The Endothelins in the Pulmonary System

Goldie, Roy G.; Knott, P.G.; Carr, Michael J.; Hay, Douglas W. P.; Henry, Peter J.

doi:10.1006/pulp.1996.0010

Cited by 54 publications

(61 citation statements)

References 62 publications

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“…In human airway smooth muscle cells, endothelin-1 challenge induced a concentration-dependent biphasic increase in [Ca 2+ ] i that was strikingly similar to that observed in rat airway smooth muscle cells and the EC 50 value for the observed dose-dependent peak [Ca 2+ ] i increase was well within the range reported for endothelin-1-induced contractions of human isolated bronchus (Review: Goldie et al, 1996). Endothelin-1-mediated increases in [Ca 2+ ] i were abolished by BQ-123, indicative of ET A receptor activation.…”

Section: +supporting

confidence: 71%

Ca²⁺ signalling by endothelin receptors in rat and human cultured airway smooth muscle cells

Maxwell

Goldie

Henry

1998

British J Pharmacology

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1 The aim of the current study was to characterize the ET receptor subtypes in cultured airway smooth muscle cells derived from rat trachea and human bronchus using radioligand binding techniques and to investigate the coupling of ET receptors to intracellular calcium signalling mechanisms using endothelin receptor-selective agonists (sarafotoxin S6c) and antagonists (BQ-123, BQ-788) and digital image¯uorescence microscopy. 2 Con¯uent rat airway smooth muscle cells in culture possessed a mixed ET receptor population (30% ET A : 70% ET B ), with a density of approximately 3400+280 ET A and 8000+610 ET B receptors/cell (n=3 experiments). The density of ET B , but not ET A receptors increased substantially in serum-containing medium. However, a 2-day period of serum deprivation, which inhibited cellular growth, substantially reduced ET B receptor density such that the ET receptor subtype proportions were approximately equal (55% ET A ; 45% ET B ) and similar to those previously observed in intact rat tracheal smooth muscle. ] i increase was due primarily to the mobilization of IP 3 -sensitive and to a lesser extent ryanodine-sensitive intracellular calcium stores. In contrast, ET B receptor activation was exclusively coupled to extracellular calcium in¯ux. 4 Somewhat surprisingly, human airway smooth muscle cells in culture contained a homogeneous population of ET A receptors at a density of 6100+800 receptors cell 71 (n=3 experiments). Serum deprivation was without eect on either ET receptor subtype proportion or ET A receptor density. Challenge of human airway smooth muscle cells with endothelin-1 provoked a concentrationdependent increase in [Ca 2+ ] i (EC 50 : 15 nM), with a peak [Ca 2+ ] i increase to greater than 700 nM. Furthermore, the ET A -mediated calcium response in these human airway smooth muscle cells in culture was entirely dependent upon the mobilization of calcium from intracellular stores. 5 In summary, rat cultured tracheal airway smooth muscle cells contained both ET A and ET B receptors. ET A receptors, the numbers of which remained constant during cell growth, were linked to the release of Ca 2+ from intracellular stores and a strong rise in [Ca 2+ ] i in the majority of airway smooth muscle cells. In stark contrast, the numbers of ET B receptors increased signi®cantly during cell growth, an eect that was diminished substantially by incubation in serum-free medium. Moreover, despite the greater number of ET B receptors, their activation in a small number of airway smooth muscle cells produced only a weak rise in [Ca 2+ ] i , which appeared to be attributable to the in¯ux of extracellular Ca 2+ . In contrast, the populations of ET receptors and their linkage to [Ca 2+ ] i were markedly dierent in the human cultured airway smooth muscle cells used in the current study compared to that previously observed in intact human isolated bronchial smooth muscle.

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Section: +supporting

confidence: 71%

Ca²⁺ signalling by endothelin receptors in rat and human cultured airway smooth muscle cells

Maxwell

Goldie

Henry

1998

British J Pharmacology

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“…Based upon the presence of ET-1 and its receptors in the lung, the diverse effects of ET-1 in this system, and the effectiveness of ET receptor antagonists in animal models of lung disease, it has been speculated that ET-1 contributes significantly to the pathogenesis of several pulmonary disorders, most notably asthma and pulmonary hypertension (Hay et al 1993;Goldie et al 1996;Michael and Markewitz 1996). A feature of asthma is bronchospasm, and several in vitro and in vivo studies, including in humans, have demonstrated that ET-1 and related peptides cause contraction of airway smooth muscle (Advenier et al 1990;Brink et al 1991;Hay et al 1993;Goldie et al 1995Goldie et al , 1996Michael and Markewitz 1996;Chalmers et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Endothelin receptors and calcium translocation pathways in human airways

Hay¹,

Luttmann²,

Muccitelli³

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

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Tension and phosphatidyl inositol (PI) turnover experiments were conducted to investigate the receptors and signal transduction pathways responsible for contractions elicited by endothelin (ET) ligands in human bronchus. Nicardipine (1 microM), the L-type calcium channel inhibitor, or incubation in Ca2+-free medium, produced marked inhibition of contractions to the ET(B) receptor-selective agonist, sarafotoxin S6c, and especially those induced by KCl. In contrast, Ca2+-free medium was without appreciable effect against contraction produced by endothelin-1 (ET-1), the non-selective ET(A) and ET(B) receptor agonist. In Ca2+-free medium, ryanodine (10 microM), which inhibits intracellular calcium mobilization, reduced sarafotoxin S6c- and ET-1-induced responses, but was without effect on responses to KCl. Similarly, nickel chloride (Ni2+; 1 mM) caused marked inhibition of contractions induced by sarafotoxin S6c or ET-1, but had no significant effect on KCI concentration-response curves. The mixed ET(A)/ET(B) receptor antagonist SB 209670 (3 microM) inhibited responses to sarafotoxin S6c and ET-1 such that concentration-response curves were shifted rightward, at the 30% maximum response level, by 10.0- and 3.8-fold, respectively, whereas BQ-123 (3 microM), the ET(A) receptor antagonist, was without effect on responses induced by either agonist. ET-1 (1 nM-0.3 microM) caused a concentration-dependent stimulation of PI turnover, whereas sarafotoxin S6c (0.3 nM-0.1 microM) induced only small and variable increases, except at the highest concentration. The increase in PI turnover evoked by ET-1 was inhibited by SB 209670 (3 microM), and also by BQ-123 (3 microM). This is consistent with linkage of ET(A) receptors to activation of inositol phosphate generation in human bronchial smooth muscle cells. Collectively, the data suggest that differences exist in the relative contributions of intracellular and extracellular Ca2+ mobilization mechanisms elicited by ET(A) and ET(B) receptor activation. Thus, sarafotoxin S6c-induced, ET(B) receptor-mediated contraction in human bronchial smooth muscle appears to be dependent, in part, upon extracellular Ca2+, although a significant component of the response was also mediated by intracellular Ca2+ release, including from ryanodine-sensitive stores. ET(A) receptor-mediated contraction of human airway smooth muscle was activated largely via the release of intracellular Ca2+.

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“…19 The diseases such as asthma. 36,50 However, if a link between extent of this remodelling has been related to several the ETs and asthma is to be convincingly established, factors, including the frequency of asthma attacks these peptides must mimic most, if not all, of the and duration of symptoms, 21,22 and the extent of infeatures and symptoms of this disease, including airflammatory cell infiltration and activity.…”

Section: Epithelial Damagementioning

confidence: 99%

“…Thus, the obearly speculation of its role in asthma, [34][35][36] and this servation that ET-1 enhanced fibronectin gene exwas further increased when it was recognized that ETpression and fibronectin release following activation 1 was synthesised in and released from the bronchial of ET A receptors in human bronchial epithelial cells, epithelium. [37][38][39][40][41] was an important additional support for the case for Asthma is an inflammatory lung disease.…”

Section: Fibroblast Proliferation Endothelins and Asthma-associatedmentioning

confidence: 99%

Airway Structure in Asthma: A Role for Confocal Microscopy?

Goldie

Fernandes

Rigby

et al. 1998

Pulmonary Pharmacology & Therapeutics

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The Endothelins in the Pulmonary System

Cited by 54 publications

References 62 publications

Ca²⁺ signalling by endothelin receptors in rat and human cultured airway smooth muscle cells

Ca²⁺ signalling by endothelin receptors in rat and human cultured airway smooth muscle cells

Endothelin receptors and calcium translocation pathways in human airways

Airway Structure in Asthma: A Role for Confocal Microscopy?

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The Endothelins in the Pulmonary System

Cited by 54 publications

References 62 publications

Ca2+ signalling by endothelin receptors in rat and human cultured airway smooth muscle cells

Ca2+ signalling by endothelin receptors in rat and human cultured airway smooth muscle cells

Endothelin receptors and calcium translocation pathways in human airways

Airway Structure in Asthma: A Role for Confocal Microscopy?

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Ca²⁺ signalling by endothelin receptors in rat and human cultured airway smooth muscle cells

Ca²⁺ signalling by endothelin receptors in rat and human cultured airway smooth muscle cells