Desensitization of β 2-adrenoceptor-mediated responses by short-acting β 2-adrenoceptor agonists in human lung mast cells

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

*Corresponding author for this work

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33 Citations (Scopus)

Abstract

1. The principal aim of the present study was to determine whether long-term treatment of human lung mast cells (HLMC) with the clinically-relevant β 2-adrenoceptor agonists, salbutamol and terbutaline, leads to desensitization of β 2-adrenoceptor-mediated responses in these cells. 2. The non-selective β-adrenoceptor agonist, isoprenaline, and the selective β 2-adrenoceptor agonists, salbutamol and terbutaline, inhibited the IgE-mediated release of histamine from HLMC. Salbutamol (pD 2; 7.7±0.3) and terbutaline (pD 2; 7.34±0.2) were roughly equipotent as inhibitors of histamine release although both agonists were less potent than isoprenaline (pD 2; 8.64±0.2). 3. Isoprenaline (10 -5 M), salbutamol (10 -5 M) and terbutaline (10 -5 M) enhanced total cell cAMP levels in HLMC over basal by 361±90, 150±38 and 165±35%, respectively. 4. Long-term exposure (24 h) of HLMC to either salbutamol (10 -7 M) or terbutaline (10 -7 M) led to a subsequent reduction in the effectiveness of salbutamol and terbutaline (both 10 -9 - 10 -4 M) to inhibit histamine release. However, salbutamol was significantly (P < 0.05) more effective than terbutaline at promoting the functional desensitization. 5. Radioligand binding studies, using iodinated cyanopindolol, were performed to determine β 2-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with either salbutamol (10 -6 M) or terbutaline (10 -6 M). Both agonists reduced β 2-adrenoceptor density in membranes to about the same extent (∼25% reduction) but these changes in receptor density were not statistically significant (P > 0.05). 6. These data indicate that long-term exposure of mast cells to salbutamol causes greater levels of desensitization to β 2-adrenoceptor-mediated responses in HLMC than terbutaline. These findings may have wider clinical significance in the context of asthma treatment as compromised mast cell inhibition could result following long-term exposure of mast cells to short-acting bronchodilators.

Original languageEnglish
Pages (from-to)512-520
Number of pages9
JournalBritish Journal of Pharmacology
Volume138
Issue number3
DOIs
Publication statusPublished - Feb 2003
Externally publishedYes

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Albuterol
Terbutaline
Mast Cells
Adrenergic Receptors
Lung
Histamine Release
Isoproterenol
Bronchodilator Agents
Immunoglobulin E
Asthma

Cite this

@article{c08e3d5103a5481a84f1df1ec55cc5e3,
title = "Desensitization of β 2-adrenoceptor-mediated responses by short-acting β 2-adrenoceptor agonists in human lung mast cells",
abstract = "1. The principal aim of the present study was to determine whether long-term treatment of human lung mast cells (HLMC) with the clinically-relevant β 2-adrenoceptor agonists, salbutamol and terbutaline, leads to desensitization of β 2-adrenoceptor-mediated responses in these cells. 2. The non-selective β-adrenoceptor agonist, isoprenaline, and the selective β 2-adrenoceptor agonists, salbutamol and terbutaline, inhibited the IgE-mediated release of histamine from HLMC. Salbutamol (pD 2; 7.7±0.3) and terbutaline (pD 2; 7.34±0.2) were roughly equipotent as inhibitors of histamine release although both agonists were less potent than isoprenaline (pD 2; 8.64±0.2). 3. Isoprenaline (10 -5 M), salbutamol (10 -5 M) and terbutaline (10 -5 M) enhanced total cell cAMP levels in HLMC over basal by 361±90, 150±38 and 165±35{\%}, respectively. 4. Long-term exposure (24 h) of HLMC to either salbutamol (10 -7 M) or terbutaline (10 -7 M) led to a subsequent reduction in the effectiveness of salbutamol and terbutaline (both 10 -9 - 10 -4 M) to inhibit histamine release. However, salbutamol was significantly (P < 0.05) more effective than terbutaline at promoting the functional desensitization. 5. Radioligand binding studies, using iodinated cyanopindolol, were performed to determine β 2-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with either salbutamol (10 -6 M) or terbutaline (10 -6 M). Both agonists reduced β 2-adrenoceptor density in membranes to about the same extent (∼25{\%} reduction) but these changes in receptor density were not statistically significant (P > 0.05). 6. These data indicate that long-term exposure of mast cells to salbutamol causes greater levels of desensitization to β 2-adrenoceptor-mediated responses in HLMC than terbutaline. These findings may have wider clinical significance in the context of asthma treatment as compromised mast cell inhibition could result following long-term exposure of mast cells to short-acting bronchodilators.",
author = "Chong, {Lee K.} and Suvarna, {S. Kim} and Russell Chess-Williams and Peachell, {Peter T.}",
year = "2003",
month = "2",
doi = "10.1038/sj.bjp.0705050",
language = "English",
volume = "138",
pages = "512--520",
journal = "British journal of pharmacology and chemotherapy",
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}

Desensitization of β 2-adrenoceptor-mediated responses by short-acting β 2-adrenoceptor agonists in human lung mast cells. / Chong, Lee K.; Suvarna, S. Kim; Chess-Williams, Russell; Peachell, Peter T.

In: British Journal of Pharmacology, Vol. 138, No. 3, 02.2003, p. 512-520.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Desensitization of β 2-adrenoceptor-mediated responses by short-acting β 2-adrenoceptor agonists in human lung mast cells

AU - Chong, Lee K.

AU - Suvarna, S. Kim

AU - Chess-Williams, Russell

AU - Peachell, Peter T.

PY - 2003/2

Y1 - 2003/2

N2 - 1. The principal aim of the present study was to determine whether long-term treatment of human lung mast cells (HLMC) with the clinically-relevant β 2-adrenoceptor agonists, salbutamol and terbutaline, leads to desensitization of β 2-adrenoceptor-mediated responses in these cells. 2. The non-selective β-adrenoceptor agonist, isoprenaline, and the selective β 2-adrenoceptor agonists, salbutamol and terbutaline, inhibited the IgE-mediated release of histamine from HLMC. Salbutamol (pD 2; 7.7±0.3) and terbutaline (pD 2; 7.34±0.2) were roughly equipotent as inhibitors of histamine release although both agonists were less potent than isoprenaline (pD 2; 8.64±0.2). 3. Isoprenaline (10 -5 M), salbutamol (10 -5 M) and terbutaline (10 -5 M) enhanced total cell cAMP levels in HLMC over basal by 361±90, 150±38 and 165±35%, respectively. 4. Long-term exposure (24 h) of HLMC to either salbutamol (10 -7 M) or terbutaline (10 -7 M) led to a subsequent reduction in the effectiveness of salbutamol and terbutaline (both 10 -9 - 10 -4 M) to inhibit histamine release. However, salbutamol was significantly (P < 0.05) more effective than terbutaline at promoting the functional desensitization. 5. Radioligand binding studies, using iodinated cyanopindolol, were performed to determine β 2-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with either salbutamol (10 -6 M) or terbutaline (10 -6 M). Both agonists reduced β 2-adrenoceptor density in membranes to about the same extent (∼25% reduction) but these changes in receptor density were not statistically significant (P > 0.05). 6. These data indicate that long-term exposure of mast cells to salbutamol causes greater levels of desensitization to β 2-adrenoceptor-mediated responses in HLMC than terbutaline. These findings may have wider clinical significance in the context of asthma treatment as compromised mast cell inhibition could result following long-term exposure of mast cells to short-acting bronchodilators.

AB - 1. The principal aim of the present study was to determine whether long-term treatment of human lung mast cells (HLMC) with the clinically-relevant β 2-adrenoceptor agonists, salbutamol and terbutaline, leads to desensitization of β 2-adrenoceptor-mediated responses in these cells. 2. The non-selective β-adrenoceptor agonist, isoprenaline, and the selective β 2-adrenoceptor agonists, salbutamol and terbutaline, inhibited the IgE-mediated release of histamine from HLMC. Salbutamol (pD 2; 7.7±0.3) and terbutaline (pD 2; 7.34±0.2) were roughly equipotent as inhibitors of histamine release although both agonists were less potent than isoprenaline (pD 2; 8.64±0.2). 3. Isoprenaline (10 -5 M), salbutamol (10 -5 M) and terbutaline (10 -5 M) enhanced total cell cAMP levels in HLMC over basal by 361±90, 150±38 and 165±35%, respectively. 4. Long-term exposure (24 h) of HLMC to either salbutamol (10 -7 M) or terbutaline (10 -7 M) led to a subsequent reduction in the effectiveness of salbutamol and terbutaline (both 10 -9 - 10 -4 M) to inhibit histamine release. However, salbutamol was significantly (P < 0.05) more effective than terbutaline at promoting the functional desensitization. 5. Radioligand binding studies, using iodinated cyanopindolol, were performed to determine β 2-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with either salbutamol (10 -6 M) or terbutaline (10 -6 M). Both agonists reduced β 2-adrenoceptor density in membranes to about the same extent (∼25% reduction) but these changes in receptor density were not statistically significant (P > 0.05). 6. These data indicate that long-term exposure of mast cells to salbutamol causes greater levels of desensitization to β 2-adrenoceptor-mediated responses in HLMC than terbutaline. These findings may have wider clinical significance in the context of asthma treatment as compromised mast cell inhibition could result following long-term exposure of mast cells to short-acting bronchodilators.

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U2 - 10.1038/sj.bjp.0705050

DO - 10.1038/sj.bjp.0705050

M3 - Article

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SP - 512

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JO - British journal of pharmacology and chemotherapy

JF - British journal of pharmacology and chemotherapy

SN - 0007-1188

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