Prolonged endothelin A receptor blockade attenuates chronic pulmonary hypertension in the ovine fetus.

Ivy, D. Dunbar; Parker, Thomas A.; Ziegler, James W.; Galan, Henry L.; Kinsella, John P.; Tuder, Rubin M.

doi:10.1172/jci119274

Cited by 117 publications

(78 citation statements)

References 51 publications

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“…Our results in the neonate are similar to the ones reported in the adult rat, in which BQ-123 and the nonpeptidic ET antagonists, bosentan and TBC11251, were able to reverse hypoxia-induced pulmonary hypertensive changes (22,25,26). A previous demonstration in an ovine fetal preparation had also shown that preventive treatment with BQ-123 could attenuate chronic pulmonary hypertension (27).…”

Section: Discussionsupporting

confidence: 90%

“…Consequently, treatment with TBC3711 may help to counteract some, but not all, of these mechanisms. Although Ivy et al (27) have described improvement of right ventricular hypertrophy after 8 d of preventive treatment with BQ-123 in an ovine model of pulmonary hypertension, complete reversal of right ventricular hypertrophy in our model may take longer. Furthermore, it is unknown, in our model, how the pharmacologic recovery compares with the rate of recovery once exposure to hypoxia is terminated.…”

Section: Discussioncontrasting

confidence: 62%

“…In previous studies, we have shown that chronic hypoxia reduces the synthesis and vasodilator response to NO (18). As shown by Ivy et al (27) in a preventive study with BQ-123, blockade of ET A receptor improves the dilator response to NO. One could argue that this improved dilator response solely reflects changes in vascular remodeling.…”

mentioning

confidence: 55%

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TBC3711, an ETA Receptor Antagonist, Reduces Neonatal Hypoxia-Induced Pulmonary Hypertension in Piglets

et al. 2001

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The pulmonary vasculature of newborns with persistent pulmonary hypertension is characterized by active vasoconstriction and vascular remodeling. It has been suggested that endothelin-1 (ET-1), a potent vasoconstrictor and growth promoter, may be involved in the pathogenesis of persistent pulmonary hypertension of the newborn. To determine whether treatment with an ET A receptor antagonist can reverse pulmonary hypertension in the neonate, 1-d-old piglets were exposed to hypoxia for 3 d to induce pulmonary hypertension and then treated for the remainder of the 14 d with an orally active, nonpeptidic ET A antagonist (TBC3711, 22 mg·kg). At the end of the exposure, Hb, pulmonary artery pressure, right ventricle to left ventricle plus septum weight ratio, percentage wall thickness, ET-1 circulating levels, perfusion pressure, and dilator response to the nitric oxide (NO) donor, SIN-1 (3-morpholinosydnonimine-N-ethylcarbamide) in isolated perfused lungs were determined. Exhaled NO and hemodynamic variables were also examined in an intact anesthetized animal preparation that had undergone the same treatment. By 3 d of exposure to hypoxia, piglets had already developed significant pulmonary hypertension as estimated by their pulmonary artery pressure (24.0 Ϯ 1.3 mm Hg versus 14.2 Ϯ 3.4 mm Hg) and percentage wall thickness (26.6 Ϯ 5.9% versus 18.7 Ϯ 2.4% for vessels 0-30 m). Whereas further exposure to hypoxia for 14 d did not enhance the increase in pulmonary artery pressure and percentage wall thickness, it did augment the right ventricle to left ventricle plus septum weight ratio (0.71 Ϯ 0.09 versus 0.35 Ϯ 0.01). ET-1 circulating levels were increased only when exposure to hypoxia was prolonged to 14 d (5.1 Ϯ 2.4 pg/mL versus 1.0 Ϯ 0.4 pg/mL). Treatment with TBC3711 from d 3 to d 14, once pulmonary hypertensive changes were established and while hypoxic exposure persisted, caused significant reduction in the right ventricle to left ventricle plus septum weight ratio (0.60 Ϯ 0.06), pulmonary artery pressure (20.0 Ϯ 4.8 mm Hg), and percentage wall thickness (18.5 Ϯ 3.3%) and restored the dilator response to the NO donor SIN-1. Prolonged hypoxia markedly reduced exhaled NO concentrations (0.3 Ϯ 0.6 ppb), although treatment of hypoxic animals with TBC3711 restored the concentration of exhaled NO (4.4 Ϯ 2.8 ppb) to the level of normoxic controls (4.9 Ϯ 3.0 ppb). Lastly, treatment with TBC3711 increased ET-1 circulating levels in both the normoxic (5.4 Ϯ 2.8 pg/mL) and hypoxic (13.0 Ϯ 6.3 pg/mL) groups. In conclusion, the specific ET A receptor antagonist, TBC3711, can significantly ameliorate the morphologic changes encountered in hypoxia-induced pulmonary hypertension in the newborn piglet and may improve the dilator response to NO.

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Section: Discussionsupporting

confidence: 90%

Section: Discussioncontrasting

confidence: 62%

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TBC3711, an ETA Receptor Antagonist, Reduces Neonatal Hypoxia-Induced Pulmonary Hypertension in Piglets

et al. 2001

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“…The physiologic role of ET-1 in the fetus and newborn is unclear. Some studies of fetal animals point to a principally vasodilatory action (15,26,27), whereas others favor a predominantly vasoconstrictive effect (14,16). We have previously reported high plasma levels and strong pulmonary expression of ET-1 in newborn piglets, with a fall to adult levels at 3 d of life (7,28).…”

Section: Discussionmentioning

confidence: 96%

Developmental Changes in Endothelial Vasoactive and Angiogenic Growth Factors in the Human Perinatal Lung

Lévy

Maurey²,

Chailley‐Heu

et al. 2005

Pediatr Res

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Little is known of the mechanisms underlying the marked fall in pulmonary vascular resistance that occurs at birth, but changes in the expression of endothelial vasoactive and angiogenic factors during lung development might play a key role. Nitric oxide, endothelin-1, and vascular endothelial growth factor have critical effects on vascular tone and cell growth. Here, we investigated the protein expression of endothelial nitric oxide synthase, endothelin-1 and its receptors, and vascular endothelial growth factor in pulmonary necropsy samples from 14 fetuses of different gestational ages and from 5 infants. Expression of endothelin-1 and its receptor endothelin-A was strong and stable. In contrast, expression of the endothelin-B receptor was weak in early gestation, then increased markedly in mid-gestation and remained high thereafter. The expression of endothelial nitric oxide synthase and vascular endothelial growth factor fell markedly after mid-gestation and remained low thereafter. These data point to a discrepancy between maturational and functional changes in human pulmonary vascular structures. The weak perinatal expression of endothelial nitric oxide could suggest that other potent vasodilatory mediators are responsible for the marked vasodilation observed at birth. During gestation, the placenta ensures the totality of maternofetal gas exchange. Fetal lung development is associated with high PVR, with Ͻ10% of ventricular output entering the lungs. The mechanisms underlying these high PVR in fetal lung are not entirely clear and might involve lack of ventilation, low oxygen pressure, and, possibly, regulated expression of endothelial vasoactive and angiogenic factors with a preponderance of vasoconstrictive ones (1-3). The perinatal transition of gas exchanges from the placenta to the lungs at birth requires a marked and sharp decrease in PVR, allowing the pulmonary blood flow to increase 8-to 10-fold during the first hours of life. The mechanisms underlying this phenomenon have not been elucidated and appear to involve rhythmic distension of the lung, increased oxygenation, shear stress, and changes in vasoactive factor expression (3). In experimental animals, the basal pulmonary vessel tone appears to be tightly regulated by a balance between endothelium-derived mediators, some of which display major vasodilating effects, such as NO, EDHF, and prostacyclin, and some potent vasoconstrictive effects, such as and ET-1 and leukotrienes (4 -10). NO, for instance, produced from L-arginine by the action of a constitutive eNOS, is clearly involved in the postnatal fall in PVR in rats, lambs, and piglets (1,11,12). The effects of ET-1, mediated through two different sets of receptors, ET-A and ET-B, are more ambiguous (13). ET-A, mostly present on vascular smooth muscle cells, mediates vasoconstriction. ET-B, on the other hand, might participate both in the release of vasodilatory mediators such as NO when located on endothelial cells and in vasoconstriction through its location on vascular smooth muscle cells...

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“…45 A Cochrane review of this class of drugs in conjunction with conventional therapy has shown that it can improve the clinical outcomes in adults with idiopathic pulmonary artery hypertension. 46 Almost no experience with ERAs exists in the neonatal population.…”

Section: Endothelin-1 Receptor Antagonists (Bosentan Sitaxsentan)mentioning

confidence: 99%

Role of iNO in the modulation of pulmonary vascular resistance

Bin‐Nun

Schreiber

2008

J Perinatol

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Inhaled nitric oxide (iNO) has quickly become a standard therapy for term and near-term infants with hypoxic respiratory failure and persistent pulmonary hypertension. Its effect on the lung is believed to be through the stimulation of soluble guanylyl cyclase and the increased production of cyclic guanosine 3 0 ,5 0 -monophosphate (cGMP). However, in addition to pulmonary vasodilation and a decrease in pulmonary vascular resistance, nitric oxide (NO) shows several additional potential beneficial effects on the lung. This article reviews NO mechanisms of action, early clinical trial of iNO and clinical aspects for the use of iNO in acute respiratory failure of the term and near-tem neonates.

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Prolonged endothelin A receptor blockade attenuates chronic pulmonary hypertension in the ovine fetus.

Abstract: Based on past studies of an experimental model of severe intrauterine pulmonary hypertension, we hypothesized that endothelin-1 (ET-1) contributes to high pulmonary vascular resistance (PVR), hypertensive lung structural changes, and right ventricular hypertrophy

Cited by 117 publications

References 51 publications

TBC3711, an ETA Receptor Antagonist, Reduces Neonatal Hypoxia-Induced Pulmonary Hypertension in Piglets

TBC3711, an ETA Receptor Antagonist, Reduces Neonatal Hypoxia-Induced Pulmonary Hypertension in Piglets

Developmental Changes in Endothelial Vasoactive and Angiogenic Growth Factors in the Human Perinatal Lung

Role of iNO in the modulation of pulmonary vascular resistance

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