Plasma Immunoreactive Endothelin-1 Concentrations in Infants with Persistent Pulmonary Hypertension of the Newborn

Prabhash, Kumar; Kazzi, Nadya J.; Shankaran, Seetha

doi:10.1055/s-2007-994352

Cited by 61 publications

(45 citation statements)

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“…Intrauterine hypoxemia, infection, hyperglycemia, and drug exposure can result in an incomplete response to perinatal vasodilator stimuli and persistently elevated pulmonary arterial blood pressure, limited pulmonary blood flow, and severe central hypoxemia. Persistent pulmonary hypertension of the newborn (PPHN) is characterized by extrapulmonary shunting of blood across the patent foreman ovale and through the patent ductus arteriosus (DA), severe hypoxemia, high levels of circulating endothelin-1, decreased nitric oxide production, and vascular remodeling due to increased cell proliferation (1,3,13,14,29).Previous work from our laboratory demonstrated that pulmonary artery smooth muscle cells (PA SMC) derived from late-gestation fetal lambs directly sense an acute increase in oxygen tension and respond with activation of a calciumsensitive K ϩ (K Ca ) channel, membrane hyperpolarization, and a decrease in intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (23). In contrast, in PA SMC derived from an ovine model of PPHN, K Ca channel expression is diminished, and an acute increase in oxygen tension has no effect on [Ca 2ϩ ] i (18).…”

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Chronic intrauterine pulmonary hypertension increases capacitative calcium entry in fetal pulmonary artery smooth muscle cells

Resnik

Keck²,

Sukovich³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Resnik ER, Keck M, Sukovich DJ, Herron JM, Cornfield DN. Chronic intrauterine pulmonary hypertension increases capacitative calcium entry in fetal pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 292: L953-L959, 2007. First published December 8, 2006 doi:10.1152/ajplung.00327.2006.-Oxygen causes perinatal pulmonary dilatation. Although fetal pulmonary artery smooth muscle cells (PA SMC) normally respond to an acute increase in oxygen (O2) tension with a decrease in cytosolic calcium ([Ca 2ϩ ]i), an acute increase in O2 tension has no net effect on [Ca 2ϩ ]i in PA SMC derived from lambs with chronic intrauterine pulmonary hypertension (PHTN). The present experimental series tests the hypothesis that an acute increase in O2 tension decreases capacitative calcium entry (CCE) in normal, but not hypertensive, fetal PA SMC. PA SMC were isolated from late-gestation fetal lambs after either ligation of the ductus arteriosus (PHTN) or sham (control) operation at 127 days gestation. PA SMC were isolated from the distal PA (Ն4th generation) and maintained under hypoxic conditions (ϳ25 Torr) in primary culture. After fura 2 loading, apparent [Ca 2ϩ ]i in PA SMC was determined as the ratio of 340-to 380-nm fluorescence intensity. Under both hypoxic and normoxic conditions, cyclopiazonic acid (CPA) increased [Ca 2ϩ ]i more in PHTN than in control PA SMC. CCE was determined in PA SMC under hypoxic and normoxic conditions, after superfusion with zero extracellular Ca 2ϩ and intracellular store depletion with CPA, followed by superfusion with Ca 2ϩ -containing solution, in the presence of the voltage-operated calcium channel blockade. CCE was increased in PHTN compared with control PA SMC under conditions of both acute and sustained normoxia. Transient receptor potential channel gene expression was greater in control compared with PHTN PA SMC. PHTN may compromise perinatal pulmonary vasodilation, in part, by modulating PA SMC CCE. cytosolic calcium; oxygen sensing; persistent pulmonary hypertension of the newborn IN UTERO, OXYGEN TENSION IS low and pulmonary vascular resistance is greater than systemic vascular resistance (11). At birth, the pulmonary circulation normally undergoes a dramatic transition as pulmonary blood flow increases 8-to 10-fold, and arterial pressure decreases concomitant with an increase in oxygen tension, establishment of an air-liquid interface, and rhythmic distention of the lung (5, 24).Fetal stress can compromise neonatal pulmonary vasodilation. Intrauterine hypoxemia, infection, hyperglycemia, and drug exposure can result in an incomplete response to perinatal vasodilator stimuli and persistently elevated pulmonary arterial blood pressure, limited pulmonary blood flow, and severe central hypoxemia. Persistent pulmonary hypertension of the newborn (PPHN) is characterized by extrapulmonary shunting of blood across the patent foreman ovale and through the patent ductus arteriosus (DA), severe hypoxemia, high levels of circulating endothelin-1, decreased nitric oxide prod...

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confidence: 99%

Chronic intrauterine pulmonary hypertension increases capacitative calcium entry in fetal pulmonary artery smooth muscle cells

Resnik

Keck²,

Sukovich³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Animal studies also suggested the role of impaired VEGF signalling in PPHN [9]. Elevated ET-1 levels are seen in PPHN concomitant with decreased eNOS activity and cGMP levels [18].…”

Section: Pathophysiologic Changes In Pphnmentioning

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Persistent Pulmonary Hypertension of the Newborn: Recent Advances in the Management

Agarwal

2013

Int J Clin Pediatr

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Persistent pulmonary hypertension of the newborn (PPHN) is a medical emergency in the neonatal period, which occurs due to failure of normal postnatal transition of fetal circulation. Despite availability of numerous treatment modalities, associated mortality and morbidity remain high. Therefore, awareness of predisposing conditions, and early diagnosis and management may help improving outcome in PPHN. To provide an overview of anatomic and functional anomalies of PPHN, and available treatment options with special focus on recent advances in the diagnosis and management of this potentially lethal illness. MEDLINE, EMBASE, The Cochrane Library, and Google Scholar databases were searched (inception until Nov-2012) using terms "persistent pulmonary hypertension of newborn", "hypoxemic respiratory failure", "nitric oxide", "sildenafil", "milrinone" and "prostacyclin" without any language restriction. www.clinicaltrials.gov website was searched for relevant ongoing trials. Additionally, manual review of article bibliographies was done for potentially relevant studies. Strategies for the management of PPHN are undergoing metamorphosis. Gentle ventilation and high-frequency ventilation have replaced prior hyperventilation strategy. Currently, iNO is the only FDA-approved selective pulmonary vasodilator for infants with hypoxemic respiratory failure/PPHN; however, it has poor/no response in upto 30% cases. Recent studies have provided evidences for the use of other therapeutic agents such as PDE-inhibitors, magnesium sulphate and prostacyclin analogues. Finally, recent laboratory studies have demonstrated the role of oxidant stress as well as potential use of free radical scavengers for example, superoxide dismutase and catalase in the management of PPHN. Assisted ventilation and pharmacologic manipulation are the mainstays of treatment of PPHN. Limited availability of the gold standard treatment option namely iNO, especially in resource-limited countries, leads to increasing use of alternative therapeutic options such as PDE-inhibitors (sildenafil and milrinone). However, as any single therapy can not be labelled as a magic bullet for PPHN, further clinical trials are required to demonstrate the efficacy and safety of available therapeutic options as well as to develop newer strategies targeted to the underlying pathophysiology.

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“…Elevated ET-1 levels have been demonstrated in animal models of meconium aspiration (7), in neonates with PPHN (3,8,9), and in older children (10) and adults (11) with pulmonary hypertension. Furthermore, the plasma ET-1 level appears to positively correlate with disease severity (8,9,12).Therapy for pulmonary hypertension in the neonate is currently targeted at preventing or reversing the sequelae of pulmonary endothelial dysfunction. iNO improves oxygenation and reduces the need for extracorporeal life support in some of the most severe cases (13).…”

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Endothelin-A Receptor Blockade and Inhaled Nitric Oxide in a Porcine Model of Meconium Aspiration Syndrome

et al. 2004

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Acute neonatal pulmonary hypertension is associated with increased activation of the endogenous endothelin pathway. We investigated the role of selective endothelin-A receptor blockade using i.v. BQ-123 in a piglet model of meconium aspiration syndrome. Meconium aspiration was induced in 18 anesthetized piglets. Six controls received no further intervention. Six piglets received 1 mg/kg BQ-123 at 120 min, with the addition of 20 ppm inhaled nitric oxide at 240 min. Six commenced nitric oxide therapy at 120 min, and were given i.v. BQ-123 at 240 min. The total study duration was 360 min. Meconium aspiration resulted in acute pulmonary hypertension and elevated endothelin-1 levels in all animals. There were no changes in pulmonary hemodynamics or endothelin-1 levels beyond 120 min in controls. In the group receiving BQ-123 first, this agent alone reduced the pulmonary artery pressure and pulmonary vascular resistance, and the subsequent addition of inhaled nitric oxide further reduced pulmonary artery pressure. In the group first receiving nitric oxide alone, this reduced the pulmonary artery pressure, and the addition of BQ-123 resulted in a fall in pulmonary vascular resistance. Endothelin-1 levels increased with both agents. BQ-123 was found to be a highly effective pulmonary vasodilator and augmented the effects of nitric oxide in this model of acute pulmonary hypertension. Abbreviations PPHN, persistent pulmonary hypertension of the newborn PVR, pulmonary vascular resistance ET, endothelin iNO, inhaled nitric oxide PPHN occurs when there is a failure of the normal rapid fall in PVR and increase in pulmonary blood flow with the onset of respiration at birth (1). Meconium aspiration syndrome is the single most common cause of PPHN, and can result in significant morbidity and mortality in term and near-term infants (2).The normal transition from the high-resistance fetal circulation to the low-resistance postnatal pulmonary circulation is associated with activation of the endogenous vasodilator nitric oxide-cyclic guanosine 5'-monophosphate pathway, and reduced release of the potent pulmonary vasoconstrictor, ET (3). The ET-1 isopeptide is a 21-amino acid polypeptide (4) that is produced within the pulmonary endothelium by the cleavage of its precursor, pro-ET (big ET), by ET converting enzyme. ET-1 is released by the vascular endothelium, and produces its effects through its interaction with at least two receptor subtypes-the A and B receptors, located on the vascular smooth muscle and endothelium. The pulmonary vasoconstrictor effects of ET-1 result mainly from activation of the G-proteincoupled smooth muscle A receptor, whereas stimulation of the endothelial ET-B receptor has been shown to result in vasodilatation (5). ET-1 is present in high levels at birth, with a gradual fall during the early neonatal period in healthy individuals (6). Elevated ET-1 levels have been demonstrated in animal models of meconium aspiration (7), in neonates with PPHN (3,8,9), and in older children (10) and adults (11) with pulmo...

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Plasma Immunoreactive Endothelin-1 Concentrations in Infants with Persistent Pulmonary Hypertension of the Newborn

Cited by 61 publications

References 16 publications

Chronic intrauterine pulmonary hypertension increases capacitative calcium entry in fetal pulmonary artery smooth muscle cells

Chronic intrauterine pulmonary hypertension increases capacitative calcium entry in fetal pulmonary artery smooth muscle cells

Persistent Pulmonary Hypertension of the Newborn: Recent Advances in the Management

Endothelin-A Receptor Blockade and Inhaled Nitric Oxide in a Porcine Model of Meconium Aspiration Syndrome

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