Eltze M, Ullrich B, Mutschler E, Moser U, Bungardt E, Friebe T, Gubitz C, Tacke R, Lambrecht G
Department of Pharmacology, Byk Gulden Pharmaceuticals, Konstanz, Germany.
Eur J Pharmacol. 1993 Jul 20;238(2-3):343-55. doi: 10.1016/0014-2999(93)90866-g.
The muscarinic receptor mediating vasodilation of resistance vessels in the rat isolated, constant-pressure perfused kidney (preconstriction by 10(-7) M cirazoline) was characterized by subtype-preferring agonists and selective antagonists. The agonists produced vasodilation with the following rank order of potency: arecaidine propargyl ester (APE) > 5-methylfurtrethonium = methacholine = oxotremorine > (S)-aceclidine > arecaidine 2-butyne-1,4-diyl bisester > 4-Cl-McN-A-343 = (R)-nipecotic acid ethyl ester = N-ethyl-guvacine propargyl ester approximately (R)-aceclidine = (S)-nipecotic acid ethyl ester > McN-A-343. Agonist-induced vasodilation disappeared after destruction of the endothelium with detergent. Highly significant correlations of agonist potencies for vasodilation were found between rat kidney and guinea-pig ileum submucosal arterioles as well as agonist potencies at smooth muscle muscarinic M3 receptors of the guinea-pig ileum. The rank order of antagonist potencies (4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) > (R)-hexahydro-difenidol approximately hexahydro-sila-difenidol > pirenzepine approximately p-fluoro-hexahydro-sila-difenidol approximately himbacine approximately AF-DX 384 approximately AQ-RA 741 > (S)-hexahydro-difenidol) to attenuate vasodilation to APE in rat kidney, correlated significantly with affinities at M3 receptors in submucosal arterioles and in smooth muscle of the guinea-pig ileum, but differed from those at M1 and M2 receptors in rabbit vas deferens. The agonist and antagonist potencies suggest that vasodilation elicited by muscarinic stimuli in endothelium-intact rat renal vasculature is mediated by functional muscarinic M3 receptors.
通过亚型选择性激动剂和选择性拮抗剂对介导大鼠离体恒压灌注肾脏（用10⁻⁷ M西拉唑啉预收缩）中阻力血管舒张的毒蕈碱受体进行了表征。激动剂产生舒张血管作用，其效价顺序如下：槟榔碱炔丙酯（APE）＞5-甲基呋氨甲酰胆碱 = 乙酰甲胆碱 = 氧化震颤素＞（S）-阿塞利定＞槟榔碱2-丁炔-1,4-二醇双酯＞4-氯-McN-A-343 = （R）-哌啶甲酸乙酯 = N-乙基-古豆碱炔丙酯≈（R）-阿塞利定 = （S）-哌啶甲酸乙酯＞McN-A-343。在用去污剂破坏内皮后，激动剂诱导的血管舒张消失。在大鼠肾脏和豚鼠回肠黏膜下小动脉之间以及在豚鼠回肠平滑肌毒蕈碱M3受体处的激动剂效价与血管舒张之间发现了高度显著的相关性。拮抗剂效价（4-二苯基乙酰氧基-N-甲基哌啶甲碘化物（4-DAMP）＞（R）-六氢二苯茚醇≈六氢硅二苯茚醇＞哌仑西平≈对氟六氢硅二苯茚醇≈辛巴辛≈AF-DX 384≈AQ-RA 741＞（S）-六氢二苯茚醇）减弱大鼠肾脏中对APE的血管舒张作用，与豚鼠回肠黏膜下小动脉和平滑肌中M3受体的亲和力显著相关，但与兔输精管中M1和M2受体的亲和力不同。激动剂和拮抗剂的效价表明，在内皮完整的大鼠肾血管系统中，毒蕈碱刺激引起的血管舒张是由功能性毒蕈碱M3受体介导的。
