Desensitisation of mast cell beta2-adrenoceptor-mediated responses by salmeterol and formoterol

Anne Marie Scola; Lee K. Chong; S. Kim Suvarna; Russell Chess-Williams; Peter T. Peachell

doi:10.1038/sj.bjp.0705599

Desensitisation of mast cell beta2-adrenoceptor-mediated responses by salmeterol and formoterol

Anne Marie Scola
, Lee K. Chong
, S. Kim Suvarna
, Russell Chess-Williams
, Peter T. Peachell^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

50 Citations (Scopus)

Abstract

1. The long-acting β ₂-adrenoceptor agonist formoterol (10 ^-10-10 ^-6 M) inhibited the IgE-dependent release of histamine from human lung mast cells in a concentration-dependent manner. Formoterol was more potent and a full agonist relative to the nonselective β-adrenoceptor agonist isoprenaline. By contrast, the long-acting β ₂-adrenoceptor agonist salmeterol (10 ^-10-10 ^-6 M) was about two-thirds less efficacious than either formoterol or isoprenaline as an inhibitor of histamine release. 2. Isoprenaline, formoterol and salmeterol (all at 10 ^-5 M) increased total cell cAMP levels in mast cells over basal by 361±90 (P<0.05), 321±89 (P<0.05) and 64±24% (P>0.05), respectively. 3. Long-term (24 h) incubation of mast cells with formoterol (10 ^-6 M) or salmeterol (10 ^-6 M) essentially abolished the subsequent ability of isoprenaline to inhibit histamine release. Both formoterol and salmeterol were more effective at inducing the functional desensitisation than isoprenaline (10 ^-6 M) or the short-acting β ₂-adrenoceptor agonist salbutamol (10 ^-6 M). 4. The desensitisation induced by long-term treatments with salmeterol and formoterol was specific for β ₂-adrenoceptor-mediated inhibition of histamine release as the inhibitory effects of alternative cAMP-elevating compounds, prostaglandin E ₂, a receptor-mediated activator of adenylate cyclase, and forskolin, a direct activator of adenylate cyclase, were unaffected by desensitising treatments. 5. Radioligand binding studies were performed to determine β ₂-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with agonists. Isoprenaline, formoterol and salmeterol (all at 10 ^-6 M) reduced β ₂-adrenoceptor density by 13±5 (P>0.05), 49±13 (P<0.05) and 35±17% (P>0.05), respectively. 6. These data indicate that long-term exposure of mast cells to both salmeterol and formoterol can cause substantial levels of desensitisation to β ₂-adrenoceptor-mediated responses in mast cells.

Original language	English
Pages (from-to)	163-171
Number of pages	9
Journal	British Journal of Pharmacology
Volume	141
Issue number	1
DOIs	https://doi.org/10.1038/sj.bjp.0705599
Publication status	Published - Jan 2004
Externally published	Yes

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@article{1184e497a2dc49499069ec7b98829429,

title = "Desensitisation of mast cell beta2-adrenoceptor-mediated responses by salmeterol and formoterol",

abstract = "1. The long-acting β 2-adrenoceptor agonist formoterol (10 -10-10 -6 M) inhibited the IgE-dependent release of histamine from human lung mast cells in a concentration-dependent manner. Formoterol was more potent and a full agonist relative to the nonselective β-adrenoceptor agonist isoprenaline. By contrast, the long-acting β 2-adrenoceptor agonist salmeterol (10 -10-10 -6 M) was about two-thirds less efficacious than either formoterol or isoprenaline as an inhibitor of histamine release. 2. Isoprenaline, formoterol and salmeterol (all at 10 -5 M) increased total cell cAMP levels in mast cells over basal by 361±90 (P<0.05), 321±89 (P<0.05) and 64±24\% (P>0.05), respectively. 3. Long-term (24 h) incubation of mast cells with formoterol (10 -6 M) or salmeterol (10 -6 M) essentially abolished the subsequent ability of isoprenaline to inhibit histamine release. Both formoterol and salmeterol were more effective at inducing the functional desensitisation than isoprenaline (10 -6 M) or the short-acting β 2-adrenoceptor agonist salbutamol (10 -6 M). 4. The desensitisation induced by long-term treatments with salmeterol and formoterol was specific for β 2-adrenoceptor-mediated inhibition of histamine release as the inhibitory effects of alternative cAMP-elevating compounds, prostaglandin E 2, a receptor-mediated activator of adenylate cyclase, and forskolin, a direct activator of adenylate cyclase, were unaffected by desensitising treatments. 5. Radioligand binding studies were performed to determine β 2-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with agonists. Isoprenaline, formoterol and salmeterol (all at 10 -6 M) reduced β 2-adrenoceptor density by 13±5 (P>0.05), 49±13 (P<0.05) and 35±17\% (P>0.05), respectively. 6. These data indicate that long-term exposure of mast cells to both salmeterol and formoterol can cause substantial levels of desensitisation to β 2-adrenoceptor-mediated responses in mast cells.",

author = "Scola, \{Anne Marie\} and Chong, \{Lee K.\} and Suvarna, \{S. Kim\} and Russell Chess-Williams and Peachell, \{Peter T.\}",

year = "2004",

month = jan,

doi = "10.1038/sj.bjp.0705599",

language = "English",

volume = "141",

pages = "163--171",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "John Wiley \& Sons",

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TY - JOUR

T1 - Desensitisation of mast cell beta2-adrenoceptor-mediated responses by salmeterol and formoterol

AU - Scola, Anne Marie

AU - Chong, Lee K.

AU - Suvarna, S. Kim

AU - Chess-Williams, Russell

AU - Peachell, Peter T.

PY - 2004/1

Y1 - 2004/1

N2 - 1. The long-acting β 2-adrenoceptor agonist formoterol (10 -10-10 -6 M) inhibited the IgE-dependent release of histamine from human lung mast cells in a concentration-dependent manner. Formoterol was more potent and a full agonist relative to the nonselective β-adrenoceptor agonist isoprenaline. By contrast, the long-acting β 2-adrenoceptor agonist salmeterol (10 -10-10 -6 M) was about two-thirds less efficacious than either formoterol or isoprenaline as an inhibitor of histamine release. 2. Isoprenaline, formoterol and salmeterol (all at 10 -5 M) increased total cell cAMP levels in mast cells over basal by 361±90 (P<0.05), 321±89 (P<0.05) and 64±24% (P>0.05), respectively. 3. Long-term (24 h) incubation of mast cells with formoterol (10 -6 M) or salmeterol (10 -6 M) essentially abolished the subsequent ability of isoprenaline to inhibit histamine release. Both formoterol and salmeterol were more effective at inducing the functional desensitisation than isoprenaline (10 -6 M) or the short-acting β 2-adrenoceptor agonist salbutamol (10 -6 M). 4. The desensitisation induced by long-term treatments with salmeterol and formoterol was specific for β 2-adrenoceptor-mediated inhibition of histamine release as the inhibitory effects of alternative cAMP-elevating compounds, prostaglandin E 2, a receptor-mediated activator of adenylate cyclase, and forskolin, a direct activator of adenylate cyclase, were unaffected by desensitising treatments. 5. Radioligand binding studies were performed to determine β 2-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with agonists. Isoprenaline, formoterol and salmeterol (all at 10 -6 M) reduced β 2-adrenoceptor density by 13±5 (P>0.05), 49±13 (P<0.05) and 35±17% (P>0.05), respectively. 6. These data indicate that long-term exposure of mast cells to both salmeterol and formoterol can cause substantial levels of desensitisation to β 2-adrenoceptor-mediated responses in mast cells.

AB - 1. The long-acting β 2-adrenoceptor agonist formoterol (10 -10-10 -6 M) inhibited the IgE-dependent release of histamine from human lung mast cells in a concentration-dependent manner. Formoterol was more potent and a full agonist relative to the nonselective β-adrenoceptor agonist isoprenaline. By contrast, the long-acting β 2-adrenoceptor agonist salmeterol (10 -10-10 -6 M) was about two-thirds less efficacious than either formoterol or isoprenaline as an inhibitor of histamine release. 2. Isoprenaline, formoterol and salmeterol (all at 10 -5 M) increased total cell cAMP levels in mast cells over basal by 361±90 (P<0.05), 321±89 (P<0.05) and 64±24% (P>0.05), respectively. 3. Long-term (24 h) incubation of mast cells with formoterol (10 -6 M) or salmeterol (10 -6 M) essentially abolished the subsequent ability of isoprenaline to inhibit histamine release. Both formoterol and salmeterol were more effective at inducing the functional desensitisation than isoprenaline (10 -6 M) or the short-acting β 2-adrenoceptor agonist salbutamol (10 -6 M). 4. The desensitisation induced by long-term treatments with salmeterol and formoterol was specific for β 2-adrenoceptor-mediated inhibition of histamine release as the inhibitory effects of alternative cAMP-elevating compounds, prostaglandin E 2, a receptor-mediated activator of adenylate cyclase, and forskolin, a direct activator of adenylate cyclase, were unaffected by desensitising treatments. 5. Radioligand binding studies were performed to determine β 2-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with agonists. Isoprenaline, formoterol and salmeterol (all at 10 -6 M) reduced β 2-adrenoceptor density by 13±5 (P>0.05), 49±13 (P<0.05) and 35±17% (P>0.05), respectively. 6. These data indicate that long-term exposure of mast cells to both salmeterol and formoterol can cause substantial levels of desensitisation to β 2-adrenoceptor-mediated responses in mast cells.

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DO - 10.1038/sj.bjp.0705599

M3 - Article

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AN - SCOPUS:1242341340

SN - 0007-1188

VL - 141

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EP - 171

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 1

ER -

Desensitisation of mast cell beta2-adrenoceptor-mediated responses by salmeterol and formoterol

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