Lambrecht G, Gross J, Mutschler E
Department of Pharmacology, Biocentre Niederursel, University of Frankfurt, Germany.
Life Sci. 1999;64(6-7):403-10. doi: 10.1016/s0024-3205(98)00579-7.
A variety of neurons in gastrointestinal and genitourinary smooth muscle express muscarinic auto- as well as heteroreceptors. These receptors are found on the soma and dendrites of many cholinergic, sympathetic and NANC neurons and on axon terminals. A given neuron may contain both excitatory and inhibitory presynaptic muscarinic receptors. The subtypes involved are species- and tissue-dependent, and neuronal M1 to M4 receptors have been shown to be expressed in smooth muscle tissues. In this study, the ability of several selective muscarinic receptor antagonists to inhibit the effect of arecaidine propargyl ester (APE) on prejunctional muscarinic receptors on sympathetic nerve endings in the rabbit anococcygeus muscle (RAM) was investigated to characterise the receptor subtype involved. Electrical field stimulation (EFS) resulted in a release of noradrenaline (NA) eliciting monophasic contractions due to stimulation of postjunctional alpha1-adrenoceptors. The selective muscarinic agonist APE did not reduce contractions to exogenous NA, but caused a concentration-related and N-methylatropine-sensitive inhibition of neurogenic responses. All muscarinic antagonists investigated failed to affect the EFS-induced contractions, but shifted the concentration-response curve of APE to the right in a parallel and surmountable fashion. Schild analysis yielded regression lines of unit slope, indicating competitive antagonism. The following rank order of antagonist potencies (pA2 values) was found: tripitramine (9.10) > AQ-RA 741 (8.26) > or = himbacine (8.04) > or = (S)-dimethindene (7.69) > pirenzepine (6.46) > or = p-F-HHSiD (6.27). A comparison of the pA2 values determined in the present study with literature binding and functional affinities obtained at native or recombinant M1 to M5 receptors strongly suggests that NA release from sympathetic nerve endings in RAM is inhibited by activation of prejunctional muscarinic M2 receptors.
胃肠道和泌尿生殖系统平滑肌中的多种神经元表达毒蕈碱自身受体以及异源受体。这些受体存在于许多胆碱能、交感神经和非肾上腺素能非胆碱能（NANC）神经元的胞体和树突以及轴突终末上。一个特定的神经元可能同时含有兴奋性和抑制性突触前毒蕈碱受体。所涉及的亚型因物种和组织而异，并且已证实在平滑肌组织中表达神经元M1至M4受体。在本研究中，研究了几种选择性毒蕈碱受体拮抗剂抑制槟榔次碱炔丙酯（APE）对兔肛门尾骨肌（RAM）交感神经末梢上突触前毒蕈碱受体作用的能力，以确定所涉及的受体亚型。电场刺激（EFS）导致去甲肾上腺素（NA）释放，由于刺激了突触后α1 - 肾上腺素能受体而引发单相收缩。选择性毒蕈碱激动剂APE并未减少对外源性NA的收缩反应，但引起了浓度相关且对N - 甲基阿托品敏感的神经源性反应抑制。所研究的所有毒蕈碱拮抗剂均未影响EFS诱导的收缩，但以平行且可克服的方式将APE的浓度 - 反应曲线向右移动。Schild分析产生单位斜率的回归线，表明为竞争性拮抗作用。发现拮抗剂效能（pA2值）的以下顺序：曲吡那敏（9.10）> AQ - RA 741（8.26）≥樟柳碱（8.04）≥（S） - 二甲茚定（7.69）>哌仑西平（6.46）≥对氟苯海索（6.27）。将本研究中确定的pA2值与在天然或重组M1至M5受体上获得的文献结合和功能亲和力进行比较，强烈表明RAM中交感神经末梢的NA释放受到突触前毒蕈碱M2受体激活的抑制。
