Circulatory effects of endothelin in newborn piglets

Bradley, Linda M.; Czaja, J. F.; Goldstein, Robert E.

doi:10.1152/ajpheart.1990.259.5.h1613

Cited by 14 publications

(16 citation statements)

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“…Though appealing, however, this concept is in apparent contrast with recent studies in vivo and the perfused organ in vitro, in which ET-1 proved to be primarily, and under certain conditions exclusively, a dilator of the perinatal pulmonary circulation. [3][4][5][6] In one of the in vivo studies,4 ET-1 action was conditioned by the tone of the vasculature, with dilatation occurring prenatally and constriction becoming prominent postnatally. Theoretically, several facts could explain this apparent inconsistency: 1) Isolated vessels lack a viable endothelium and, consequently, are unable to produce dilator agents, such as nitric oxide and PGI2, in response to ET-1.36 2) Contractile tone in vitro is inadequate for the expression of receptors mediating vasodilatation.…”

Section: Effects Of Endothelin-1mentioning

confidence: 99%

Isolated pulmonary resistance vessels from fetal lambs. Contractile behavior and responses to indomethacin and endothelin-1.

Wang

Coceani

1992

Circulation Research

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A method was developed for recording isometric tension from isolated small arteries (mean internal diameter, 169 microns) and veins (mean internal diameter, 273 microns) of the term fetal lung and was then applied to the study of the mechanisms controlling perinatal pulmonary hemodynamics. The specific purpose was to determine whether the activity of the prostaglandin synthetic system in vessels is conditioned by the oxygen tension and the mode of action of endothelin-1. Both preparations appeared structurally intact and, after normalizing their lumen diameter to either the transmural pressure in vivo (artery) or the contractile capacity of the vessel in vitro (vein), generated force to the activating solution (5 mM Ca2+ in K+ Krebs' solution) in excess of the expected performance under physiological conditions. Treatment with indomethacin (2.8 microM) had no effect on arteries preequilibrated at low PO2 (21 +/- 1 mm Hg); however, the same treatment contracted (approximately 45% of the response to activating solution) arteries at either an intermediate (40 +/- 0.8 mm Hg) or high (70 +/- 0.9 mm Hg) PO2. Endothelin-1 contracted both arteries and veins in a concentration-dependent manner, the threshold being lower with veins (1-10 versus 10-100 pM). Endothelin-1 constriction was also seen in arteries whose tone had been raised with a thromboxane A2 analogue, whereas in thromboxane-treated veins constriction was preceded by a modest relaxation over the range of 1-1,000 pM. The findings with indomethacin lead us to infer that small pulmonary arteries are endowed with a prostaglandin-relaxing mechanism that becomes functional on raising the PO2 from fetal to neonatal levels. Endothelin-1 is a constrictor regardless of the level of intrinsic tone, suggesting a possible role of the peptide in maintaining elevated pulmonary vascular tone in the fetus.

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Section: Effects Of Endothelin-1mentioning

confidence: 99%

Isolated pulmonary resistance vessels from fetal lambs. Contractile behavior and responses to indomethacin and endothelin-1.

Wang

Coceani

1992

Circulation Research

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“…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.…”

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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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“…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 .…”

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Endothelin-A Receptor Blockade in Porcine Pulmonary Hypertension

et al. 2002

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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...

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Circulatory effects of endothelin in newborn piglets

Cited by 14 publications

References 0 publications

Isolated pulmonary resistance vessels from fetal lambs. Contractile behavior and responses to indomethacin and endothelin-1.

Isolated pulmonary resistance vessels from fetal lambs. Contractile behavior and responses to indomethacin and endothelin-1.

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

Endothelin-A Receptor Blockade in Porcine Pulmonary Hypertension

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