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

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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 languageEnglish
Pages (from-to)163-171
Number of pages9
JournalBritish Journal of Pharmacology
Volume141
Issue number1
DOIs
Publication statusPublished - Jan 2004
Externally publishedYes

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Mast Cells
Adrenergic Receptors
Isoproterenol
Histamine Release
Adenylyl Cyclases
Receptors, Prostaglandin E, EP2 Subtype
Salmeterol Xinafoate
Formoterol Fumarate
Albuterol
Colforsin
Immunoglobulin E
Cell Membrane
Lung

Cite this

Scola, Anne Marie ; Chong, Lee K. ; Suvarna, S. Kim ; Chess-Williams, Russell ; Peachell, Peter T. / Desensitisation of mast cell beta2-adrenoceptor-mediated responses by salmeterol and formoterol. In: British Journal of Pharmacology. 2004 ; Vol. 141, No. 1. pp. 163-171.
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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.",
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Desensitisation of mast cell beta2-adrenoceptor-mediated responses by salmeterol and formoterol. / Scola, Anne Marie; Chong, Lee K.; Suvarna, S. Kim; Chess-Williams, Russell; Peachell, Peter T.

In: British Journal of Pharmacology, Vol. 141, No. 1, 01.2004, p. 163-171.

Research output: Contribution to journalArticleResearchpeer-review

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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

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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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