside was unaltered.…”

Section: Discussionmentioning

confidence: 98%

Correlation of inhaled nitric-oxide induced reduction of pulmonary artery pressure and vascular changes

Jiang

Maruyama²,

Yokochi³

et al. 2002

European Respiratory Journal

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The purpose of the present study was to determine the relationship between hypertensive pulmonary vascular remodelling and the changes in mean pulmonary artery pressure (mPAP) during low-dose nitric oxide (NO) inhalation.Rats were exposed to chronic hypobaric hypoxia (air at 50.5 kPa (380 mmHg), 10% oxygen, for 5-29 days) to induce chronic pulmonary hypertension (PH) with pulmonary vascular structural changes. After the chronic hypoxic exposure, the rats had an indwelling pulmonary artery catheter inserted and changes in mPAP with NO were correlated to morphometrical analysis of pulmonary vascular changes.All concentrations of inhaled NO (0.1-2.0 parts per million) reduced mPAP with a similar per cent reduction from baseline mPAP in PH rats, while no changes were observed in control rats. During NO inhalation in PH rats, the absolute value of the decrease in mPAP, but not per cent reduction in mPAP, significantly correlated with baseline mPAP, the percentage of muscularised arteries at the alveolar wall level and at the alveolar duct level, and the per cent medial wall thickness of muscularised arteries.In the chronic hypoxic pulmonary hypertension model, the severity of pulmonary vascular remodelling did not alter the reactivity of the pulmonary arteries to nitric oxide and might, in part, determine the magnitude of nitric-oxide induced absolute reduction in mean pulmonary artery pressure. In all conditions causing pulmonary hypertension (PH), vascular changes include new muscularisation of normally non-muscular peripheral pulmonary arteries and medial muscle hypertrophy of normally muscular arteries. Abnormal muscular pulmonary vasculature might have a heightened reactivity [1, 2], which may explain the effect of nitric oxide (NO) inhalation in hypertensive pulmonary disease, because NO dilates constricted pulmonary vasculature. Although inhaled NO can dilate these structurallyremodelled pulmonary arteries, the degree of response to inhaled NO was quite variable in patients with congenital heart disease [1], primary pulmonary hypertension (PPH) [3], limited scleroderma and isolated PH [4] and severe acute respiratory distress syndrome (ARDS) [5]. The differences in severity of pulmonary vascular structural changes might explain the differences in inhaled NO-induced reduction in pulmonary artery pressure (PAP) among patients.Chronic hypoxia induces PH and hypertensive pulmonary vascular changes in rats [6][7][8]. With increasing exposure to hypoxia, there is a progressive increase in the severity of the hypertensive pulmonary vascular changes [7]. These findings allowed the authors to make a rat model of experimentally different degrees of PH and hypertensive pulmonary vascular changes. To determine the relationship between the hypertensive pulmonary vascular changes and response to inhaled NO, NO inhalation was carried out in a rat model of chronic PH induced by chronic hypoxic exposure of varying durations. Quantitative morphometrical analysis was applied to determine the severity of hypertensive pu...

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Section: Discussionmentioning

confidence: 98%

Correlation of inhaled nitric-oxide induced reduction of pulmonary artery pressure and vascular changes

Jiang

Maruyama²,

Yokochi³

et al. 2002

European Respiratory Journal

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“…NO, a wellknown vasodilator, plays a crucial role in pulmonary vascular expansion during fetal transition. 16 Unlike adult vascular tissue, the pulmonary vasculature in newborn infants displays marked reactivity to variations in NO concentrations, especially in an hypoxic environment. 16 Direct effects of thyroid hormone on endogenous NO metabolism have been investigated.…”

Section: Thyroid Hormone and Lung Developmentmentioning

confidence: 99%

“…16 Unlike adult vascular tissue, the pulmonary vasculature in newborn infants displays marked reactivity to variations in NO concentrations, especially in an hypoxic environment. 16 Direct effects of thyroid hormone on endogenous NO metabolism have been investigated. The production of NO is positively controlled through the enzyme NO synthase (NOS).…”

Section: Thyroid Hormone and Lung Developmentmentioning

confidence: 99%

“…This enzyme can be inhibited by endogenous l-guanine analogs such as asymmetric N G ,N G -dimethyl-l-arginine (ADMA), N-monomethyl-l-arginine, and N-nitro-l-arginine methyl ester. 16,17 Conflicting data exist regarding the effects of NOS inhibitors on pulmonary vasoconstriction and subsequent increases in PVR among adults. Adult patients treated with NOS inhibitors failed to show significant increases in PVR.…”

Section: Thyroid Hormone and Lung Developmentmentioning

confidence: 99%

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Neonatal Thyrotoxicosis and Persistent Pulmonary Hypertension Necessitating Extracorporeal Life Support

Oden

Cheifetz

2005

Pediatrics

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ABSTRACT. We report a case of neonatal Graves' disease involving an infant with severe persistent pulmonary hypertension (PPHN) associated with neonatal thyrotoxicosis that necessitated extracorporeal membrane oxygenation. Hyperthyroidism, although uncommon in the newborn period, has been associated with pulmonary hypertension among adults. The exact mechanisms responsible for this effect on pulmonary vascular pressure are not well understood. Recent studies have provided evidence that thyrotoxicosis has direct and indirect effects on pulmonary vascular maturation, metabolism of endogenous pulmonary vasodilators, oxygen economy, vascular smooth muscle reactivity, and surfactant production, all of which may contribute to the pathophysiologic development of PPHN. Therefore, because PPHN is a significant clinical entity among term newborns and the symptoms of hyperthyroidism may be confused initially with those of other underlying disorders associated with PPHN (eg, sepsis), it would be prudent to perform screening for hyperthyroidism among affected newborns. ABBREVIATIONS. PPHN, persistent pulmonary hypertension; PVR, pulmonary vascular resistance; ECMO, extracorporeal membrane oxygenation; NO, nitric oxide; NOS, nitric oxide synthase; TTF-1, thyroid transcription factor-1; ADMA, asymmetricH yperthyroidism, although uncommon in the newborn period, has been associated with pulmonary hypertension among adults. 1,2 The exact mechanisms responsible for this effect on pulmonary vascular pressure are not well understood. Persistent pulmonary hypertension (PPHN), a major cause of morbidity and death among term newborns, 3 is associated with perinatal asphyxia and perhaps chronic intrauterine hypoxia. Acute hypoxemia induces pulmonary vasoconstriction, whereas prolonged hypoxia causes hypertrophy of the smooth muscle layer of the small pulmonary arterioles, resulting in persistently elevated pulmonary vascular tone. 3 In either situation, increased pulmonary vascular resistance (PVR) causes a subsequent increase in right ventricular pressure, a patent foramen ovale, and a patent ductus arteriosis in the postnatal period. The resultant, potentially severe, right-to-left shunting is the hallmark of PPHN. Infants with severe PPHN may require extracorporeal membrane oxygenation (ECMO) for adequate oxygen delivery until the elevated PVR resolves.Although the pathophysiologic development of PPHN is multifactorial, certain conditions, such as congenital diaphragmatic hernia, cyanotic congenital heart disease, and sepsis, predispose infants to elevated PVR. These conditions are associated with hypoxia, acidosis, and elevated levels of proinflammatory cytokines. This environment promotes altered vasodilator synthesis and increased vasoconstriction through several poorly defined pathways. Interestingly, thyrotoxicosis is associated with similar clinical and biochemical findings.The association between hyperthyroidism and pulmonary hypertension is unclear. Thyroid hormone has dramatic and contrasting effects on the cardiovascular sy...

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“…Nevertheless, the reaction of the epithelium can contribute to the development of changes observed in the pulmonary parenchyma. The expression of NO synthase, producing potent vasoactive substance NO, was demonstrated in airway epithelial cells of rats (Xue et al, 1994; for review see Hampl and Herget, 2000). The immunoreactivity of endothelin-1 (ET-1), that causes vasoconstriction of pulmonary vessels, was described in the epithelium of small airways in rats, too (Aguirre et al, 2000).…”

mentioning

confidence: 99%

Normobaric hypoxia induces mild damage to epithelium of terminal bronchioles in rabbits (ultrastructural study)

Uhlı́k¹,

Konrádová²,

Vajner³

et al. 2005

Vet. Med. - Czech

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ABSTRACT:We studied the ultrastructure of the epithelium of terminal bronchioles in rabbits exposed for 96 hours to hypoxia (10% O 2 ) in isobaric hypoxic chamber. Rabbits of the first control group (treated controls) were exposed for the same time in the same hypoxic chamber with atmosphere regulated at 21% O 2 . In both groups, the temperature in the chamber was 23°C and humidity 100% during the whole experiment. The second control group (untreated controls) was kept under standard conditions. The target cells for the effect of high temperature, humidity and normobaric hypoxia were the secretory elements. Both in hypoxic animals and treated controls, isolated Clara cells revealed signs of pathological alteration. More degenerative changes of Clara cells and marks of their compensatory proliferation were ascertained after exposure to hypoxia. Electron dense secretory granules were observed in most Clara cells. This finding reflected the initial stage of their secretory product formation. The secretory granules were usually stored in cytoplasm; morphological signs of their evacuation were found only exceptionally. The ciliated cells were less damaged than the secretory ones. On their apical surfaces, formation of cytoplasmic protrusions, which sometimes led to degeneration of free cilia, was ascertained. The damage of the epithelium and mild secretory stimulation of its secretory elements could play a role in the lung injury caused by the subacute normobaric hypoxia.

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Role of Nitric Oxide in the Pathogenesis of Chronic Pulmonary Hypertension

Cited by 224 publications

References 376 publications

Correlation of inhaled nitric-oxide induced reduction of pulmonary artery pressure and vascular changes

Correlation of inhaled nitric-oxide induced reduction of pulmonary artery pressure and vascular changes

Neonatal Thyrotoxicosis and Persistent Pulmonary Hypertension Necessitating Extracorporeal Life Support

Normobaric hypoxia induces mild damage to epithelium of terminal bronchioles in rabbits (ultrastructural study)

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