Desensitization β2-adrenoceptor-mediated responses by shortacting β2-adrenoceptor agonists in human lung mast cells

被引:28
作者
Chong, LK
Suvarna, K
Chess-Williams, R
Peachell, PT
机构
[1] Univ Sheffield, Royal Hallamshire Hosp, Unit Mol Pharmacol & Pharmacogenet, Sheffield S10 2JF, S Yorkshire, England
[2] No Gen Hosp, Dept Histopathol, Sheffield S5 7AU, S Yorkshire, England
[3] Univ Sheffield, Dept Biomed Sci, Sheffield S10 2TN, S Yorkshire, England
关键词
mast cells; beta(2)-adrenoceptor; salbutamol; terbutaline;
D O I
10.1038/sj.bjp.0705050
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 beta(2)-adrenoceptor agonists, salbutamol and terbutaline, leads to desensitization Of beta(2)-adrenoceptor-mediated responses in these cells. 2 The non-selective beta-adrenoceptor agonist, isoprenaline, and the selective beta(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); 7.3+/-0.2) were roughly equipotent as inhibitors of histamine release although both agonists were less potent than isoprenaline (pD(2); 8.6+/-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 beta(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 beta(2)-adrenoceptor density in membranes to about the same extent (similar to25% 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 beta(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.
引用
收藏
页码:512 / 520
页数:9
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