Postnatal Changes in Response to Norepinephrine in the Normal and Pulmonary Hypertensive Lung

Schindler, Margrid; Hislop, Alison A.; Haworth, Sheila G.

doi:10.1164/rccm.200311-1551oc

Cited by 21 publications

(19 citation statements)

References 25 publications

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“…In the human lung, expression of the ET-B receptor was lower in early gestation than soon after birth (20). Norepinephrine-induced contractile responses were also significantly higher in the fetal compared with 14-day-old and adult porcine pulmonary veins and arteries (26). Thus the veins may be important in maintaining high pulmonary vascular resistance in utero and in the reduction of resistance after birth.…”

Section: Discussionmentioning

confidence: 98%

“…The rings were suspended in a 10-ml organ chamber, and isometric tension was measured in grams with a Grass FT .03 force transducer (Grass Instruments, Quincy, MA). The forces were digitally converted at 1.7-Hz using a MacLab Macintosh Digital recorder (AD Instruments, United Kingdom) as previously described (26). The organ chambers were filled with modified Krebs-Ringer solution and gassed with 95% O 2 and 5% CO2 at 37°C.…”

Section: Methodsmentioning

confidence: 99%

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Postnatal changes in pulmonary vein responses to endothelin-1 in the normal and chronically hypoxic lung

Schindler

Hislop²,

Haworth³

2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Schindler MB, Hislop AA, Haworth SG. Postnatal changes in pulmonary vein responses to endothelin-1 in the normal and chronically hypoxic lung. Am J Physiol Lung Cell Mol Physiol 292: L1273-L1279, 2007. First published January 26, 2007; doi:10.1152/ajplung.00173.2006.-The response of pulmonary arteries to endothelin-1 (ET-1) changes with age in normal pigs and is abnormal in pulmonary hypertension. The purpose of this study was to determine if the same is true of the pulmonary veins. We studied the wall structure and functional response to ET-1 in pulmonary veins from normal pigs from fetal life to adulthood and from pigs subjected to chronic hypobaric hypoxia either from birth for 3 days or from 3 to 6 days of age. In isolated normal veins, the contractile response decreased by 40% between late fetal life and 14 days of age with a concomitant twofold increase in endothelium-dependent relaxant response. The ET A antagonist BQ-123 reduced the contractile response significantly more in newborn than older animals, whereas the ET-B antagonist BQ-788 had no effect in fetal animals and maximally increased contraction at 14 days of age. Hypoxic exposure significantly increased pulmonary vein smooth muscle area and contractile response to ET-1. The relaxation response was impaired following hypoxic exposure from birth but not from 3 to 6 days of age. The ET A antagonist BQ-123 decreased contractile and increased dilator responses significantly more than in age-matched controls. Thus pulmonary veins show age-related changes similar to those seen in the pulmonary arteries with a decrease in ETA-mediated contractile and increase in ET-B-mediated relaxant response with age. Contractile response was also increased in hypoxia as in the arteries. This study suggests that pulmonary veins are involved in postnatal adaptation and the pathogenesis of pulmonary hypertension. postnatal adaptation; pulmonary hypertension A NUMBER OF ANIMAL AND HUMAN studies suggest a role for endothelin-1 (ET-1) in adaptation to extrauterine life (8,21) and in the pathogenesis of pulmonary hypertension (18). Endo et al. (8) found plasma ET-1 concentrations to be threefold higher at birth compared with 5 or 30 days in healthy human neonates, and similar changes have been described in piglets (21). ET-1 blood levels are elevated in patients with pulmonary hypertension and decrease following resolution in persistent pulmonary hypertension of the newborn (24), pulmonary hypertension due to congenital heart disease (18), and pulmonary hypertension due to acute lung injury (19).Experimental studies have shown that the contractile response to ET-1 decreases with increasing age in rabbit pulmonary arteries (7). The effect of age on the pharmacological responses of the porcine pulmonary veins to ET-1 has not been reported; however, as the threshold for ET-1-induced contraction is lower in pulmonary veins than in pulmonary arteries in the fetal lamb (29) and human (4), it is likely that the veins may also exhibit developmental changes in response to ET-1.In h...

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Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Postnatal changes in pulmonary vein responses to endothelin-1 in the normal and chronically hypoxic lung

Schindler

Hislop²,

Haworth³

2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…We have previously shown that the pulmonary arterial relaxation response to norepinephrine in piglets greater than 24 h of age was largely mediated by nitric oxide release from the endothelium and that following exposure to hypoxia from birth for 3 d, the relaxation response was absent or severely attenuated (20). We have now shown that norepinephrineinduced relaxation is also significantly decreased in the airways.…”

mentioning

confidence: 79%

Porcine Pulmonary Artery and Bronchial Responses to Endothelin-1 and Norepinephrine on Recovery from Hypoxic Pulmonary Hypertension

Schindler

Hislop²,

Haworth³

2006

Pediatr Res

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Many infants recovering from acute lung disease and pulmonary hypertension still have evidence of reactive airways disease at one year of age, suggesting longer-term airway effects. We hypothesized that parallel changes in smooth muscle would occur in airways and pulmonary arteries from animals with pulmonary hypertension and during normoxic recovery. Thus, two-hour-old piglets were subjected to 3 d chronic hypobaric hypoxia and 3-d-old piglets were subjected to 11 d hypoxia. Some animals were allowed to recover in room air for 3 or 6 d. The amount of smooth muscle and responses of isolated paired bronchial and pulmonary artery rings to endothelin-1 (ET-1) and norepinephrine were studied at the end of hypoxic exposure, on recovery and in age-matched control animals. In all hypoxia induced pulmonary hypertensive animals, smooth muscle area and ET-1 contractile response was increased in the pulmonary arteries and bronchi. Norepinephrine-induced relaxant response was impaired significantly in both bronchi and pulmonary arteries. After 3 d recovery, pulmonary arterial smooth muscle area decreased by 65%, and ET-1-induced contractile responses were normal for age. In the airways, ET-1 contractile response only normalized after six days and bronchial smooth muscle was still increased. After 6 d recovery pulmonary arterial norepinephrineinduced relaxant response had returned to normal, but bronchial response remained impaired. Thus during pulmonary hypertension, both bronchial and pulmonary arterial smooth muscle area and contractile responses are increased. On recovery, regression of bronchial structural and functional abnormalities is slower than in pulmonary arteries. A natomically, the pulmonary arteries and airways lie in close proximity and local mediator release may affect both bronchial and pulmonary vascular reactivity. Pulmonary hypertension in children with congenital heart disease is associated not only with an elevated pulmonary arterial vascular resistance and medial smooth muscle hypertrophy, but also with increased respiratory system resistance and bronchial smooth muscle hypertrophy (1).Fifty percent of infants requiring Extra Corporeal Membrane Oxygenation (ECMO) for persistent pulmonary hypertension of the newborn still required pulmonary medications after six months, despite ECMO utilizing a strategy of lung rest to prevent lung injury (2). Twenty-six percent of infants who participated in the UK randomized ECMO trial, many of whom had severe persistent pulmonary hypertension, still had evidence of reactive airways disease with cough and wheeze at one year of age, and 8% still required regular pulmonary medications (3). These changes could be due to the damaging effects of high pressure and the high FiO 2 used during the mechanical ventilation given before instituting ECMO (4), however pulmonary hypertension may have contributed to the end result by affecting both the pulmonary arteries and bronchi. The clinical findings also suggest that any bronchial changes, once present, are slow to re...

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“…Many laboratories (including ours) that study isolated vessels in conventional tissue baths use a 94% oxygen and 6% CO 2 gas mixture (8,23,24). The PO 2 of the buffer solution bathing the tissue is close to 500 mm Hg and PCO 2 is approximately 40 mm Hg.…”

Section: -D-old Lambsmentioning

confidence: 99%

“…NE constriction of pulmonary arteries isolated from fetal and neonatal animals after normal transition has been studied in detail (7)(8)(9). However, the effect of oxygen exposure during resuscitation and or ventilation on the contractile response to NE is not known.…”

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Pulmonary Arterial Contractility in Neonatal Lambs Increases with 100% Oxygen Resuscitation

et al. 2006

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ABSTRACT:The optimal FiO 2 during neonatal resuscitation is a subject of controversy. The effect of exposure to high levels of inspired oxygen on pulmonary arterial (PA) contractility is not known. We studied differences in PA vasoreactivity in term lambs initially ventilated with 21% or 100% oxygen, followed by continued ventilation using oxygen as needed for 24 h, or ventilated with 100% oxygen for 24 h and room air breathing 1-d-old lambs. Term lambs were delivered by cesarean section, intubated, and ventilated with 21% (21%Res) or 100% oxygen (100%Res) for the first 30 min of life. Subsequently, the ventilator FiO 2 was adjusted to maintain a PaO 2 between 45 and 65 mm Hg for 24 h. Five lambs were ventilated continuously with 100% oxygen (100%24h). Six spontaneously breathing newborn lambs (RA Spont) were studied for comparison. Lambs were killed at 24 h of life and PA rings were isolated and contracted with norepinephrine (NE) and KCl and some were relaxed with A23187 and SNAP in tissue baths. NE and KCl induced contractions were highest in PA isolated from 100%24h lambs, and were significantly higher in 100%Res lambs than PA from 21%Res lambs. Contraction responses in PA from RA Spont lambs were similar to 21%Res lambs. Relaxations to A23187 and SNAP were similar among all ventilated groups. PA contractility to NE and KCl is increased following both brief (30 min) and prolonged (24 h) exposure to 100% oxygen during mechanical ventilation. In contrast, normoxic resuscitation and ventilation do not increase PA contractility. T he extent of oxygen supplementation during optimal resuscitation of a newborn infant remains controversial. Oxygen plays a crucial role in mediating pulmonary vascular transition at birth and even small increases in fetal oxygenation (similar to or less than that induced by room air ventilation) result in a dramatic decrease in pulmonary vascular resistance (1-3). However, the debate regarding the use of oxygen for neonatal resuscitation has intensified in recent years. New arguments have been added to the debate as more and more data indicate that not only is room air as good as 100% oxygen for resuscitation but that even a brief exposure to pure oxygen at birth might be detrimental (4). It has been suggested that breathing 100% oxygen dilates constricted pulmonary arteries more efficiently than room air. However, ultrasound and direct estimation of pulmonary arterial pressure in asphyxiated piglets demonstrated that pulmonary hypertension normalized as quickly with room air as with 100% oxygen (5,6).NE constriction of pulmonary arteries isolated from fetal and neonatal animals after normal transition has been studied in detail (7-9). However, the effect of oxygen exposure during resuscitation and or ventilation on the contractile response to NE is not known.We hypothesized that exposure to 100% oxygen during resuscitation would result in formation of reactive oxygen species and induce increased pulmonary arterial contractile response and that the increased contractility would be prop...

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Postnatal Changes in Response to Norepinephrine in the Normal and Pulmonary Hypertensive Lung

Cited by 21 publications

References 25 publications

Postnatal changes in pulmonary vein responses to endothelin-1 in the normal and chronically hypoxic lung

Postnatal changes in pulmonary vein responses to endothelin-1 in the normal and chronically hypoxic lung

Porcine Pulmonary Artery and Bronchial Responses to Endothelin-1 and Norepinephrine on Recovery from Hypoxic Pulmonary Hypertension

Pulmonary Arterial Contractility in Neonatal Lambs Increases with 100% Oxygen Resuscitation

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