Receptors for endothelin‐1 in asthmatic human peripheral lung

Knott, P.G.; D'Aprile, A.C.; Henry, Peter J.; Hay, Douglas W. P.; Goldie, Roy G.

doi:10.1111/j.1476-5381.1995.tb14895.x

Cited by 50 publications

(33 citation statements)

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“…At this level ET-1, ET-2 and ET-3 induce strong and potent contractions, which can be mimicked by an ETB agonist (IRL 1620) and blocked by a combined ETA/ETB receptor antagonist (PD 145065), whereas a selective ETA receptor antagonist (FR139317) has no effect. Our pharmacological results, indicating the presence of a contractile ETB receptor on small human bronchi are in good agreement with recent autoradiographic findings, indicating dominance of ETB receptors in the human peripheral lung [29].…”

Section: Discussionsupporting

confidence: 81%

Contractile endothelin-B (ETB) receptors in human small bronchi

Adner

Cardell²,

Sjöberg

et al. 1996

Eur Respir J

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C Co on nt tr ra ac ct ti il le e e en nd do ot th he el li in n--B B ( (E ETTBIn the present paper, improved methodology was used which enables in vitro studies of small human bronchi down to a diameter of 0.5-1.0 mm. Using the new methodology we have tried to further characterize this receptor.Small bronchi from the distal parts of the bronchial tree were obtained from pulmonary tissue removed from 15 patients with lung cancer. They were dissected and cut into ring segments, in which isometric tension was recorded.ET-1, ET-2 and ET-3 elicited strong concentration-dependent contractions of the human small bronchus. Basically, the three peptides were equipotent with about the same maximal response. Upon reapplication, they all showed the same tachyphylaxis pattern, reaching half the initial contraction. Comparative analysis of IRL 1620, a selective ETB receptor agonist, revealed that the effect of the ETB agonist was, in all respects, similar to the responses induced by the ETs. PD 145065, a combined ETA/ETB receptor antagonist competitively inhibited the contractions induced by IRL 1620, whereas FR139317, a selective ETA receptor antagonist, was without effect.In conclusion, the present study shows that accurate measurements can be made in vitro on small human bronchi and all present data are in favour of an ETB receptor mediating endothelin-induced contraction of human bronchi smaller than 1.0 mm.

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Section: Discussionsupporting

confidence: 81%

Contractile endothelin-B (ETB) receptors in human small bronchi

Adner

Cardell²,

Sjöberg

et al. 1996

Eur Respir J

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“…Binding, autoradiographic and functional studies have detected both ETA and ETB receptors in human lung (Goldie et al, 1994;Knott et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Endothelin‐1‐induced potentiation of human airway smooth muscle proliferation: an ET_A receptor‐mediated phenomenon

Panettieri

Goldie

Rigby

et al. 1996

British J Pharmacology

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113

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1 In this study the mitogenic effects in human cultured tracheal smooth muscle cells of endothelin-l (ET-1), ET-3, and sarafotoxin S6c (S6c), the ETB receptor-selective agonist, were explored either alone or in combination with the potent mitogen, epidermal growth factor (EGF). 2 In confluent, growth-arrested human airway smooth, neither ET-1 (0.01 nM-1 Mm) nor (0.001 nM-1 Mm) or S6c (0.01 nM-1 yM) induced cell proliferation, as assessed by [3H]-thymidine incorporation. In contrast, EGF (1.6 PM-16 nM) produced concentration-dependent stimulation of DNA synthesis (EC50 of about 0.06 nM). The maximum increase of about 60 fold above control, elicited by 16nM EGF, was similar to that obtained with 10% foetal bovine serum (FBS). EGF (0.16-16nM) also produced a concentration-dependent increase in cell counts, whereas ET-1 (1 -100 nM) was without effect on this index of mitogenesis. 3 ET-1 (1 -100 nM) potentiated EGF-induced proliferation of human tracheal smooth muscle cells. For example, ET-1 (100nM), which alone was without significant effect, increased by 3.0 to 3.5 fold the mitogenic influence of EGF (0.16 nM). The potentiating effect of ET-1 on EGF-induced proliferation was antagonized by BQ-123 (3pM), the ETA receptor antagonist, but was unaffected by the ETB receptor antagonist BQ-788 (lOM). 4 Neither ET-3 (1-100 nM) nor S6c (1-100 nM) influenced the mitogenic effects of EGF (0.16-1.6 nM). 5 ['251]-ET-I binding studies revealed that on average the ratio of ETA to ETB receptors in human cultured tracheal smooth muscle cells was 35:65 (±3; n=4), confirming the predominance of the ETB receptor subtype in human airway smooth muscle. 6 These data indicate that ET-1 alone does not induce significant human airway smooth muscle cell proliferation. However, it potently potentiated mitogenesis induced by EGF, apparently via an ETA receptor-mediated mechanism. These findings suggest that ET-1, a mediator detected in increased amounts in patients with acute asthma, may potentiate the proliferative effects of mitogens and contribute to the airway smooth muscle hyperplasia associated with chronic severe asthma.

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“…Airway smooth muscle cells at a predetermined stage of culture were repeatedly washed in PBS containing (in mM) NaCl (145), KH 2 PO 4 (1.8), Na 2 HPO 4 (8.2), BSA (0.25% w/v) and the protease inhibitor phenylmethylsulphonyl¯uoride (10 mM) (binding medium) and left to air dry for 3 h. Air-dried cells were incubated in binding medium (0.5 ml) containing 0. Knott et al, 1995). Cells were then washed (1.5 ml) twice for 10 min with ice-cold binding medium and then once for 20 min (2 ml).…”

Section: Radioligand Binding In Cultured Airway Smooth Muscle Cellsmentioning

confidence: 99%

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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Receptors for endothelin‐1 in asthmatic human peripheral lung

Cited by 50 publications

References 11 publications

Contractile endothelin-B (ETB) receptors in human small bronchi

Contractile endothelin-B (ETB) receptors in human small bronchi

Endothelin‐1‐induced potentiation of human airway smooth muscle proliferation: an ET_A receptor‐mediated phenomenon

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

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Receptors for endothelin‐1 in asthmatic human peripheral lung

Cited by 50 publications

References 11 publications

Contractile endothelin-B (ETB) receptors in human small bronchi

Contractile endothelin-B (ETB) receptors in human small bronchi

Endothelin‐1‐induced potentiation of human airway smooth muscle proliferation: an ETA receptor‐mediated phenomenon

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

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Endothelin‐1‐induced potentiation of human airway smooth muscle proliferation: an ET_A receptor‐mediated phenomenon

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