Pitschner H F, Schulte B, Neuzner J, Wellstein A, Palm D, Schlepper M
Kerckhoff-Klinik Bad Nauheim.
Z Kardiol. 1994;83 Suppl 5:9-20.
The cDNAs for five different muscarinic cholinoceptors have been cloned. The biochemical and physiological relevance of the m1, m2 and m3 receptors is understood in many aspects. The pharmacological defined M1, M2 and M3 related to antagonists binding studies closely correspond with those cloned. We compared effects of atropine and of the subtype selective M-cholinoceptor antagonists pirenzepine and AF-DX 116 in humans. Dose- or time-response curves have been established for heart rate. Plasma samples were drawn in parallel with the effect measurements and analysed for drug concentrations. Subtype-selective radioceptor assays of the samples served to estimate the respective receptor occupancy in vivo. After low dosis of pirenzepine (M1-selective blockade) a negative chronotropic effect on heart rate could be observed. After high doses of pirenzepine or atropine (M-unselective blockade) the wellknown tachycardia appeared in parallel with occupancy of both the M2 and M3 subtypes. AF-DX 116 induced a tachycardia without a decrease of salivary flow in agreement with its selectivity profile (M2 > M1 > M3). Gastric emptying was only slightly inhibited by AF-DX 116 but nearly completely by a very high dose of pirenzepine blocking M1-, M2- and M3-cholinoceptors. The negative chronotropic effect on heart rate of a low dose of pirenzepine (M1 selective) was multi-folded by pretreatment with isoprenaline but disappeared during bicycle exercise. The implications of the functional M cholinoceptor heterogeneity in humans revealed by antagonists are discussed according to its possible importance for the control of autonomous nerve system.
已克隆出五种不同毒蕈碱型胆碱能受体的cDNA。m1、m2和m3受体在生物化学和生理学方面的相关性在许多方面已为人所知。药理学上定义的与拮抗剂结合研究相关的M1、M2和M3与克隆的受体密切对应。我们比较了阿托品以及亚型选择性M胆碱能受体拮抗剂哌仑西平和AF-DX 116在人体中的作用。已建立心率的剂量-或时间-反应曲线。在进行效应测量的同时采集血浆样本，并分析药物浓度。对样本进行亚型选择性放射受体测定以估计体内各自的受体占有率。低剂量哌仑西平（M1选择性阻断）后，可观察到对心率的负性变时作用。高剂量哌仑西平或阿托品（M非选择性阻断）后，众所周知的心动过速与M2和M3亚型的占有率同时出现。AF-DX 116诱导心动过速且唾液分泌无减少，与其选择性概况（M2>M1>M3）相符。AF-DX 116仅轻微抑制胃排空，但高剂量哌仑西平阻断M1、M2和M3胆碱能受体时几乎完全抑制胃排空。低剂量哌仑西平（M1选择性）对心率的负性变时作用在用异丙肾上腺素预处理后增强，但在自行车运动时消失。根据拮抗剂揭示的人体功能性M胆碱能受体异质性对自主神经系统控制的可能重要性，讨论了其意义。
