短效β2肾上腺素能受体激动剂对人肺肥大细胞中β2肾上腺素能受体介导反应的脱敏作用。
Desensitization of beta2-adrenoceptor-mediated responses by short-acting beta2-adrenoceptor agonists in human lung mast cells.
作者信息
Chong Lee K, Suvarna Kim, Chess-Williams Russell, Peachell Peter T
机构信息
Unit of Molecular Pharmacology & Pharmacogenetics, University of Sheffield, The Royal Hallamshire Hospital (Floor L), Glossop Road, UK.
出版信息
Br J Pharmacol. 2003 Feb;138(3):512-20. doi: 10.1038/sj.bjp.0705050.
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 (approximately 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 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.
- 本研究的主要目的是确定用临床相关的β₂肾上腺素能受体激动剂沙丁胺醇和特布他林对人肺肥大细胞（HLMC）进行长期治疗是否会导致这些细胞中β₂肾上腺素能受体介导的反应脱敏。2. 非选择性β肾上腺素能受体激动剂异丙肾上腺素以及选择性β₂肾上腺素能受体激动剂沙丁胺醇和特布他林抑制了HLMC中IgE介导的组胺释放。沙丁胺醇（pD₂；7.7±0.3）和特布他林（pD₂；7.3±0.2）作为组胺释放抑制剂的效力大致相当，尽管这两种激动剂均不如异丙肾上腺素有效（pD₂；8.6±0.2）。3. 异丙肾上腺素（10⁻⁵ M）、沙丁胺醇（10⁻⁵ M）和特布他林（10⁻⁵ M）使HLMC中的总细胞cAMP水平分别比基础水平提高了361±90%、150±38%和165±35%。4. HLMC长期暴露（24小时）于沙丁胺醇（10⁻⁷ M）或特布他林（10⁻⁷ M）会导致随后沙丁胺醇和特布他林（均为10⁻⁹ - 10⁻⁴ M）抑制组胺释放的效力降低。然而，在促进功能脱敏方面，沙丁胺醇比特布他林显著更有效（P<0.05）。5. 使用碘化氰吲哚洛尔进行放射性配体结合研究，以确定在用沙丁胺醇（10⁻⁶ M）或特布他林（10⁻⁶ M）对细胞进行预处理（24小时）后细胞膜中β₂肾上腺素能受体的密度。两种激动剂使膜中β₂肾上腺素能受体密度降低的程度大致相同（约降低25%）但这些受体密度的变化无统计学意义（P>0.05）。6. 这些数据表明，肥大细胞长期暴露于沙丁胺醇比特布他林会导致HLMC中对β₂肾上腺素能受体介导的反应产生更高水平的脱敏。在哮喘治疗背景下，这些发现可能具有更广泛的临床意义，因为肥大细胞长期暴露于短效支气管扩张剂后可能导致肥大细胞抑制受损。
Zotero 插件