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Investigation on regulatory mechanism of acetylcholine release at cholinergic nerve endings.

胆碱能神经末梢乙酰胆碱释放调节机制的研究

基本信息

批准号：
62570995
负责人：
KAWASHIMA Koichiro
金额：
$ 1.34万
依托单位：
Kyoritsu College of Pharmacy
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1987
资助国家：
日本
起止时间：
1987 至 1988
项目状态：
已结题

项目摘要

To investigate subtypes of nuscarinic receptor regulating acetylcholine (ACh) release at cholinertic nerve endings, a radioimmunoassay (RIA) for ACh was applied to the direct determination of ACh release in longitudinal muscle strips of guinea pig ileum. The strips were preincubated with irreversible cholinesterase inhibitor and superfused with Kreds' solution under various experimental conditions. Pirenzepine (PZ), a specific M_1 antagonist, produced an increase in electrically evoked ACh release at a concentrtion of 100-times less than that inhibiting the electrically evoked contractile response. On the other hand, atropine (AT), a nonspecific muscarinic antagonist, produced an inhibition of presynaptic muscarinic receptors at a concentration of 10-fold less than that inhibiting postsynaptic muscarinic receptors. These results suggest that presyn aptic M_1 receptors regulating ACh release may be present in the guinea pig ileum.To confirm our previous data, the effect of three muscari … More nic antagonists on electrically evoked ACh release and contractile response were investigated in the same preparation. Telenzapine (TZ), a selective M_1 antagonist, increased electrically evoked ACh release at a concentration of 100-fold less than that inhiditing the contractile response. AF-DX 116, a cardioselective M_2 entagonist, inhibited the contractile response at 10 uM, but did not affect electrically evoked ACh release at this concentration. (-)N-Methylscopolamine (NMS) produced an inhibition of the contractile response without any effect on ACh release. The data-obtained in the present and previous studies demonstrate that presynaptic muscarinic receptors modulating ACh release can be classified as M_1 subtype.To examine effect of TRH on ACh release in the central nervous system, high potassium (50 mM)-evoked ACh release from rat basal forebrain slices was betermined using a RIA. TRH (100 uM) caused a slight and statistically insignificant increase in potassium-evoked ACh release. DN-1417, a TRH analogue, at a concentration of 100 uM increased potassium-evoked ACh release significantly. These findings indicate that DN-1417 is able to increase ACh release in the central nervous system at a high concentration. Less

为研究调节胆碱神经末梢乙酰胆碱释放的神经碱受体亚型，采用放射免疫法（RIA）直接测定豚鼠回肠纵肌条乙酰胆碱释放量。在不同的实验条件下，用不可逆胆碱酯酶抑制剂进行预孵育，并用Kreds溶液进行超滤。特异性M_1拮抗剂吡renzepine （PZ）对乙酰胆碱（ACh）的电诱发释放量的增加比抑制电诱发收缩反应的浓度少100倍。另一方面，阿托品（AT），一种非特异性毒蕈碱拮抗剂，对突触前毒蕈碱受体的抑制浓度比抑制突触后毒蕈碱受体的浓度低10倍。上述结果提示豚鼠回肠中可能存在调节乙酰胆碱释放的前突触aptic M_1受体。为了证实我们之前的研究结果，我们研究了三种麝香草抗剂在相同的制备条件下对电诱发的乙酰胆碱释放和收缩反应的影响。选择性M_1拮抗剂特仑扎平（Telenzapine， TZ）在低于抑制收缩反应100倍的浓度下，增加了电诱发的乙酰胆碱释放。AF-DX 116是一种心脏选择性的M_2拮抗剂，在10 μ m时抑制收缩反应，但在此浓度下不影响电诱发的ACh释放。（-） n -甲基东莨菪碱（NMS）对收缩反应有抑制作用，但不影响乙酰胆碱的释放。本研究和以往的研究数据表明，突触前毒蕈碱受体调节ACh释放可归类为M_1亚型。为了研究TRH对中枢神经系统乙酰胆碱释放的影响，采用RIA法测定高钾（50 mM）诱发的大鼠基底前脑片乙酰胆碱释放。TRH （100 uM）引起钾诱导的乙酰胆碱释放轻微增加，统计学上不显著。TRH类似物DN-1417在100um浓度下显著增加钾诱导的乙酰胆碱释放。这些结果表明，DN-1417在高浓度时能够增加中枢神经系统乙酰胆碱的释放。少