Eltze M, Galvan M
Department of Pharmacology, Byk Gulden Pharmaceuticals, Konstanz, Federal Republic of Germany.
Pulm Pharmacol. 1994 Apr;7(2):109-20. doi: 10.1006/pulp.1994.1013.
The inhibition of preganglionic and postganglionic contractions of the rabbit isolated bronchus/trachea by antagonists with selectivity for different muscarinic receptor subtypes was compared with their affinities at M1, M2, M3 and M4 receptors. Neither M1/M3 receptor-unselective antagonists (atropine, hexahydro-siladifenidol, thiazinamium, p-fluoro-hexahydro-sila-difenidol) nor antagonists with selectivity for the M1 over M3 subtype ((+)-biperiden, UH-AH 37, telenzepine, o-methoxy-sila-hexocyclium, pirenzepine) consistently showed a preferential inhibition of the response to preganglionic over postganglionic stimulation. Potencies for inhibition of contraction to preganglionic stimulation by antagonists discriminating more than threefold both between M1 and M3, and between M3 and M2 receptors (hexocyclium, (+)-biperiden, UH-AH 37, telenzepine, o-methoxy-silahexocyclium, p-fluoro-hexahydro-sila-difenidol, pirenzepine) are most consistent with affinities at smooth muscle M3 receptors as determined on methacholine-contracted rabbit trachea. Antagonists with a 10-fold higher affinity at M2 over M3 receptors enhanced contractions to field stimulation (AQ-RA 741 = AF-DX 384 = idaverine > himbacine = imperialine = AF-DX 116 = methoctramine >> gallamine), whereas antagonists with a selectivity profile of M4 > or = M3 > M2 (hexahydro-sila-difenidol, pirenzepine, dicyclomine) failed to increase the contractions. Secoverine (selectivity profile M4 > M2 > M3) enhanced contractions at concentrations consistent with its M2 receptor affinity. These results (1) exclude a ganglionic M1 receptor modulating excitatory vagal neurotransmission but (2) suggest the presence of an inhibitory prejunctional M2 rather than an M4 receptor and (3) identify a postjunctional smooth muscle M3 receptor in rabbit bronchus/trachea.
将对不同毒蕈碱受体亚型具有选择性的拮抗剂对兔离体支气管/气管节前和节后收缩的抑制作用，与其对M1、M2、M3和M4受体的亲和力进行了比较。M1/M3受体非选择性拮抗剂（阿托品、六氢硅环戊哌啶、噻嗪铵、对氟六氢硅环戊哌啶）以及对M1亚型比对M3亚型具有选择性的拮抗剂（(+)-比哌立登、UH-AH 37、替仑西平、邻甲氧基硅环戊铵、哌仑西平）均未始终如一地表现出对节前刺激反应的抑制优先于节后刺激。对M1与M3以及M3与M2受体之间的区分能力超过三倍的拮抗剂（六甲铵、(+)-比哌立登、UH-AH 37、替仑西平、邻甲氧基硅六甲铵、对氟六氢硅环戊哌啶、哌仑西平）抑制节前刺激收缩的效力，与在乙酰甲胆碱收缩的兔气管上测定的对平滑肌M3受体的亲和力最为一致。对M2受体的亲和力比对M3受体高10倍的拮抗剂增强了对场刺激的收缩（AQ-RA 741 = AF-DX 384 = 伊达韦林 > 辛巴生 = 帝王碱 = AF-DX 116 = 甲溴辛托品 >> 加拉明），而具有M4≥M3>M2选择性特征的拮抗剂（六氢硅环戊哌啶、哌仑西平、双环维林）未能增加收缩。塞克维林（选择性特征为M4>M2>M3）在与其M2受体亲和力一致的浓度下增强了收缩。这些结果（1）排除了神经节M1受体调节兴奋性迷走神经传递的可能性，但（2）提示存在抑制性节前M2而非M4受体，以及（3）确定了兔支气管/气管中的节后平滑肌M3受体。
