ET<sub>A</sub>-receptor blockade and ET<sub>B</sub>-receptor stimulation in experimental congenital diaphragmatic hernia

Thébaud, Bernard; Forgues, D.; Aigrain, Yves; Mercier, Jean-Christophe; Dinh-Xuan, A.T.

doi:10.1152/ajplung.2000.278.5.l923

Cited by 31 publications

(32 citation statements)

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“…ET1 is elevated at admission in patients with CDH compared with healthy control subjects (31), and pulmonary expression of both endothelin A and B (ETA and ETB) receptors are increased in infants who died with PH at less than 3 days of age (32). Experimental models have yielded limited data, suggesting a possible developmental role of ET1 in CDH-associated lung hypoplasia (33) and abnormal ET1 signaling in fetal CDH (34)(35)(36). However, there are no longitudinal data in either humans or animal models to lend insight into the potential pathophysiological role of ET1 in vascular remodeling and growth in infants with CDH.…”

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confidence: 99%

Congenital Diaphragmatic Hernia

Keller

Tacy²,

Hendricks‐Muñoz³

et al. 2010

Am J Respir Crit Care Med

140

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Rationale: Endothelin-1 (ET1) is dysregulated in pulmonary hypertension (PH). It may be important in the pathobiology of congenital diaphragmatic hernia (CDH). Objectives: We hypothesized that ET1 levels in the first month would be higher in infants with CDH who subsequently expired or were discharged on oxygen (poor outcome). We further hypothesized that ET1 levels would be associated with concurrent severity of PH. Methods: We sampled plasma at 24 to 48 hours, and 1, 2, and 4 weeks of age in 40 prospectively enrolled newborns with CDH. We performed echocardiograms to estimate pulmonary artery pressure at less than 48 hours of age and weekly to 4 weeks. PH was classified in relationship to systemic blood pressure (SBP): less than 2/3 SBP, 2/3 SBP-systemic is related to pressure, or systemic-to-suprasystemic pressure. Measurements and Main Results: ET1 levels at 1 and 2 weeks were higher in infants with poor outcome compared with infants discharged on room air (median and interquartile range: 27.2 [22.6, 33.7] vs. 19.1 [16.1, 29.5] pg/ml, P 5 0. 03; and 24.9 [17.6, 39.5] vs. 17.4 [13.7, 21.8] pg/ml, P 5 0.01 at 1 and 2 weeks, respectively). Severity of PH was significantly associated with increasing ET1 levels at 2 weeks (16.1 [13.7, 21.8], 21.0 [17.4, 31.1], and 23.6 [21.9, 39.5] pg/ml for increasing PH class, P 5 0.03). Increasing severity of PH was also associated with poor outcome at that time (P 5 0.001). Conclusions: Infants with CDH and poor outcome have higher plasma ET1 levels and severity of PH than infants discharged on room air. Severity of PH is associated with ET1 levels.

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confidence: 99%

Congenital Diaphragmatic Hernia

Keller

Tacy²,

Hendricks‐Muñoz³

et al. 2010

Am J Respir Crit Care Med

140

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“…Two previous studies have demonstrated a preventive effect of ET-A receptor blockade on the subsequent development of pulmonary hypertension in an acute hypoxic rat model (25) and in a model of meconium aspiration (26). The beneficial effects of other ET-A receptor antagonists in the treatment of acute pulmonary hypertension have recently been demonstrated in lamb (16,17), and pig (27) models of acute hypoxic pulmonary hypertension, and in a lamb model of congenital diaphragmatic hernia (19). Furthermore, the intravenous combined ET-A and -B receptor antagonist, tezosentan, has been shown to reduce PVR in a model of oleic acidinduced lung injury (28).…”

Section: Discussionmentioning

confidence: 99%

“…bolus of the selective ET-A receptor antagonist BQ-123, in children after surgery for congenital heart disease (15). Acute, selective ET-A receptor blockade has been shown to reduce PVR in piglet and lamb models of hypoxic pulmonary hypertension (16 -18) and congenital diaphragmatic hernia (19). Previous investigators have suggested that ET-A receptor blockade may improve smooth muscle responsiveness to iNO in monocrotaline-induced pulmonary hypertension (20), and it has recently been proposed that ET-A receptor antagonists may have a role in the prevention of rebound pulmonary hypertension upon iNO withdrawal (21).…”

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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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“…Vasoconstrictors such as endothelin-1 (ET-1) or thromboxane A 2 increase the vascular resistance (6,7), although ET-1 may also play a role in vasodilation in the new-born (8). There exist direct vasodilators such as endothelium-derived nitric oxide (EDNO/EDRF) (9,10), also known as endothelium-derived relaxing factor (EDRF) (11)(12)(13), which activates soluble guanylate cyclase (GC) found in vascular smooth muscle, and endotheliumderived hyperpolarizing factor (EDHF) (14) and prostacycline (PGI 2 ) (15) which activate the smooth muscle membrane bound enzyme, adenylate cyclase (AC) (11).…”

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confidence: 99%

“…There exist direct vasodilators such as endothelium-derived nitric oxide (EDNO/EDRF) (9,10), also known as endothelium-derived relaxing factor (EDRF) (11)(12)(13), which activates soluble guanylate cyclase (GC) found in vascular smooth muscle, and endotheliumderived hyperpolarizing factor (EDHF) (14) and prostacycline (PGI 2 ) (15) which activate the smooth muscle membrane bound enzyme, adenylate cyclase (AC) (11). Other factors such as atrial natriuretic factor (ANF), acetylcholine (Ach) (16), bradykinine (16), endothelin (ET) (6,7), adenosine triphosphate (ATP) (17), and shear-stress (5,18) are also potent dilators which act mainly by as releasors of EDNO and/or EDHF. Ventilation (19) alone induces pulmonary vasodilation.…”

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Role of ATP-Dependent Potassium Channels in Pulmonary Vascular Tone of Fetal Lambs With Congenital Diaphragmatic Hernia

et al. 2006

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High mortality in newborn babies with congenital diaphragmatic hernia (CDH) is principally due to persistent pulmonary hypertension. ATP-dependent potassium (K ATP ) channels might modulate pulmonary vascular tone. We have assessed the effects of Pinacidil, a K ATP channel opener, and glibenclamide (GLI), a K ATP channel blocker, in near full-term lambs with and without CDH. In vivo, pulmonary hemodynamics were assessed by means of pressure and blood flow catheters. In vitro, we used isolated pulmonary vessels and immunohistochemistry to detect the presence of K ATP channels in pulmonary tissue. In vivo, pinacidil (2 mg) significantly reduced pulmonary vascular resistance (PVR) in both controls and CDH animals. GLI (30 mg) significantly increased pulmonary arterial pressure (PAP) and PVR in control animals only. In vitro, pinacidil (10 M) relaxed, precontracted arteries from lambs with and without CDH. GLI (10 Ϫ5 M) did not raise the basal tone of vessels. We conclude that activation of K ATP channels could be of interest to reduce pulmonary vascular tone in fetal lambs with CDH, a condition often associated with persistent pulmonary hypertension of the newborn. (Pediatr Res 60: 537-542, 2006)

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ET_A-receptor blockade and ET_B-receptor stimulation in experimental congenital diaphragmatic hernia

Cited by 31 publications

References 41 publications

Congenital Diaphragmatic Hernia

Congenital Diaphragmatic Hernia

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

Role of ATP-Dependent Potassium Channels in Pulmonary Vascular Tone of Fetal Lambs With Congenital Diaphragmatic Hernia

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ETA-receptor blockade and ETB-receptor stimulation in experimental congenital diaphragmatic hernia

Cited by 31 publications

References 41 publications

Congenital Diaphragmatic Hernia

Congenital Diaphragmatic Hernia

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

Role of ATP-Dependent Potassium Channels in Pulmonary Vascular Tone of Fetal Lambs With Congenital Diaphragmatic Hernia

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ET_A-receptor blockade and ET_B-receptor stimulation in experimental congenital diaphragmatic hernia