Endothelin-A Receptor Blockade in Porcine Pulmonary Hypertension

Ambalavanan, Namasivayam; Philips, Joseph B.; Bulger, Arlene; Oparil, Suzanne; Chen, Yiu-Fai

doi:10.1203/00006450-200212000-00017

Cited by 15 publications

(15 citation statements)

References 39 publications

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“…The administration of BQ-123 in our study resulted in a further increase in plasma ET-1 despite a fall in PVR. This pattern of response has been demonstrated by others in acute and chronic models of hypoxic pulmonary hypertension (18,29), the proposed mechanism being an increase in "unbound" ET-1 after receptor blockade.…”

Section: Discussionsupporting

confidence: 69%

“…There are no published studies that compare the clinical effects of ET-A receptor antagonists with iNO in acute pulmonary hypertension, and a single published study has examined the combined influences of ET-A receptor blockade and iNO in an acute hypoxic pulmonary hypertension. In this model, receptor blockade reduced PVR, and this fell further with the addition of iNO (29).…”

Section: Discussionmentioning

confidence: 69%

“…No animal had an intracardiac shunt, which could potentially influence (or limit) any acute effect of an intravenous pulmonary vasodilator upon oxygenation. However, a number of previous investigations of pulmonary vasodilators in models of acute pulmonary hypertension (27,29,41) and, specifically, therapies for meconium aspiration syndrome (42,43) have been explored in more mature animals. Indeed, having demonstrated an acute rise in ET-1 levels coincident with an increase in PVR after meconium aspiration, it would seem appropriate to investigate the subsequent actions of an ET-A receptor antagonist in our model.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

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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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“…Our previous studies showed that selective ET A receptor antagonists attenuate acute hypoxia-induced, but not group B streptococcal-induced, pulmonary hypertension in juvenile piglets (18). We have also shown that selective ET A receptor antagonists attenuate and reverse chronic hypoxic pulmonary hypertensive vascular and cardiac changes in adult rats (19,20).…”

mentioning

confidence: 81%

“…A dose of 5 L was used for the first 5 d of life, followed by 10 L from d 6 to 10 and 15 L from d 11 to 14. BQ610 was chosen as the ET A antagonist as we had previously noted its efficacy in the juvenile piglet model of hypoxia-induced pulmonary hypertension (18). Cottonseed oil was used as the vehicle and intraperitoneal administration was done to slow the release and obtain a prolonged effect.…”

Section: Methodsmentioning

confidence: 99%

Endothelin-A Receptor Blockade Prevents and Partially Reverses Neonatal Hypoxic Pulmonary Vascular Remodeling

et al. 2005

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Hypoxia-induced pulmonary vascular remodeling (HPVR) may lead to persistent pulmonary hypertension of the newborn or cor pulmonale. Endothelin-1 (ET-1), via endothelin-A (ET A ) receptor activation, mediates hypoxic pulmonary vasoconstriction. Our objectives were to develop a newborn mouse model of HPVR and to test the hypothesis that ET A blockade would prevent and reverse HPVR in this model. C57BL/6 mice (n ϭ 64) were exposed to 12% oxygen (HYP group) or room air (RA group) from birth to 2 wk of age. The mice were injected intraperitoneally daily with either BQ-610 (ET A blocker) or vehicle (cottonseed oil) from birth (prevention study) or from 6 d of age (reversal study). HPVR was assessed histologically by pulmonary vascular morphometry by an examiner masked to study group, and by measurement of the right ventricle to left ventricle (RV/LV) thickness ratio. Hypoxia increased medial wall thickness (%WT) in pulmonary arteries Ͻ100 m in diameter and RV/LV thickness ratio. BQ-610 prevented the hypoxiainduced increase in %WT and RV/LV thickness ratio when given from birth, and later therapy partially reversed the hypoxiainduced increase in %WT but not RV/LV thickness ratio. These data show that in the newborn mouse model, chronic hypoxia leads to HPVR that can be completely prevented and partially reversed by ET A blockade. These results indicate that ET-1, acting via ET A receptors, is a mechanism of pathophysiologic significance underlying neonatal HPVR. Development of this newborn mouse model of HPVR facilitates investigation of mechanisms underlying this important and severe disease entity in human infants. In human neonates, chronic hypoxemia increases muscularity of the pulmonary arteries and extends muscularity to more distal arteries (1). Fetal (2) and neonatal (3,4) hypoxemia also leads to pulmonary vascular remodeling in animal models. This pulmonary vascular remodeling may predispose to pulmonary vasoconstriction and PPHN in response to normal changes in oxygenation and acid-base status occurring during labor and early neonatal life. PPHN affects more than 10,000 infants every year in the United States (5) and is associated with considerable morbidity and mortality. Disorders such as bronchopulmonary dysplasia that affect extremely premature newborn infants are also associated with elevated pulmonary arterial pressures and pulmonary vascular remodeling (6). Congenital heart diseases associated with hypoxemia and/or increased pulmonary blood flow may also result in hypoxia-or high flow-induced pulmonary vascular remodeling (7,8). In a newborn piglet model, increased vascular smooth muscle tone was the primary cause of elevated pulmonary pressure following 3-5 d of hypoxia exposure, while with longer hypoxia exposure (10 -12 d), structural changes in the pulmonary arteries contributed to the elevated pulmonary arterial pressure (4).ET-1 is a 21-amino acid polypeptide with strong vasoactive properties that acts via two major receptor isoforms in the vascular bed, ET A and ET B . In the pulmonary artery, E...

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Pathophysiologic mechanisms of persistent pulmonary hypertension of the newborn

Dakshinamurti

2005

Pediatric Pulmonology

124

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Persistent pulmonary hypertension of the newborn (PPHN), among the most rapidly progressive and potentially fatal of vasculopathies, is a disorder of vascular transition from fetal to neonatal circulation, manifesting as hypoxemic respiratory failure. PPHN represents a common pathway of vascular injury activated by numerous perinatal stresses: hypoxia, hypoglycemia, cold stress, sepsis, and direct lung injury. As with other multifactorial diseases, a single inciting event may be augmented by multiple concurrent/subsequent phenomena that result in differing courses of disease progression. I review the various mechanisms of vascular injury involved in neonatal pulmonary hypertension: endothelial dysfunction, inflammation, hypoxia, and mechanical strain, in the context of downstream effects on pulmonary vascular endothelial-myocyte interactions and myocyte phenotypic plasticity.

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Endothelin-A Receptor Blockade in Porcine Pulmonary Hypertension

Cited by 15 publications

References 39 publications

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

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

Endothelin-A Receptor Blockade Prevents and Partially Reverses Neonatal Hypoxic Pulmonary Vascular Remodeling

Pathophysiologic mechanisms of persistent pulmonary hypertension of the newborn

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