Endothelin Receptor Subtypes: Distribution and Function in the Lung

Goldie, Roy G.

doi:10.1006/pupt.1998.0124

Cited by 18 publications

(17 citation statements)

References 12 publications

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“…The cellular sources of the endothelins include the epithelium, endothelium, macrophages, and neuroendocrine cells [5,6]. Endothelins act in a paracrine or autocrine fashion and exert their biological effects via two receptor subtypes: ET A and ET B [6].…”

Section: Inhaled Endothelin a Antagonist Improves Arterial Oxygenatiomentioning

confidence: 99%

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Inhaled endothelin A antagonist improves arterial oxygenation in experimental acute lung injury

et al. 2000

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Section: Inhaled Endothelin a Antagonist Improves Arterial Oxygenatiomentioning

confidence: 99%

“…Endothelins act in a paracrine or autocrine fashion and exert their biological effects via two receptor subtypes: ET A and ET B [6]. ET A receptors are expressed in the lung mainly on airway and vascular smooth muscle cells.…”

Section: Inhaled Endothelin a Antagonist Improves Arterial Oxygenatiomentioning

confidence: 99%

Inhaled endothelin A antagonist improves arterial oxygenation in experimental acute lung injury

et al. 2000

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“…Elevated plasma levels of ET-1 have been reported previously in these animals, 11 presumably a result of reduced ET clearance from the circulation because of the ET-B receptor deficiency. Similar mechanisms likely operate within the lung parenchyma itself, given that normal rats express the ET-B receptor in their alveolar walls 26 and that the sl/sl rat has virtually no functional ET-B receptors in the lung, as demonstrated by radioligand binding assays. 11 That hypoxia increased lung ET content in the transgenic control animals also agrees with previous studies showing that hypoxia can increase lung ET content by increasing preproendothelin gene transcription.…”

Section: Discussionmentioning

confidence: 86%

Endothelin B Receptor Deficiency Predisposes to Pulmonary Edema Formation via Increased Lung Vascular Endothelial Cell Growth Factor Expression

Carpenter

Schomberg

Steudel

et al. 2003

Circulation Research

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Abstract-Endothelin (ET) may contribute to pulmonary edema formation, particularly under hypoxic conditions, and decreases in ET-B receptor expression can lead to reduced ET clearance. ET increases vascular endothelial cell growth factor (VEGF) production in vitro, and VEGF overexpression in the lung causes pulmonary edema in vivo. We hypothesized that pulmonary vascular ET-B receptor deficiency leads to increased lung ET, that excess ET increases lung VEGF levels, promoting pulmonary edema formation, and that hypoxia exaggerates these effects. We studied these hypotheses in ET-B receptor-deficient rats. In normoxia, homozygous ET-B-deficient animals had significantly more lung vascular leak than heterozygous or control animals. Hypoxia increased vascular leak regardless of genotype, and hypoxic ET-B-deficient animals leaked more than hypoxic control animals. ET-B-deficient animals had higher lung ET levels in both normoxia and hypoxia. Lung HIF-1␣ and VEGF content was greater in the ET-B-deficient animals in both normoxia and hypoxia, and both HIF-1␣ and VEGF levels were reduced by ET-A receptor antagonism. Both ET-A receptor blockade and VEGF antagonism reduced vascular leak in hypoxic ET-B-deficient animals. We conclude that ET-B receptor-deficient animals display an exaggerated lung vascular protein leak in normoxia, that hypoxia exacerbates that leak, and that this effect is in part attributable to an ET-mediated increase in lung VEGF content. Key Words: hypoxia Ⅲ vascular permeability Ⅲ albumin extravasation Ⅲ HIF-1␣ P ulmonary edema, characterized by leakage of intravascular proteins into the airspaces, occurs in many clinical conditions, including respiratory infections and acute respiratory distress syndrome (ARDS). The basic mechanisms leading to increased vascular permeability and pulmonary edema formation in these circumstances remain uncertain. Some evidence suggests that the vasoconstrictor peptide endothelin (ET) may contribute to this phenomenon. For example, patients with ARDS have elevated plasma levels of ET, 1,2 and infusion of ET causes pulmonary edema formation in isolated perfused rat lungs. 3,4 Also, ET receptor antagonists ameliorate experimental pulmonary vascular leak caused by oleic acid, leukotoxin, or exposure to hypoxia after viral infection. [5][6][7] Exposure to hypoxia alone also leads to increased lung water in some species, including the development of high-altitude pulmonary edema (HAPE) in humans. The mechanisms by which exposure to hypoxia leads to pulmonary edema formation also remain uncertain, although at least in humans intense pulmonary vasoconstriction and elevated pulmonary artery pressures are thought to be critical factors. ET, a potent pulmonary vasoconstrictor, also may contribute to the pathogenesis of HAPE, given that plasma ET levels are elevated in humans with HAPE. 8,9 ET acts through two receptor subtypes, the ET-A and ET-B receptors. Activation of vascular ET-A receptors leads to vasoconstriction, whereas activation of vascular ET-B receptors leads to eith...

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“…ET-1 is synthesized and metabolized in lung, and ET-1 receptors (ET A and ET B ) are widely distributed in airway cells (21,26,41). ET-1 is one of the most potent contractile agents of human airway smooth muscle and can induce airway inflammation, airway hyperresponsiveness, and airway remodeling in animals and humans (25,26,27,41), suggesting that ET-1 could be a major component of asthma pathophysiology (10,22,26,27).…”

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confidence: 99%

In vitro sensitization of human bronchus by β₂-adrenergic agonists

Faisy¹,

Naline²,

Diehl

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Ϫ7 M fenoterol induced sensitization characterized by an increase in maximal contraction to endothelin-1 (ET-1) and acetylcholine (ACh). Incubation of human bronchi with 10 Ϫ6 , 3 ϫ 10 Ϫ6 , and 10 Ϫ5 M forskolin (an adenyl cyclase activator) reproduced sensitization to ET-1 and ACh. The sensitizing effect of fenoterol was inhibited by coincubation with gliotoxine (a nuclear factor-B inhibitor), dexamethasone, indomethacin (a cyclooxygenase inhibitor), GR-32191 (a TP prostanoid receptor antagonist), MK-476 (a cysteinyl leukotriene type 1 receptor antagonist), SR-140333 ϩ SR-48968 ϩ SR-142801 (neurokinin types 1, 2, and 3 tachykinin receptor antagonists) with or without HOE-140 (a bradykinin B 2 receptor antagonist), SB-203580 (an inhibitor of the 38-kDa mitogen-activated protein kinase, p38 MAPK ), or calphostin C (a protein kinase C blocker). Our results suggest that chronic exposure to fenoterol induces proinflammatory effects mediated by nuclear factor-B and pathways involving leukotrienes, prostanoids, bradykinin, tachykinins, protein kinase C, and p38 MAPK , leading to the regulation of smooth muscle contraction to ET-1 and ACh.␤ 2-agonists; airway sensitization; airway smooth muscle; endothelin-1; asthma THE FATAL ACUTE ASTHMA CASES attributable to fenoterol abuse in the 1980s in New Zealand started a controversy concerning the potential worsening of the bronchial hyperresponsiveness by the ␤ 2 -adrenoceptor agonists (7,14,42). Studies in animals and humans showed that chronic exposure to fenoterol or salbutamol induces a nonspecific bronchial sensitization, whereas the relaxant effects of these ␤ 2 -agonists on the airway smooth muscle are not decreased (11,59,60). The bronchial sensitization induced by fenoterol is similar to the sensitization provoked by ovalbumin in sensitized guinea pigs (60). Chronic administration of salbutamol at low doses to guinea pigs increases airway reactivity to histamine and methacholine (11). In humans, long-term use of salbutamol increases the bronchial hyperresponsiveness to histamine but does not cause subsensitization of ␤ 2 -adrenoceptors to salbutamol (59). In a bovine tracheal model, Katsunuma and colleagues (36) showed that prolonged incubation with fenoterol induced an increased contractile responsiveness to neurokinin A (NKA). In 1995, Peters and colleagues (47) suggested that the continuous activation of the intracellular signal transduction caused by the ␤ 2 -adrenoceptor stimulation could induce a proinflammatory process mediated by nuclear transcription factors in rat lung. A recent study in our institution showed that the transcription factor nuclear factor-B (NF-B) is involved in fenoterol-induced hyperresponsiveness to NKA in guinea pig isolated trachea (52).Endothelin-1 (ET-1) is a 21-amino acid peptide recently implicated in chronic inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease (25,26,41,46). ET-1 is synthesized and metabolized in lung, and ET-1 receptors (ET A and ET B ) are widely distributed in airway cells (21,26...

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Endothelin Receptor Subtypes: Distribution and Function in the Lung

Cited by 18 publications

References 12 publications

Inhaled endothelin A antagonist improves arterial oxygenation in experimental acute lung injury

Inhaled endothelin A antagonist improves arterial oxygenation in experimental acute lung injury

Endothelin B Receptor Deficiency Predisposes to Pulmonary Edema Formation via Increased Lung Vascular Endothelial Cell Growth Factor Expression

In vitro sensitization of human bronchus by β₂-adrenergic agonists

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Endothelin Receptor Subtypes: Distribution and Function in the Lung

Cited by 18 publications

References 12 publications

Inhaled endothelin A antagonist improves arterial oxygenation in experimental acute lung injury

Inhaled endothelin A antagonist improves arterial oxygenation in experimental acute lung injury

Endothelin B Receptor Deficiency Predisposes to Pulmonary Edema Formation via Increased Lung Vascular Endothelial Cell Growth Factor Expression

In vitro sensitization of human bronchus by β2-adrenergic agonists

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In vitro sensitization of human bronchus by β₂-adrenergic agonists