ten Berge R E, Zaagsma J, Roffel A F
Department of Medicinal Chemistry and Molecular Pharmacology, University of Groningen, The Netherlands.
Am J Respir Crit Care Med. 1996 Jul;154(1):43-9. doi: 10.1164/ajrccm.154.1.8680697.
The present study was undertaken to investigate the functional presence of inhibitory muscarinic M2 autoreceptors on postganglionic cholinergic nerve endings in different generations of human airways. To this end, the effects of the M2-selective muscarinic receptor antagonists AQ-RA 741 and gallamine were studied on electrical field stimulation-induced twitch contractions of preparations from trachea and from bronchial airways of varying diameter. Furthermore, electrically evoked release of endogenous acetylcholine from human bronchial preparations, and the effect of the muscarinic receptor antagonist atropine thereon, was measured by high-performance liquid chromatography. On average, twitch contractions were significantly but only slightly (11 to 15%) potentiated by M2-selective concentrations of AQ-RA 741 and gallamine, despite approximately half of the preparations showing no potentiation at all. A subdivision into airway generations showed that M2 autoreceptor function was not readily detectable in bronchioles and subsegmental bronchi. By contrast, both with AQ-RA 741 and gallamine a clear potentiation (26 to 36%) of the twitch contractions was observed in approximately half of the terminal bronchi and in all central airway preparations. Moreover, the evoked release of endogenous acetylcholine in terminal and subsegmental bronchi was significantly facilitated by atropine, to 162 to 189% of controls. These results provide strong and partly direct evidence for the existence of inhibitory muscarinic M2 receptors on postganglionic cholinergic nerve endings in human central airways and subsegmental and terminal bronchi, but not in bronchioli. It remains to be established, however, why these M2 receptors exhibit a rather variable functionality in regulating cholinergic nerve-mediated contraction in different airway generations.
本研究旨在调查抑制性毒蕈碱M2自身受体在不同代人类气道节后胆碱能神经末梢上的功能存在情况。为此，研究了M2选择性毒蕈碱受体拮抗剂AQ - RA 741和加拉明对气管及不同直径支气管气道标本电场刺激诱发的抽搐收缩的影响。此外，通过高效液相色谱法测量了人支气管标本中内源性乙酰胆碱的电诱发释放以及毒蕈碱受体拮抗剂阿托品对其的影响。平均而言，尽管约一半的标本完全没有增强作用，但M2选择性浓度的AQ - RA 741和加拉明仍使抽搐收缩显著但仅轻微（11%至15%）增强。按气道代进行细分显示，在细支气管和亚段支气管中不易检测到M2自身受体功能。相比之下，使用AQ - RA 741和加拉明时，在约一半的终末支气管和所有中央气道标本中均观察到抽搐收缩明显增强（26%至36%）。此外，阿托品显著促进了终末和亚段支气管中内源性乙酰胆碱的诱发释放，达到对照值的162%至189%。这些结果为人类中央气道、亚段支气管和终末支气管而非细支气管的节后胆碱能神经末梢上存在抑制性毒蕈碱M2受体提供了有力且部分直接的证据。然而，仍有待确定为什么这些M2受体在调节不同气道代中胆碱能神经介导的收缩方面表现出相当可变的功能。
