Chong L K, Morice A H, Yeo W W, Schleimer R P, Peachell P T
Department of Medicine and Pharmacology, University of Sheffield, Royal Hallamshire Hospital, United Kingdom.
Am J Respir Cell Mol Biol. 1995 Nov;13(5):540-6. doi: 10.1165/ajrcmb.13.5.7576689.
The beta adrenergic agonist isoprenaline inhibited the IgE-triggered release of the preformed mediator histamine from human lung mast cells (HLMC) in a dose-dependent fashion. After prolonged (> or = 4 h) preexposure of HLMC to isoprenaline, there was a subsequent diminution in the effectiveness of a second exposure of isoprenaline to inhibit the release of histamine from activated HLMC. This induced hyporesponsiveness to isoprenaline was both concentration and time dependent. Although maximal levels of desensitization were obtained after an initial prolonged (14-h) preincubation with a high (10(-5) M) concentration of isoprenaline, exposure of HLMC for a shorter (4-h) time period with a lower (3 x 10(-7) M) concentration of isoprenaline was also effective at inducing a functional desensitization to isoprenaline. The inhibitory activity of the beta 2 agonist fenoterol was attenuated after a prolonged (14-h) pretreatment step with isoprenaline (10(-5)M), whereas the inhibitory properties of other adenylate cyclase activators, prostaglandin E2 and forskolin, were not affected appreciably. Prolonged (12-h) exposure of HLMC to the beta agonists fenoterol, salbutamol, and terbutaline also induced hyporesponsive states of beta agonists, qualitatively similar to that obtained with isoprenaline. The beta receptor antagonist propranolol, if coincubated with isoprenaline during the prolonged pretreatment step, protected against the subsequent refractoriness of the HLMC to isoprenaline. The glucocorticoid dexamethasone failed to prevent the isoprenaline-induced functional desensitization. In total, these results indicate that prolonged exposure of HLMC to beta agonists induces a state of selective hyporesponsiveness to agonists that act at beta adrenoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
β肾上腺素能激动剂异丙肾上腺素以剂量依赖的方式抑制人肺肥大细胞（HLMC）中由IgE触发的预先形成的介质组胺的释放。在HLMC长时间（≥4小时）预先暴露于异丙肾上腺素后，再次暴露异丙肾上腺素抑制活化的HLMC释放组胺的有效性会随之降低。这种诱导的对异丙肾上腺素的低反应性是浓度和时间依赖性的。尽管在最初用高浓度（10⁻⁵M）的异丙肾上腺素长时间（14小时）预孵育后获得了最大程度的脱敏，但用较低浓度（3×10⁻⁷M）的异丙肾上腺素将HLMC暴露较短时间（4小时）也能有效诱导对异丙肾上腺素的功能性脱敏。在用异丙肾上腺素（10⁻⁵M）进行长时间（14小时）预处理步骤后，β₂激动剂非诺特罗的抑制活性减弱，而其他腺苷酸环化酶激活剂前列腺素E₂和福斯可林的抑制特性没有受到明显影响。将HLMC长时间（12小时）暴露于β激动剂非诺特罗、沙丁胺醇和特布他林也会诱导β激动剂的低反应状态，在性质上与用异丙肾上腺素获得的相似。如果在长时间预处理步骤中β受体拮抗剂普萘洛尔与异丙肾上腺素共同孵育，则可防止HLMC随后对异丙肾上腺素产生不应性。糖皮质激素地塞米松未能预防异丙肾上腺素诱导的功能性脱敏。总的来说，这些结果表明，HLMC长时间暴露于β激动剂会诱导对作用于β肾上腺素能受体的激动剂产生选择性低反应状态。（摘要截断于250字）
