雌激素预处理和怀孕大鼠子宫中毒蕈碱受体的药理学特性

Pharmacological characterization of muscarinic receptors in the uterus of oestrogen-primed and pregnant rats.

作者信息

Munns M, Pennefather J N

机构信息

Department of Pharmacology, Monash University, Clayton, Victoria, Australia.

出版信息

Br J Pharmacol. 1998 Apr;123(8):1639-44. doi: 10.1038/sj.bjp.0701794.

DOI:10.1038/sj.bjp.0701794

PMID:9605571

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1565341/

Abstract

Radioligand binding and contractility studies were undertaken to determine the subtype/s of muscarinic receptors present in uteri of oestrogen-treated and late pregnant rats. 2. Competition binding studies with uterine membrane preparations and [3H]-QNB (quinuclidinyl benzilate) provided negative log dissociation constants (pKi) for each antagonist as follows; oestrogen-treated - atropine (7.98) > or = himbacine (7.83) > methoctramine (7.52) > or = hexahydrosiladiphenidol (HHSiD; 7.32) > or = 5,11-dihydro- 11-[[[2-[2 - [(dipropylamino)methyl] - 1 piperidinyl]ethyl]amino] - carbonyl] - 6H-pyrido-[2,3-b][1,4]- benzodiazepin-6-one (AF-DX 384; 7.10)> 11 -[[2- [(diethylamino)methyl]-1-piperidinyl]-acetyl]5,11-dihydro-6H-pyridol+ ++]2,3,-b][1,4]benzodiazepin-6-one (AF-DX 116, 6.77)>pirenzepine (6.17); late pregnant atropine (8.05)> or =methoctramine (7.95)> or =himbacine (7.71)> or =HHSiD (7.52)> or =AF-DX 384 (7.34)>AF-DX 116 (6.72)>pirenzepine (6.18). 3. The potency of carbachol in causing uterine contraction was similar in preparations from pregnant and non-pregnant animals (pD2=5.57 and 5.46, respectively). Each muscarinic antagonist caused parallel, rightward shifts of carbachol concentration-response curves. The pA2 estimates were: oestrogen-treated - atropine (9.42)> himbacine (8.73) HHSiD (8.68) methoctramine (8.49)> or =AF-DX 384 (7.91)> or =AF-DX 116 (7.36)> or =pirenzepine (7.26); late pregnant atropine (9.48)>himbacine (8.37)> or = HHSiD (8.22) > or =methoctramine (8.01) > or =AF-DX 116 (7.73)> or = AF-DX 384 (7.44)> or = pirenzepine (6.92). 4. The relative pKi estimates for antagonists obtained in membrane preparations from oestrogen-treated rats suggest the presence of muscarinic M2 subtypes. In functional studies pA2 values indicated the additional presence of muscarinic M3 receptor or, possibly an atypical receptor subtype. The similarity between pKi and pA2 estimates obtained in uteri from oestrogen-treated and pregnant animals, respectively, indicates that pregnancy does not affect myometrial muscarinic receptors in the rat.

摘要

进行放射性配体结合和收缩性研究，以确定雌激素处理的大鼠和妊娠晚期大鼠子宫中存在的毒蕈碱受体亚型。2. 用子宫膜制剂和[3H]-QNB（喹宁环基苯甲酸酯）进行竞争结合研究，得出各拮抗剂的负对数解离常数（pKi）如下：雌激素处理组——阿托品（7.98）≥樟柳碱（7.83）＞甲奥克胺（7.52）≥六甲铵（HHSiD；7.32）≥5,11-二氢-11-[[[2-[2-[(二丙基氨基)甲基]-1-哌啶基]乙基]氨基]-羰基]-6H-吡啶并-[2,3-b][1,4]-苯并二氮杂卓-6-酮（AF-DX 384；7.10）＞11-[[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（AF-DX 116，6.77）＞哌仑西平（6.17）；妊娠晚期组——阿托品（8.05）≥甲奥克胺（7.95）≥樟柳碱（7.71）≥六甲铵（7.52）≥AF-DX 384（7.34）＞AF-DX 116（6.72）＞哌仑西平（6.18）。3. 卡巴胆碱引起子宫收缩的效力在妊娠和未妊娠动物的制剂中相似（pD2分别为5.57和5.46）。每种毒蕈碱拮抗剂均使卡巴胆碱浓度-反应曲线平行右移。pA2估计值为：雌激素处理组——阿托品（9.42）＞樟柳碱（8.73）＞六甲铵（8.68）＞甲奥克胺（8.49）≥AF-DX 384（7.91）≥AF-DX 116（7.36）≥哌仑西平（7.26）；妊娠晚期组——阿托品（9.48）＞樟柳碱（8.37）≥六甲铵（8.22）≥甲奥克胺（8.01）≥AF-DX 116（7.73）≥AF-DX 384（7.44）≥哌仑西平（6.92）。4. 从雌激素处理的大鼠的膜制剂中获得的拮抗剂相对pKi估计值表明存在毒蕈碱M2亚型。在功能研究中，pA2值表明还存在毒蕈碱M3受体或可能存在非典型受体亚型。分别在雌激素处理的大鼠和妊娠大鼠子宫中获得的pKi和pA2估计值之间的相似性表明，妊娠不影响大鼠子宫肌层的毒蕈碱受体。