Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb.

Roberts, Jesse D.; Chen, T Y; Kawai, Nobuyoshi; Wain, John C.; Dupuy, P.; Shimouchi, Akito; Bloch, Kenneth D.; Polaner, David M.; Zapol, Warren M.

doi:10.1161/01.res.72.2.246

Cited by 192 publications

(56 citation statements)

References 38 publications

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“…Endogenous nitric oxide is present in exhaled air from animals and humans (26). Inhaled nitric oxide gas reverses pulmonary hypertension (27), reverses pulmonary vasoconstriction (28), improves lung function in affected patients and increases ventilation-perfusion ratios (29). In addition, nitric oxide inhibits platelet aggregation (13 -15), platelet (30,31) and leukocyte (16)(17)(18) adhesion on endothelial cells and vascular albumin leakage (19,20).…”

Section: Discussionmentioning

confidence: 99%

Impairment of Endothelium-Dependent Relaxation by Diesel Exhaust Particles in Rat Thoracic Aorta.

et al. 1995

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ABSTRACT-Nitric oxide released from vascular endothelium plays important regulatory roles in cardiovascular and pulmonary systems. Epidemiological studies suggest that diesel exhaust particles (DEP) seem to be one of the causative factors responsible for the recent increase in pulmonary diseases. To clarify the pathogenic mechanism, the effects of DEP on vascular endothelial functions were investigated in terms of endothelium-dependent relaxation. Ring preparations of rat thoracic aorta were preincubated for 10 min with a DEP suspension (1, 10, 100 pg/ml) at 37°C in organ baths and relaxed with cumulative additions of acetylcholine following precontraction with phenylephrine (10-6 M). The relaxation was attenuated by DEP-exposure in a concentration-dependentmanner. An addition of superoxide dismutase (SOD) completely abolished the inhibitory effect of DEP at lower concentrations, but only partially at the higher concentration. DEP (10 tg/ml) neither affected the contractile response to phenylephrine in intact aortic rings nor the endothelium-independent relaxation by sodium nitroprusside in denuded rings, while DEP (100 pg/ml) significantly attenuated both responses. These results suggest that 1) inhaled DEP causes pulmonary inflammation by inhibiting the endothelial formation and/or the effect of nitric oxide and 2) SOD reduces the adverse effects. Keywords: Diesel exhaust particle, Endothelium-dependent relaxation, Thoracic aorta (rat), Superoxide, Acetylcholine Several epidemiological studies indicate that patients with pulmonary diseases such as asthma and chronic bronchitis are increasing in Japan, especially in children living in urban areas. Diesel exhaust contains 2 to 20 times more nitrogen oxides and 30 to 100 times more particles than gasoline exhaust. Moreover, it has been recently reported that diesel exhaust particles (DEP) suspended in phosphate buffer generate superoxide anion radicals (02'-) and hydroxyl radicals ('OH) on incubation at 371C. Sagai et al. suggested that these active oxygen radicals would cause endothelial cell damage leading to pulmonary edema (1). It was reported that reactive oxygens (02'-, 'OH and H202) were causes of pulmonary injury (2) and that 02'-produced from dihydroxyfumarate induced pulmonary endothelial cell damage (3). The earliest stages of histologically observable lung injury occurred in the pulmonary capillary bed (4) and the endothelial cells in capillaries (5). Edward reports that injury of the pulmonary endothelial cells is the pathogenesis of acute lung injury (6). These observations imply that the endothelium plays important protective roles in the development of pulmonary injury.Since the alveolar capillary endothelium lies close to the alveolar epithelium (7), inhaled DEP may easily interact with the endothelium, blood cells and blood components by releasing reactive oxygens and some soluble materials. The endothelium releases numerous biologically important materials, one of which is endothelium-derived relaxing factor (EDRF): nitric oxide (8) or nitrosot...

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Section: Discussionmentioning

confidence: 99%

Impairment of Endothelium-Dependent Relaxation by Diesel Exhaust Particles in Rat Thoracic Aorta.

et al. 1995

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“…NO (5-20 ppm) produced an increase in pulmonary artery blood flow, an effect that was equal to the response seen when the Fioz was increased to 1 .O. In all of these studies there was no effect on the systemic circulation, specifically on SVR, and in two studies (14,15) an increase in left-to-right shunting across the ductus occurred during NO inhalation, demonstrating that inhaled NO is a potent selective pulmonary vasodilator in these models.…”

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confidence: 83%

Nitric Oxide Reverses Acute Hypoxic Pulmonary Hypertension in the Newborn Piglet

et al. 1994

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ABSTRACT. Inhaled nitric oxide has been reported to act as a specific pulmonary vasodilator. We used the newborn piglet to create acute hypoxic pulmonary hypertension and examined the effect of inhaled nitric oxide in this model. Six newborn piglets were instrumented in order to measure cardiac index, pulmonary arterial pressure, and systemic arterial pressure. Pulmonary hypertension was induced by reducing the fraction of inspired oxygen to 0.12 to 0.14. With hypoxia (arterial oxygen saturation between 35 and 45%), pulmonary arterial pressure increased by 48% ( p < 0.01), pulmonary vascular resistance increased by 74% ( p < 0.01), and both systemic arterial pressure and systemic vascular resistance decreased by 38 and 31% respectively There is now good evidence that at a cellular level vascular muscle tone is regulated in large measure by NO or an NOrelated compound, which is thought to be identical to the previously described EDRF (1-4). Nitroso-containing vasodilators, such as nitroprusside, are thought to act through liberating NO in tissue (5, 6). NO is synthesized by the vascular endothelium from L-arginine (7, 8), and acts through the stimulation of guanylate cyclase, leading to the production of cyclic GMP (9. 10). The mechanism by which cyclic GMP relaxes vascular smooth muscle is not clear, but probably involves inhibition of activation-induced elevation in cytosolic calcium concentrationUsing a pulmonary hypertension model induced by the infusion of a thromboxane analog, heparin-protamine reaction, or hypoxia, Frostell, Fratacci and co-worker5 ( 12, 1 3) demonstrated reversal of pulmonary vasoconstriction using 40 to 80 ppm of inhaled NO without significant effect on the systemic circulation in 25-to 35-kg mature lambs. Similar results using pulmonary vasoconstriction produced by hypoxia with or without respiratory acidosis were obtained by Roberts et al. (14) who also demonstrated elevated plasma cyclic GMP levels after NO inhalation in a newborn lamb model. Kinsella et al. (1 5) evaluated the effects of NO in mechanically ventilated ovine fetuses maintained at intrauterine arterial oxygen levels. NO (5-20 ppm) produced an increase in pulmonary artery blood flow, an effect that was equal to the response seen when the Fioz was increased to 1 .O. In all of these studies there was no effect on the systemic circulation, specifically on SVR, and in two studies (14, 15) an increase in left-to-right shunting across the ductus occurred during NO inhalation, demonstrating that inhaled NO is a potent selective pulmonary vasodilator in these models.The aims of the current study were to investigate the feasibility of administering NO to a neonatal model, i.e. the 1-to 2-d-old piglet, and to evaluate the dose response characteristics and the time course of the effect of NO on hypoxic pulmonary vasoconstriction. MATERIALS AND METHODS

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“…Other clinical trials showed that low-dose iNO given to human newborn infants with persistent pulmonary hypertension reduces the need for extracorporeal membrane oxygenation (41,56). Likewise, experimental animal studies showed that iNO reverses pulmonary vasoconstriction following either hypoxia or prenatal closure of the ductus arteriosus (154,203). The systemic circulation was not dilated in those studies.…”

Section: Evolving Neonatal Cld Leads To Increased Hydrostatic Pulmonamentioning

confidence: 96%

Utility of large-animal models of BPD: chronically ventilated preterm lambs

Albertine

2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Albertine KH. Utility of large-animal models of BPD: chronically ventilated preterm lambs. Am J Physiol Lung Cell Mol Physiol 308: L983-L1001, 2015. First published March 13, 2015; doi:10.1152/ajplung.00178.2014.-This paper is focused on unique insights provided by the preterm lamb physiological model of bronchopulmonary dysplasia (BPD). Connections are also made to insights provided by the former preterm baboon model of BPD, as well as to rodent models of lung injury to the immature, postnatal lung. The preterm lamb and baboon models recapitulate the clinical setting of preterm birth and respiratory failure that require prolonged ventilation support for days or weeks with oxygen-rich gas. An advantage of the preterm lamb model is the large size of preterm lambs, which facilitates physiological studies for days or weeks during the evolution of neonatal chronic lung disease (CLD). To this advantage is linked an integrated array of morphological, biochemical, and molecular analyses that are identifying the role of individual genes in the pathogenesis of neonatal CLD. Results indicate that the mode of ventilation, invasive mechanical ventilation vs. less invasive high-frequency nasal ventilation, is related to outcomes. Our approach also includes pharmacological interventions that test causality of specific molecular players, such as vitamin A supplementation in the pathogenesis of neonatal CLD. The new insights that are being gained from our preterm lamb model may have important translational implications about the pathogenesis and treatment of BPD in preterm human infants.neonatal chronic lung disease; alveolarization; alveolar simplification; pulmonary hypertension; airway expiratory resistance; nitric oxide; vitamin A; endothelial nitric oxide synthase; nasal CPAP; insulin-like growth factor-1; epigenetics ACUTE RESPIRATORY FAILURE of preterm human infants reflects immaturity of the lung following preterm birth, disrupted developmental processes, and dysregulated repair responses. This reflection occurs in the neonatal intensive care setting of continuous invasive mechanical ventilation support with oxygen-rich gas that is necessary to keep many preterm human infants alive. Among survivors of preterm birth and initial days of ventilation support with oxygen-rich gas, human infants who require prolonged invasive ventilation support with oxygen-rich gas frequently develop bronchopulmonary dysplasia (BPD). BPD is a significant pediatric health problem because, almost four decades after its initial description (134), this disease of preterm infants remains the most common cause of long-term pour outcomes, including postnatal growth failure, recurrent hospitalization for respiratory tract infections, and intraventricular hemorrhage (53, 178). In the United States, since 2006, the overall rate of prematurity is 1 in 8 births, or ϳ12% (74, 118). However, the underlying pathogenic mechanisms are incompletely understood.Gaps in knowledge about the underlying pathogenic mechanisms that contribute to BPD are related, in p...

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Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb.

Cited by 192 publications

References 38 publications

Impairment of Endothelium-Dependent Relaxation by Diesel Exhaust Particles in Rat Thoracic Aorta.

Impairment of Endothelium-Dependent Relaxation by Diesel Exhaust Particles in Rat Thoracic Aorta.

Nitric Oxide Reverses Acute Hypoxic Pulmonary Hypertension in the Newborn Piglet

Utility of large-animal models of BPD: chronically ventilated preterm lambs

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