Endothelin receptor antagonists

Motte, Sophie; McEntee, Kathleen; Naeije, Robert

doi:10.1016/j.pharmthera.2005.08.012

Cited by 168 publications

(130 citation statements)

References 331 publications

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“…Besides its vasoconstrictive effects, ET-1 also mediates cardiac and vascular remodeling, including proliferation of vascular smooth muscle cells in chronic disease states. The latter has successfully been treated in models of PH by inhibition of the ET A receptor or dual blockade of both receptors (12). However, in this model we are not able to draw any conclusions on these chronic aspects of ET-1.…”

Section: Discussionmentioning

confidence: 90%

“…It is predominantly released from endothelial cells and mediates its vasoactive properties via two different G protein-coupled receptors, namely the ET A and the ET B receptor (4). With regard to the pulmonary vasculature, the ET A receptor is localized on vascular smooth muscle cells, whereas under normal conditions the ET B receptor is preferentially found on endothelial cells and only to a minor extent on smooth muscle cells of pulmonary vessels (12,17). Both receptors expressed on vascular smooth muscle cells mediate vasoconstriction (9, 19) via activation of phospholipase C. Stimulation of ET B receptors on endothelial cells leads to a release of vasodilating factors, such as nitric oxide and prostacyclin.…”

mentioning

confidence: 99%

“…Moreover, systemic administration of ET-1 blockers has been proven beneficial in experimental and clinical PH (12). However, despite extensive earlier studies on chronic systemic administration of endothelin receptor antagonists (ETRA), the inhalational route has not been investigated so far.…”

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confidence: 99%

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Inhalation of endothelin receptor blockers in pulmonary hypertension

Leuchte

Meis²,

El-Nounou³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Leuchte HH, Meis T, El-Nounou M, Michalek J, Behr J. Inhalation of endothelin receptor blockers in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 294: L772-L777, 2008. First published February 22, 2008 doi:10.1152/ajplung.00405.2007.-Endothelin 1 (ET-1) is a potent pulmonary vasoconstrictor and mediator of lung diseases. Antagonism of the ET-1-mediated effects has become an important therapeutic approach. ET-1 (A and B) receptors are differentially distributed in the lung vasculature. Whereas the ETA receptors mainly mediate vasoconstriction, the endothelial ETB receptor seems to have vasodilative properties. We sought to determine if antagonism of ET receptors can be achieved by inhalation of specific blockers in a model of ET-1-mediated pulmonary hypertension.endothelin-1 ENDOTHELIN-1 (ET-1) is a potent pulmonary vasoconstrictor and mediator of lung diseases. Antagonizing ET-1-mediated effects in the lungs has become an important therapeutic approach. ET-1 causes elevated pulmonary pressures in acute (5, 10, 15) and chronic pulmonary hypertension (PH) (4). Blocking the ET-1 pathway is an established therapy in PH. Since pulmonary vasoconstriction is an important component of the pathophysiology of PH, the application of vasoactive substances has been in focus to attenuate pulmonary artery pressures in pulmonary hypertensive states (21,22). To restrict the action of these substances to the lungs and maximize their deposition, the inhalative route of application has been suggested.ET-1 is one of the most potent endogenous vasoconstrictors in systemic and pulmonary circulation. It is predominantly released from endothelial cells and mediates its vasoactive properties via two different G protein-coupled receptors, namely the ET A and the ET B receptor (4). With regard to the pulmonary vasculature, the ET A receptor is localized on vascular smooth muscle cells, whereas under normal conditions the ET B receptor is preferentially found on endothelial cells and only to a minor extent on smooth muscle cells of pulmonary vessels (12,17). Both receptors expressed on vascular smooth muscle cells mediate vasoconstriction (9, 19) via activation of phospholipase C. Stimulation of ET B receptors on endothelial cells leads to a release of vasodilating factors, such as nitric oxide and prostacyclin. These opposite ET-1-mediated effects suggest an equilibrium between the receptors under normal conditions (12, 16).Besides its acute vasoactive properties, ET-1 is an important smooth muscle and fibroblast mitogen, chemoattractant, and stimulant of collagen synthesis and is a mediator of different lung diseases (3). Consequently, ET-1 is in the scope of extensive work on lung diseases. ET-1 has been shown to be crucially involved in the remodeling in models of chronic proliferating diseases (6) and PH (2,7,26,27). Moreover, systemic administration of ET-1 blockers has been proven beneficial in experimental and clinical PH (12). However, despite extensive earlier studies on chronic systemic administration of endothelin r...

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Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 99%

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Inhalation of endothelin receptor blockers in pulmonary hypertension

Leuchte

Meis²,

El-Nounou³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Long-term administration of an ET A receptor antagonist decreased arterial pressure, normalized endothelial dysfunction in hypertension, ameliorated glomerulosclerosis and vascular and cardiac hypertrophy, independently of blood pressure decrease. 4,9 It also improved endothelium-dependent relaxation and inhibited vascular lesion formation in humans and in animal models of atherosclerosis. 10,11 It has been documented that ET-1 is involved in the interplay between oxidative stress and the development of hypertension-and diabetes-induced cardiovascular complications.…”

Section: Introductionmentioning

confidence: 95%

Carotid atherosclerosis in elderly hypertensive patients: potential role of endothelin and plasma antioxidant capacity

Skalska

Grodzicki

2009

J Hum Hypertens

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Endothelin-1 (ET-1) and oxidative stress are involved in the development of hypertension-induced cardiovascular complications. The aim of this study was to evaluate the relationship between plasma ET-1 level and plasma antioxidant capacity and carotid atherosclerosis. In 61 treated patients with hypertension (44 women, 35 diabetics, mean age 72.4 ± 7.2 years) medical histories, ambulatory blood pressure, blood tests (glucose, creatinine, cholesterol, haemoglobin A1c (HbA1c), ET-1) and common carotid artery intima-media thickness (CCA-IMT) measurement were carried out. Plasma antioxidant capacity was assessed by the ferric-reducing ability of plasma (FRAP). Subjects with diabetes presented with higher concentrations of glucose (7.01 ± 2.3 vs 5.14±0.6 mmol l À1 , Po0.001), HbA1c (7.75±2.1 vs 6.1±1.2%, Po0.001) and ET-1 (1.36±0.53 vs 1.01± 0.4 pg ml À1 , Po0.01), and lower cholesterol level (5.02±0.8 vs 5.86±1.3 mmol l À1 , Po0.01). A significant positive correlation between CCA-IMT and ET-1 plasma concentration (r ¼ 0.40, Po0.001) and reverse relationship between CCA-IMT and FRAP (r ¼ À0.36, Po0.01) was observed. In a stepwise regression analysis, after adjustment for all confounders, CCA-IMT was independently influenced by age, systolic blood pressure (SBP), HbA1c and ET-1. When FRAP was included in the regression model, CCA-IMT was significantly influenced by age, FRAP, HbA1c and SBP. ET-1 promotes the increase in CCA-IMT contributing to the development of end-organ damage. Plasma antioxidant capacity may modulate this deleterious effect, but whether better antioxidant defence may prevent against the development of atherosclerosis remains to be elucidated.

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“…The ECMs of the cervix, fetal membranes, placenta and uterus are comprised mainly of collagen types I and III. Investigators have shown that a remodeling of these collagens, mediated by the MMPs, may play a role in the pathway leading to birth (14). Using cDNA microarray analysis of human placental tissue, we recently showed that human placental matrix metalloproteinase-1 (MMP-1) is upregulated in labor (15).…”

Section: Introductionmentioning

confidence: 99%

Prevention of Inflammation-Associated Preterm Birth by Knockdown of the Endothelin-1-Matrix Metalloproteinase-1 Pathway

Wang

Yen

Chen

et al. 2010

Mol Med

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Premature delivery occurs in 12% of all births, accounts for nearly half of neonatal morbidity and is increasing in frequency. Current therapeutic approaches to preterm delivery are ineffective and present serious risks to both the mother and fetus. Although there are multiple factors that contribute to the etiology of preterm birth, the single most common cause is infection. Recently, using cDNA microarray analysis of human placental tissue, we demonstrated that human placental matrix metalloproteinase-1 (MMP-1) is upregulated during labor. In a separate line of investigation, we have shown that blockade of endothelin-1 (ET-1) action through the use of an endothelin-converting enzyme-1 (ECE-1) inhibitor, an established commercially available endothelin receptor antagonist or a novel quinolone-derived endothelin receptor antagonist synthesized by our group also prevents preterm labor and delivery in a mouse model. We have now shown that induction of preterm labor with lipopolysaccharide in our mouse model is associated with increased levels of MMP-1. Furthermore, we showed that silencing the ECE-1/ET-1 pathway by using ECE-1 RNA interference prevents both the onset of preterm labor and upregulation of MMP-1. The data indicate that ET-1 and MMP-1 act in the same molecular pathway in preterm labor.

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Endothelin receptor antagonists

Cited by 168 publications

References 331 publications

Inhalation of endothelin receptor blockers in pulmonary hypertension

Inhalation of endothelin receptor blockers in pulmonary hypertension

Carotid atherosclerosis in elderly hypertensive patients: potential role of endothelin and plasma antioxidant capacity

Prevention of Inflammation-Associated Preterm Birth by Knockdown of the Endothelin-1-Matrix Metalloproteinase-1 Pathway

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