Witt-Enderby P A, Yamamura H I, Halonen M, Lai J, Palmer J D, Bloom J W
Department of Pharmacology, College of Medicine, University of Arizona Health Sciences Center, Tucson 85724.
Mol Pharmacol. 1995 Mar;47(3):485-90.
Anticholinergic agents are commonly used as bronchodilators for patients with airway obstructive diseases. The effects of chronic anticholinergic therapy on airway function and bronchial responsiveness are not known, but data from clinical studies suggest the possibility of adverse effects. We demonstrated in rabbits that, after atropine treatment for 4 weeks, the efficacy (maximum contraction) of in vitro methacholine-induced contraction of mainstem bronchi was increased [control (untreated), 1.0 +/- 0.1 g; atropine-treated, 1.6 g +/- 0.2 g; p = 0.04]. However, there was no significant change in the potency (EC50) of methacholine-induced contraction. Chronic atropine treatment increased the maximum density (Bmax) of muscarinic receptors in the airways, as determined by radioligand binding studies with tritiated quinuclidinyl benzilate. Individual muscarinic receptor subtypes were measured using antibodies selective for the m1-m5 subtypes. Of the subtypes detected in rabbit tracheal smooth muscle (m2, m3, and m4), only the m2 and m3 muscarinic receptor subtypes were significantly up-regulated compared with control, after chronic atropine treatment. Because cholinergic agent-mediated contraction of smooth muscle has been shown to be mediated by m3 muscarinic receptors, the atropine-induced increase in the methacholine response in airway smooth muscle appears to be the result of the up-regulation of m3 muscarinic cholinergic receptors. Such a mechanism may explain the clinical observations that chronic anticholinergic therapy for asthmatic patients is associated with an increase in bronchial responsiveness and that continuous versus "on demand" anticholinergic bronchodilator therapy may cause an accelerated decline in ventilatory function.
抗胆碱能药物常用于气道阻塞性疾病患者的支气管扩张治疗。慢性抗胆碱能治疗对气道功能和支气管反应性的影响尚不清楚，但临床研究数据提示了不良反应的可能性。我们在兔子身上证明，阿托品治疗4周后，体外乙酰甲胆碱诱导的主支气管收缩的效力（最大收缩）增加了[对照组（未治疗），1.0±0.1克；阿托品治疗组，1.6克±0.2克；p = 0.04]。然而，乙酰甲胆碱诱导收缩的效能（半数有效浓度）没有显著变化。通过用氚标记的喹核醇基苯甲酸酯进行放射性配体结合研究确定，慢性阿托品治疗增加了气道中毒蕈碱受体的最大密度（Bmax）。使用对m1 - m5亚型具有选择性的抗体来测量各个毒蕈碱受体亚型。在兔子气管平滑肌中检测到的亚型（m2、m3和m4）中，慢性阿托品治疗后，与对照组相比，只有m2和m3毒蕈碱受体亚型显著上调。由于胆碱能药物介导的平滑肌收缩已被证明是由m3毒蕈碱受体介导的，阿托品诱导的气道平滑肌对乙酰甲胆碱反应增加似乎是m3毒蕈碱胆碱能受体上调的结果。这样一种机制可能解释了临床观察结果，即哮喘患者的慢性抗胆碱能治疗与支气管反应性增加相关，以及持续与“按需”抗胆碱能支气管扩张剂治疗可能导致通气功能加速下降。
