Duckles S P, Garcia-Villalon A L
Department of Pharmacology, College of Medicine, University of California, Irvine.
J Pharmacol Exp Ther. 1990 May;253(2):608-13.
The goal of this study was to use a functional bioassay to compare muscarinic receptors in two vascular preparations: the rabbit ear artery, which manifests an endothelial-dependent relaxation to cholinergic stimulation, and the bovine coronary artery, in which contraction is elicited independently of the endothelium. Four antagonists were selected, 4-diphenylacetoxy-N-methylpiperidine methobromide, dicyclomine, methoctramine and hexahydrosiladifenidol, to complement previous studies using pirenzepine and 11,2- ([2-(diethylaminomethyl)-1-piperidinyl]acetyl)-5,11-dihydro-6H- pyrido(2,3-b)(1,4)benzodiazepine-6-one, in order to distinguish M1, M2 and M3 receptors. All the antagonists produced competitive inhibition of responses to methacholine, with Schild plot slopes not different from one, with one exception: for 4-diphenylacetoxy-N-methylpiperidine methobromide, Schild plot slopes were greater than one in both tissues. Comparison of antagonist affinities suggests that the muscarinic receptor subtype is not different between the two tissues, despite the different cell types that mediate these responses. Furthermore, the pattern of antagonist affinity agrees most closely with that found previously for the M3 receptor, with high affinity for 4-diphenylacetoxy-N-methylpiperidine methobromide, hexahydrosiladifenidol and dicyclomine, intermediate affinity for pirenzepine, and low affinity for 11,2- ([2-(diethylaminomethyl)-1-piperidinyl]acetyl)-5,11-dihydro-6H- pyrido(2,3-b)(1,4)benzodiazepine-6-one and methoctramine. These findings demonstrate that currently available muscarinic antagonists do not discriminate between receptors found on endothelial and vascular smooth muscle cells, even though the ultimate responses produced are opposed.
兔耳动脉，其对胆碱能刺激表现出内皮依赖性舒张；牛冠状动脉，其收缩不依赖于内皮。选择了四种拮抗剂，即4-二苯基乙酰氧基-N-甲基哌啶甲基溴化物、双环胺、甲奥克明和六氢硅二苯二醇，以补充先前使用哌仑西平和11,2-([2-(二乙氨基甲基)-1-哌啶基]乙酰基)-5,11-二氢-6H-吡啶并(2,3-b)(1,4)苯并二氮杂卓-6-酮的研究，以区分M1、M2和M3受体。所有拮抗剂均对乙酰甲胆碱的反应产生竞争性抑制，Schild图斜率除一个例外均与1无差异：对于4-二苯基乙酰氧基-N-甲基哌啶甲基溴化物，在两种组织中Schild图斜率均大于1。拮抗剂亲和力的比较表明，尽管介导这些反应的细胞类型不同，但两种组织中的毒蕈碱受体亚型并无差异。此外，拮抗剂亲和力模式与先前发现的M3受体最为一致，对4-二苯基乙酰氧基-N-甲基哌啶甲基溴化物、六氢硅二苯二醇和双环胺具有高亲和力，对哌仑西平具有中等亲和力，对11,2-([2-(二乙氨基甲基)-1-哌啶基]乙酰基)-5,11-二氢-6H-吡啶并(2,3-b)(1,4)苯并二氮杂卓-6-酮和甲奥克明具有低亲和力。这些发现表明，目前可用的毒蕈碱拮抗剂无法区分在内皮细胞和血管平滑肌细胞上发现的受体，即使产生的最终反应是相反的。
