Emergence of Smooth Muscle Cell Endothelin B–Mediated Vasoconstriction in Lambs With Experimental Congenital Heart Disease and Increased Pulmonary Blood Flow

Black, Stephen M.; Mata‐Greenwood, Eugenia; Dettman, Robert W.; Ovadia, Boaz; Fitzgerald, Robert D.; Reinhartz, Olaf; Thelitz, Stefan; Steinhorn, Robin H.; Gerrets, Rene P.; Hendricks‐Muñoz, Karen D.; Ross, Gregory A.; Bekker, Janine M.; Johengen, Michael J.; Fineman, Jeffrey R.

doi:10.1161/01.cir.0000087596.01416.2f

Cited by 70 publications

(47 citation statements)

References 34 publications

(48 reference statements)

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“…Aberrant expression of the ETB receptor has been demonstrated in the vascular smooth muscle layer in adults with PH (53) and infants with CDH and PH (32). Lambs with PH and abnormal reactivity have similar findings (54), but rats exposed to chronic exogenous ET1 resolve aberrant ETB receptor expression while abnormal vascular reactivity persists (55). Thus, in our patients, changes in pulmonary clearance or production of ET1 could explain the fall in plasma ET1 levels we observed.…”

Section: Discussionsupporting

confidence: 58%

Congenital Diaphragmatic Hernia

Keller

Tacy²,

Hendricks‐Muñoz³

et al. 2010

Am J Respir Crit Care Med

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136

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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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Section: Discussionsupporting

confidence: 58%

Congenital Diaphragmatic Hernia

Keller

Tacy²,

Hendricks‐Muñoz³

et al. 2010

Am J Respir Crit Care Med

Self Cite

136

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“…The ET-B receptor is overexpressed in overcirculation-induced PAH models (4,5,13). However, the pathogenetic role of the ET-B receptor in PAH remains undefined, as both the nonselective ET-A/B receptor blocker bosentan and the selective ET-A blockers sitaxsentan and ambrisentan similarly improved PAH patients in randomized controlled trials (14 -16).…”

mentioning

confidence: 99%

“…The ET system is activated in patients with advanced PAH, who present with increased circulating levels of ET-1 (21)(22)(23) and an overexpression of lung tissue ET-1 (23). In overcirculation-induced PAH, there is also an overexpression of the ET-B receptor, while the expression of the ET-A receptor remains unchanged (4,5,13). In hypoxic pulmonary hypertension, both the ET-A and the ET-B receptors are overexpressed, and lung tissue ET-1 mRNA and circulating ET-1 are increased (24).…”

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confidence: 99%

Sitaxsentan for the Prevention of Experimental Shunt-Induced Pulmonary Hypertension

et al. 2007

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ABSTRACT:We previously reported on the partial prevention of experimental shunt-induced pulmonary arterial hypertension (PAH) by the nonselective endothelin (ET) ET-A/ET-B receptor antagonist bosentan. As the respective roles of the ET-A and ET-B receptor signaling in the pathobiology of the disease remain undefined, we investigated the effects of selective ET-A receptor blockade by sitaxsentan in the same early stage PAH model. Twenty-one 3-wkold piglets were randomized to placebo or sitaxsentan therapy (1.5 mg/kg/d), after anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry and real-timequantitative-PCR for ET-1, angiopoietin-1, and bone morphogenetic receptor (BMPR) signaling molecules. Three months of left to right shunting induced an increase in pulmonary vascular resistance (PVR) and medial thickness, an overexpression of ET-1, ET-B receptor, and angiopoietin-1, and a decreased expression of BMPR-2 and BMPR-1A. Pretreatment with sitaxsentan prevented shunt-induced increase in PVR and decreased medial thickness by 64%. Sitaxsentan therapy completely prevented the decreased expression of BMPR-2 and limited the overexpression of ET-1, ET-B and angiopoietin-1, and the decreased expression of BMPR-1A. In conclusion, selective ET-A receptor blockade partially prevents shunt-induced PAH. T he pathogenesis of PAH remains incompletely understood (1,2). Because of the therapeutic efficacy of ET receptor blockers, and because BMPR-2 mutation is associated with a high risk to develop the disease, the ET and BMP signaling pathways are each thought to play a major role in the pathobiology of PAH (1,2). We previously reported on a left-toright shunt-induced pulmonary hypertension in piglets as a model for the study of early stage PAH (3-5). This model is characterized by an increase of PVR, medial hypertrophy of the small arterioles, and overexpression of ET-1, ET-B, and Ang-1, together with decreased expressions of BMPR-2 and BMPR-1A (4,5). Thus, both endothelin and BMP signaling are involved in the early stages of PAH (4,5).ET-1 interacts with ET-A and the ET-B receptors on pulmonary vascular smooth muscle cells to induce constriction and proliferation (6 -9), and with ET-B receptors on pulmonary artery endothelial cells for nitric oxide (NO) modulation of endothelin synthesis (10), endothelin clearance (11), and release of NO and prostacyclin (12). The ET-B receptor is overexpressed in overcirculation-induced PAH models (4,5,13). However, the pathogenetic role of the ET-B receptor in PAH remains undefined, as both the nonselective ET-A/B receptor blocker bosentan and the selective ET-A blockers sitaxsentan and ambrisentan similarly improved PAH patients in randomized controlled trials (14 -16). We observed that bosentan therapy prevented the increase in PVR and approximately 70% of pulmonary arteriolar remodeling in growing piglets with a left-to-rig...

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“…For example, in a lamb model of increased pulmonary blood flow, created by a systemic to pulmonary shunt, ET B localization to smooth-muscle cells increased by 8 weeks of age, with an associated increase in ET B -receptor-mediated pulmonary vasoconstriction. 180 Moreover, Bauer and colleagues found that ET B -receptors were selectively up-regulated and appeared to be localized to the hypertrophied medial layer of pulmonary arteries in 14 patients undergoing pulmonary thromboendarterectomy for chronic thromboembolic PH. 181 Two oral ET A -receptor antagonists have been studied for the treatment of PH: sitaxsentan and ambrisentan.…”

Section: Nitric Oxide-cgmp Cascade: Inhaled Nitric Oxidementioning

confidence: 99%

Advances in the Management of Pediatric Pulmonary Hypertension

2011

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Pulmonary hypertension is a rare disease in neonates, infants, and children, and is associated with substantial morbidity and mortality. An adequate understanding of the controlling pathophysiologic mechanisms is lacking. Moreover, a minority of research is focused specifically on neonatal and pediatric populations. Although therapeutic options have increased over the past several decades, they remain limited. In advanced pulmonary hypertension, progressive pulmonary vascular functional and structural changes ultimately cause increased pulmonary vascular impedance, rightventricular failure, and death. Management includes the prevention and/or treatment of active pulmonary vasoconstriction, the support of right-ventricle function, treatment of the underlying disease (if possible), and the promotion of regressive remodeling of structural pulmonary vascular changes. Most currently available therapies augment or inhibit factors, or mediators of their downstream signaling cascades, that originate in the pulmonary vascular endothelium. These pathways include nitric-oxide/cyclic guanosine monophosphate (cGMP), prostacyclin, and endothelin-1. The ability to reverse advanced structural changes remains an as yet unattained goal. This paper reviews the epidemiology, pathophysiology, current treatments, and emerging therapies related to neonatal and pediatric pulmonary hypertension.

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Emergence of Smooth Muscle Cell Endothelin B–Mediated Vasoconstriction in Lambs With Experimental Congenital Heart Disease and Increased Pulmonary Blood Flow

Cited by 70 publications

References 34 publications

Congenital Diaphragmatic Hernia

Congenital Diaphragmatic Hernia

Sitaxsentan for the Prevention of Experimental Shunt-Induced Pulmonary Hypertension

Advances in the Management of Pediatric Pulmonary Hypertension

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