Itabashi S, Aikawa T, Sekizawa K, Ohrui T, Sasaki H, Takishima T
First Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Eur J Pharmacol. 1991 Nov 12;204(3):235-41. doi: 10.1016/0014-2999(91)90847-j.
To examine muscarinic receptor subtypes involved in cholinergically mediated contractions of the airway, we studied the effects of the M1-selective antagonist, pirenzepine, the M2-selective antagonist, AF-DX 116, the M3-selective antagonist, 4-diphenyl-acetoxy-N-methylpiperidine (4-DAMP) methiodide, and the non-selective antagonist, atropine, on acetylcholine (ACh)- and electrically induced contractions in dog bronchi and bronchioles. The relative potencies of the antagonists based on IC50 values of each antagonist for contractions induced by the two concentrations of ACh that produced 50% of the maximum (ED50) and the maximum (EDmax) contractions and the pA2 values were atropine greater than or equal to 4-DAMP methiodide greater than pirenzepine = AF-DX 116 in both the bronchi and bronchioles. The IC50 and pA2 values of each antagonist did not differ significantly between the bronchi and bronchioles. 4-DAMP methiodide significantly inhibited the contractile response to electrical field stimulation (EFS) at 5 Hz at concentrations that did not alter the contractile responses to exogenous ACh in both the bronchi and bronchioles, whereas pirenzepine, AF-DX 116 and atropine inhibited the EFS-induced contraction only at the concentrations that reduced the contraction induced by exogenous ACh. The present results suggest that the cholinergic contraction is mediated via the postsynaptic receptor M3, based on functional potencies of muscarinic antagonists and presynaptic receptor auto-facilitatory M3, based on the suppression of the contractile response to EFS by 4-DAMP methiodide in central and peripheral airways.
为了研究参与胆碱能介导的气道收缩的毒蕈碱受体亚型，我们研究了M1选择性拮抗剂哌仑西平、M2选择性拮抗剂AF-DX 116、M3选择性拮抗剂4-二苯基乙酰氧基-N-甲基哌啶（4-DAMP）甲碘化物以及非选择性拮抗剂阿托品对犬支气管和细支气管中乙酰胆碱（ACh）和电诱导收缩的影响。基于每种拮抗剂对产生50%最大收缩（ED50）和最大收缩（EDmax）的两种浓度ACh诱导的收缩的IC50值以及pA2值，拮抗剂的相对效力在支气管和细支气管中均为阿托品≥4-DAMP甲碘化物＞哌仑西平 = AF-DX 116。每种拮抗剂的IC50和pA2值在支气管和细支气管之间无显著差异。4-DAMP甲碘化物在不改变支气管和细支气管对外源性ACh收缩反应的浓度下，显著抑制了5 Hz电场刺激（EFS）引起的收缩反应，而哌仑西平、AF-DX 116和阿托品仅在降低外源性ACh诱导的收缩的浓度下抑制EFS诱导的收缩。基于毒蕈碱拮抗剂的功能效力，目前的结果表明胆碱能收缩是通过突触后受体M3介导的；基于4-DAMP甲碘化物对中央和外周气道中EFS收缩反应的抑制作用，提示存在突触前受体自身促进性M3。
