Gilbert R, Rattan S, Goyal R K
J Pharmacol Exp Ther. 1984 Aug;230(2):284-91.
Lower esophageal sphincter pressures were monitored with water-filled catheters in anesthetized opossums. Muscarinic agonists McN-A-343 and bethanechol were administered in the arterial supply of the sphincter. McN-A-343 caused relaxation after a brief contraction of the sphincter. Bethanechol caused a dose-dependent contraction. Tetrodotoxin antagonized the inhibitory effect of McN-A-343 but did not antagonized sphincter contraction caused by McN-A-343 or bethanechol. The mean ED50 values were 6.9 nmol/kg i.a. for McN-A-343-induced relaxation, 10.5 nmol/kg i.a. for McN-A-343-induced contraction and 0.4 nmol/kg i.a. for bethanechol-induced contraction. Atropine caused a dose-dependent rightward shift in the dose-response curves of inhibitory and excitatory effects of the two muscarinic agonists. Pirenzepine caused a dose-dependent rightward shift in the dose-response curves of McN-A-343-induced relaxation. Pirenzepine did not modify sphincter contraction caused by the muscarinic agonists. 4-Diphenylacetoxy-N-methylpiperidine methiodide, on the other hand, did not modify McN-A-343-induced sphincter relaxation but caused dose-dependent rightward shifts in the dose-response curves of sphincter contraction caused by McN-A-343 or bethanechol. These studies suggest that there are two distinct types of muscarine receptors in the opossum lower esophageal sphincter. The M1 muscarine receptors are present on the inhibitory neurons and participate in the synaptic transmission between vagal preganglionic and intramural postganglionic inhibitory neurons. They are activated by McN-A-343 and antagonized by pirenzepine. The M2 muscarine receptors are located directly on the sphincter muscle. They are also activated by McN-A-343, but are selectively activated by bethanechol and are antagonized by 4-diphenylacetoxy-N-methylpiperidine methiodide.
在麻醉的负鼠身上，使用充满水的导管监测食管下括约肌压力。在括约肌的动脉供应中给予毒蕈碱激动剂 McN-A-343 和氨甲酰甲胆碱。McN-A-343 在括约肌短暂收缩后引起松弛。氨甲酰甲胆碱引起剂量依赖性收缩。河豚毒素拮抗 McN-A-343 的抑制作用，但不拮抗 McN-A-343 或氨甲酰甲胆碱引起的括约肌收缩。McN-A-343 诱导松弛的平均半数有效剂量（ED50）值为 6.9 nmol/kg 动脉内给药，McN-A-343 诱导收缩的为 10.5 nmol/kg 动脉内给药，氨甲酰甲胆碱诱导收缩的为 0.4 nmol/kg 动脉内给药。阿托品使两种毒蕈碱激动剂的抑制和兴奋作用的剂量反应曲线发生剂量依赖性右移。哌仑西平使 McN-A-343 诱导松弛的剂量反应曲线发生剂量依赖性右移。哌仑西平不改变毒蕈碱激动剂引起的括约肌收缩。另一方面，4-二苯基乙酰氧基-N-甲基哌啶甲基碘化物不改变 McN-A-343 诱导的括约肌松弛，但使 McN-A-343 或氨甲酰甲胆碱引起的括约肌收缩的剂量反应曲线发生剂量依赖性右移。这些研究表明，负鼠食管下括约肌存在两种不同类型的毒蕈碱受体。M1 毒蕈碱受体存在于抑制性神经元上，参与迷走神经节前和壁内节后抑制性神经元之间的突触传递。它们被 McN-A-343 激活，被哌仑西平拮抗。M2 毒蕈碱受体直接位于括约肌肌肉上。它们也被 McN-A-343 激活，但被氨甲酰甲胆碱选择性激活，被 4-二苯基乙酰氧基-N-甲基哌啶甲基碘化物拮抗。
