Sustained effects of endothelin-1 on rabbit, dog, and rat pulmonary circulations

Barnard, J. W.; Barman, Scott A.; Adkins, W. K.; Longenecker, Gesina L.; Taylor, Aubrey E.

doi:10.1152/ajpheart.1991.261.2.h479

Cited by 24 publications

(20 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During the dose-response part of our study, ET-1 caused severe systemic and pulmonary vasoconstriction, lung edema, reduced cardiac performance, and bradycardia, consistent with the findings of other investigators (34,35). Tezosentan attenuated the ET-induced deterioration of hemodynamics most efficiently at infusion rates of 1 and 2 mg·kg Ϫ1 ·hr Ϫ1 , Figure 5.…”

Section: Discussionsupporting

confidence: 90%

Novel endothelin receptor antagonist attenuates endotoxin-induced lung injury in sheep

Kuklin

Киров

Evgenov

et al. 2004

Critical Care Medicine

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 90%

Novel endothelin receptor antagonist attenuates endotoxin-induced lung injury in sheep

Kuklin

Киров

Evgenov

et al. 2004

Critical Care Medicine

View full text Add to dashboard Cite

show abstract

“…A subtype of the ET B receptor (ET B2 ) present on vascular smooth muscle cells also mediates vasoconstriction (10). The biologic actions of ET-1 vary depending on age (11), vascular bed, dosage (12), and species (13). Specifically, ET-1 has many different functions in the fetus and neonate compared with the adult.…”

mentioning

confidence: 99%

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

et al. 2005

View full text Add to dashboard Cite

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...

show abstract

“…Disorders such as bronchopulmonary dysplasia are also associated with elevated pulmonary pressures and pulmonary vascular remodeling in infants (2). Endothelin-1 (ET-1) is a 21-amino acid polypeptide with strong vasoactive properties that vary depending on age (3), vascular bed, dosage (4), and species (5). ET-1 acts via two different receptors in the vascular bed, ET A and ET B .…”

mentioning

confidence: 99%

Endothelin-A Receptor Blockade in Porcine Pulmonary Hypertension

et al. 2002

View full text Add to dashboard Cite

Endothelin-1 can cause pulmonary vasoconstriction via endothelin-A (ET A ) receptor activation. We hypothesized that ET A blockers (EMD 122946 and BQ 610) would reduce hypoxiainduced (HYP) but not group B streptococcal infusion (GBS)-induced pulmonary hypertension in a juvenile whole animal model. Pulmonary hypertension was created by exposing chronically instrumented piglets to HYP (n ϭ 12) or heat-killed GBS (n ϭ 11). ET A blockade was produced by increasing bolus doses of EMD122946 or BQ 610. Pulmonary arterial pressure (PAP), systemic arterial pressure (SAP), left atrial pressure, central venous pressure, and cardiac output were continuously measured. Pulmonary and systemic vascular resistance indices (PVRI and SVRI) were calculated. HYP doubled PAP and PVRI. Both ET A blockers decreased PAP and PVRI in a dose-dependent manner in HYP, with high doses decreasing PVRI to baseline and reducing PAP by 50%. GBS also doubled both PAP and PVRI. EMD 122946 did not change PAP or PVRI in GBS, although BQ 610 markedly increased PVRI (Ͼ100% increase with 0.15 mg/kg) and showed a trend toward increasing PAP. Both models showed minimal (Ͻ25%) changes in SAP or SVRI.Neither ETA blocker changed baseline hemodynamics in the absence of HYP or GBS. PaO 2 did not change with GBS but decreased with BQ 610. ET A receptor blockade attenuated hypoxic, but not GBS induced pulmonary hypertension. BQ 610 worsened PVRI and oxygenation in the GBS model. Differences in response to ET A blockade in pulmonary hypertension may be seen depending on the etiology (hypoxia versus infectionassociated), and the specific ET A antagonist used. Persistent pulmonary hypertension of the newborn (PPHN) affects over 10,000 infants every year in the United States (1) and is associated with considerable morbidity and mortality. Prenatal hypoxia may predispose to PPHN (1). Disorders such as bronchopulmonary dysplasia are also associated with elevated pulmonary pressures and pulmonary vascular remodeling in infants (2). Endothelin-1 (ET-1) is a 21-amino acid polypeptide with strong vasoactive properties that vary depending on age (3), vascular bed, dosage (4), and species (5). ET-1 acts via two different receptors in the vascular bed, ET A and ET B . In the pulmonary artery, ET A receptors mediate vasoconstriction and are found on vascular smooth muscle cells, while ET B receptors that are mostly located on endothelial cells mediate vasodilation (6). There is substantial evidence that ET-1 is elevated in neonates, infants (7-9), and older children (10) with pulmonary hypertension, and is a marker of disease severity. Animal studies have also indicated that ET-1 may play a role in the pathogenesis of neonatal pulmonary hypertension due to hypoxia (11), meconium aspiration (12), and increased pulmonary blood flow (13). Therefore, there has been interest in endothelin receptor blockade as a possible therapy for pediatric pulmonary hypertension.Our previous studies have shown that selective ET A receptor antagonists attenuate acute hypoxic pulmonary hypertensio...

show abstract

Sustained effects of endothelin-1 on rabbit, dog, and rat pulmonary circulations

Cited by 24 publications

References 0 publications

Novel endothelin receptor antagonist attenuates endotoxin-induced lung injury in sheep

Novel endothelin receptor antagonist attenuates endotoxin-induced lung injury in sheep

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

Endothelin-A Receptor Blockade in Porcine Pulmonary Hypertension

Contact Info

Product

Resources

About