Stimulation of the Dopamine 1 Receptor Increases Lung Edema Clearance

Barnard, M. L.; Ridge, Karen M.; Saldías, Fernando; Friedman, Eliot; Gare, Meir; Guerrero, Carmen; Lecuona, Emilia; Bertorello, Alejandro M.; Katz, Adrian I.; Sznajder, Jacob I.

doi:10.1164/ajrccm.160.3.9812003

Cited by 54 publications

(45 citation statements)

References 27 publications

(45 reference statements)

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“…Low to moderate doses of dopamine were associated with faster rates of alveolar fluid clearance. This finding confirms several recent reports that dopamine upregulates the rate of alveolar fluid clearance in both the normal (3) and the injured (34) rat lung, an effect that is mediated by binding to the dopamine-1 receptor, not the ␤-adrenergic receptors (4). By contrast, the four donors who received high doses of dopamine, out of the dopaminergic range, had very low rates of alveolar fluid clearance.…”

Section: Discussionsupporting

confidence: 90%

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Selected Contribution: Mechanisms that may stimulate the resolution of alveolar edema in the transplanted human lung

Ware

Fang

Wang

et al. 2002

Journal of Applied Physiology

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nary edema is common in organ donors and lung transplant recipients. Therefore, we assessed the responsiveness of human donor lungs to pharmacological agents that stimulate clearance of alveolar edema. Organ donors whose lungs were rejected for transplantation were studied. After resection, transport (4°C), and rewarming (37°C) of lungs, alveolar fluid clearance was measured with (n ϭ 8 donors) or without (n ϭ 23 donors) ␤-adrenergic stimulation. Terbutaline-stimulated clearance (10 Ϫ4 M) was higher than unstimulated clearance (7.1 Ϯ 1.3 vs. 4.8 Ϯ 2.4%/h, P Ͻ 0.01). Second, we determined whether medications given to the organ donor were associated with the extent of pulmonary edema or the rate of alveolar fluid clearance in the harvested lung. Preharvest administration of dopamine in low to moderate doses was associated with faster alveolar fluid clearance (r ϭ 0.62, P Ͻ 0.01). Preharvest administration of diuretics was associated with lower extravascular lung water-to-dry weight ratios. This study provides the first evidence that a ␤ 2-adrenergic agonist stimulates alveolar fluid clearance in the human donor lung. Aerosolized ␤ 2-adrenergic agonists may have therapeutic value for hastening the resolution of alveolar edema during the management of donors before resection of lungs for transplantation or in the posttransplant setting. pulmonary edema; ␤-agonist; alveolar epithelial fluid transport; alveolar epithelium; lung preservation PULMONARY EDEMA IS A COMMON problem in both organ donors and lung transplant recipients. In organ do-

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Section: Discussionsupporting

confidence: 90%

“…Low to moderate doses have dopaminergic effects and have been shown to increase alveolar fluid clearance experimentally (3,4,34). Therefore, the primary analysis of dopamine was done on lungs that had been exposed to low to moderate doses of dopamine.…”

Section: Methodsmentioning

confidence: 99%

Selected Contribution: Mechanisms that may stimulate the resolution of alveolar edema in the transplanted human lung

Ware

Fang

Wang

et al. 2002

Journal of Applied Physiology

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“…Briefly, cell lysates were prepared by the addition of lysis buffer (20 mM Tris, pH 7.5, 150 mm NaCl, 1 mM EDTA, 1 mm EGTA, 1% Triton X-100, 2.5 mM sodium pyrophosphate, 1 mm Na 3 VO 4 , 1 g/ml leupeptin, 1 mM phenylmethylsulfonyl fluoride) and centrifugation at 14,000 ϫ g to eliminate the insoluble material. Basolateral membranes (BLM) were prepared using Percoll gradient centrifugation as described (17,18). Briefly, peripheral lung tissue was homogenized in a buffer containing 300 mM mannitol in 12 mM Tris-HEPES, pH 7.6, and protease inhibitors as described above, then centrifuged twice to discard the nuclear and mitochondrial pellets.…”

Section: Methodsmentioning

confidence: 99%

β-Adrenergic Receptor Stimulation and Adenoviral Overexpression of Superoxide Dismutase Prevent the Hypoxia-mediated Decrease in Na,K-ATPase and Alveolar Fluid Reabsorption

Litvan

Briva

Wilson

et al. 2006

Journal of Biological Chemistry

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Hypoxia has been shown to cause lung edema and impair lung edema clearance. In the present study, we exposed isolated rat lungs to pO 2 ‫؍‬ 40 mm Hg for 60 min or rats to 8% O 2 for up to 24 h and then measured changes in alveolar fluid reabsorption (AFR) and Na,K-ATPase function. Low levels of oxygen severely impaired AFR in both ex vivo and in vivo models. The decrease in AFR was associated with a decrease in Na,K-ATPase activity and protein abundance in the basolateral membranes from peripheral lung tissue of hypoxic rats. ␤-Adrenergic agonists restored AFR in rats exposed to 8% O 2 (from 0.02 ؎ 0.07 ml/h to 0.59 ؎ 0.03 ml/h), which was associated with parallel increases in Na,K-ATPase protein abundance in the basolateral membrane. Hypoxia is associated with increased production of reactive oxygen species. Therefore, we examined whether overexpression of SOD2, manganese superoxide dismutase, would prevent the hypoxia-mediated decrease in AFR. Spontaneously breathing rats were infected with a replication-deficient human type 5 adenovirus containing cDNA for SOD2. An otherwise identical virus that contained no cDNA was used as a control (Adnull). Hypoxic Adnull rats had decreased rates of AFR (0.12 ؎ 0.1 ml/h) as compared with hypoxic AdSOD2 and normoxic control rats (0.47 ؎ 0.04 ml/h and 0.49 ؎ 0.02 ml/h, respectively), with parallel changes in Na,K-ATPase.Severe hypoxia can occur during ascent to high altitude (1) and in patients with acute respiratory distress syndrome and pulmonary edema. One of the primary defense mechanisms in the lung against alveolar fluid accumulation is the active transport of sodium out of the air spaces, which generates a transepithelial osmotic gradient that leads to alveolar fluid reabsorption (AFR).2 Sodium enters the apical membrane of alveolar epithelial cells through amiloride-sensitive Na ϩ channels (2, 3) and is then transported out across the basolateral membrane by the ouabain-inhibitable Na,K-ATPase (4 -7). Hypoxia has been shown to impair AFR and may contribute to alveolar fluid accumulation (8, 9). However, the mechanisms by which hypoxia impairs AFR and alveolar epithelial sodium transport proteins has not been fully elucidated.A mechanism by which hypoxia might impair AFR is by altering the function of either apical epithelial sodium channels and/or basolateral Na,K-ATPase proteins. Several in vitro studies using cultured alveolar epithelial cells have demonstrated that exposure to hypoxia results in the decrease in epithelial sodium channels and Na,K-ATPase protein abundance (10 -12), which was reversed upon reoxygenation. Other investigators have reported various mechanisms associated with the decrease in alveolar fluid reabsorption in animals exposed to hypoxia in vivo (9,11,13).In the current study, we provide evidence that exposure to hypoxia results in decreased Na,K-ATPase activity and protein abundance at the plasma membrane, which contributes to a decrease in alveolar fluid reabsorption in both in vivo and ex vivo models of hypoxia. These data suggest that (a...

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“…Administration of DA increased alveolar edema clearance in rodents with normal lungs and during lung injury (Barnard et al, 1999;Saldias et al, 1999). At the cellular level, DA increases Na ϩ ,K ϩ -ATPase activity by mechanisms that include the activation of a signaling network leading to an increase in Na ϩ ,K ϩ -ATPase abundance at the plasma membrane (Ridge et al, 2002).…”

Section: Am Bertorello Et Almentioning

confidence: 99%

Analysis of Na⁺,K⁺-ATPase Motion and Incorporation into the Plasma Membrane in Response to G Protein–coupled Receptor Signals in Living Cells

Bertorello

Komarova

Smith

et al. 2003

MBoC

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Dopamine (DA) increases Na+,K+-ATPase activity in lung alveolar epithelial cells. This effect is associated with an increase in Na+,K+-ATPase molecules within the plasma membrane ( Ridge et al., 2002 ). Analysis of Na+,K+-ATPase motion was performed in real-time in alveolar cells stably expressing Na+,K+-ATPase molecules carrying a fluorescent tag (green fluorescent protein) in the α-subunit. The data demonstrate a distinct (random walk) pattern of basal movement of Na+,K+-ATPase–containing vesicles in nontreated cells. DA increased the directional movement (by 3.5 fold) of the vesicles and an increase in their velocity (by 25%) that consequently promoted the incorporation of vesicles into the plasma membrane. The movement of Na+,K+-ATPase–containing vesicles and incorporation into the plasma membrane were microtubule dependent, and disruption of this network perturbed vesicle motion toward the plasma membrane and prevented the increase in the Na+,K+-ATPase activity induced by DA. Thus, recruitment of new Na+,K+-ATPase molecules into the plasma membrane appears to be a major mechanism by which dopamine increases total cell Na+,K+-ATPase activity.

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Stimulation of the Dopamine 1 Receptor Increases Lung Edema Clearance

Cited by 54 publications

References 27 publications

Selected Contribution: Mechanisms that may stimulate the resolution of alveolar edema in the transplanted human lung

Selected Contribution: Mechanisms that may stimulate the resolution of alveolar edema in the transplanted human lung

β-Adrenergic Receptor Stimulation and Adenoviral Overexpression of Superoxide Dismutase Prevent the Hypoxia-mediated Decrease in Na,K-ATPase and Alveolar Fluid Reabsorption

Analysis of Na⁺,K⁺-ATPase Motion and Incorporation into the Plasma Membrane in Response to G Protein–coupled Receptor Signals in Living Cells

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Stimulation of the Dopamine 1 Receptor Increases Lung Edema Clearance

Cited by 54 publications

References 27 publications

Selected Contribution: Mechanisms that may stimulate the resolution of alveolar edema in the transplanted human lung

Selected Contribution: Mechanisms that may stimulate the resolution of alveolar edema in the transplanted human lung

β-Adrenergic Receptor Stimulation and Adenoviral Overexpression of Superoxide Dismutase Prevent the Hypoxia-mediated Decrease in Na,K-ATPase and Alveolar Fluid Reabsorption

Analysis of Na+,K+-ATPase Motion and Incorporation into the Plasma Membrane in Response to G Protein–coupled Receptor Signals in Living Cells

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Analysis of Na⁺,K⁺-ATPase Motion and Incorporation into the Plasma Membrane in Response to G Protein–coupled Receptor Signals in Living Cells