PDF(Pubmed)
Abstract：
BACKGROUND: Proper function of the gastro-esophageal high pressure zone is essential for the integrity of the antireflux barrier. Mechanisms include tonic contractions and the decreased tone during transient lower esophageal sphincter relaxations.
METHODS: We characterized the pharmacology of nicotinic receptors mediating relaxations of the human upper gastric sphincter (clasp and sling fibers) using currently available subtype selective nicotinic antagonists in tissue from organ transplant donors. Donors with either a history of gastro-esophageal reflux disease or histologic evidence of Barrett\'s esophagus were excluded. Clasp and sling muscle fiber strips were used for one of three paradigms. For paradigm 1, each strip was exposed to carbachol, washed, exposed to nicotinic antagonists then re-exposed to carbachol. In paradigm 2, strips were exposed to a near maximally effective bethanechol concentration then nicotine was added. Strips then were washed, exposed to nicotinic antagonists then re-exposed to bethanechol followed by nicotine. In paradigm 3, strips were exposed to bethanechol then choline or cytisine.
RESULTS: 100 μM methyllycaconitine has no inhibitory effects on relaxations, eliminating homomeric α7 subtypes. Subtypes composed of α4β2 subunits are also eliminated because choline acts as an agonist and dihydro-beta-erythroidine is ineffective.
CONCLUSIONS: Because mecamylamine blocks the relaxations and both choline and cytisine act as agonists in both clasp and sling fibers, the nicotinic receptor subtypes responsible for these relaxations could be composed of α3β4β2, α2β4, or α4β4 subunits.
METHODS: We characterized the pharmacology of nicotinic receptors mediating relaxations of the human upper gastric sphincter (clasp and sling fibers) using currently available subtype selective nicotinic antagonists in tissue from organ transplant donors. Donors with either a history of gastro-esophageal reflux disease or histologic evidence of Barrett\'s esophagus were excluded. Clasp and sling muscle fiber strips were used for one of three paradigms. For paradigm 1, each strip was exposed to carbachol, washed, exposed to nicotinic antagonists then re-exposed to carbachol. In paradigm 2, strips were exposed to a near maximally effective bethanechol concentration then nicotine was added. Strips then were washed, exposed to nicotinic antagonists then re-exposed to bethanechol followed by nicotine. In paradigm 3, strips were exposed to bethanechol then choline or cytisine.
RESULTS: 100 μM methyllycaconitine has no inhibitory effects on relaxations, eliminating homomeric α7 subtypes. Subtypes composed of α4β2 subunits are also eliminated because choline acts as an agonist and dihydro-beta-erythroidine is ineffective.
CONCLUSIONS: Because mecamylamine blocks the relaxations and both choline and cytisine act as agonists in both clasp and sling fibers, the nicotinic receptor subtypes responsible for these relaxations could be composed of α3β4β2, α2β4, or α4β4 subunits.
摘要：
背景：胃食管高压区的适当功能对于抗反流屏障的完整性至关重要。机制包括短暂的食管下括约肌松弛期间的紧张性收缩和张力降低。
方法：我们使用目前可用的亚型选择性烟碱拮抗剂在器官移植供体的组织中表征了介导人胃上括约肌（扣环和吊带纤维）松弛的烟碱受体的药理学。排除有胃食管反流病病史或Barrett食管组织学证据的供体。表扣和吊带肌纤维条用于三种范例之一。对于范例1，每个条带都暴露于卡巴胆碱，washed,暴露于烟碱拮抗剂，然后再暴露于卡巴胆碱。在范例2中,将条带暴露于接近最大有效的氨甲胆碱浓度,然后添加尼古丁。然后洗涤带子，暴露于烟碱拮抗剂，然后再暴露于苯甲胆碱，然后是尼古丁。在范例3中，将条带暴露于苯甲胆碱，然后暴露于胆碱或金雀花碱。
结果：100μM甲基乌头碱对松弛没有抑制作用，消除同源α7亚型。由α4β2亚基组成的亚型也被消除,因为胆碱充当激动剂并且二氢-β-红定是无效的。
结论：因为美加明阻断了松弛，胆碱和金雀花碱在扣环和吊带纤维中都是激动剂，负责这些松弛的烟碱受体亚型可以由α3β4β2，α2β4或α4β4亚基组成。
方法：我们使用目前可用的亚型选择性烟碱拮抗剂在器官移植供体的组织中表征了介导人胃上括约肌（扣环和吊带纤维）松弛的烟碱受体的药理学。排除有胃食管反流病病史或Barrett食管组织学证据的供体。表扣和吊带肌纤维条用于三种范例之一。对于范例1，每个条带都暴露于卡巴胆碱，washed,暴露于烟碱拮抗剂，然后再暴露于卡巴胆碱。在范例2中,将条带暴露于接近最大有效的氨甲胆碱浓度,然后添加尼古丁。然后洗涤带子，暴露于烟碱拮抗剂，然后再暴露于苯甲胆碱，然后是尼古丁。在范例3中，将条带暴露于苯甲胆碱，然后暴露于胆碱或金雀花碱。
结果：100μM甲基乌头碱对松弛没有抑制作用，消除同源α7亚型。由α4β2亚基组成的亚型也被消除,因为胆碱充当激动剂并且二氢-β-红定是无效的。
结论：因为美加明阻断了松弛，胆碱和金雀花碱在扣环和吊带纤维中都是激动剂，负责这些松弛的烟碱受体亚型可以由α3β4β2，α2β4或α4β4亚基组成。
