Effects of thiopental and its optical isomers on nicotinic acetylcholine receptors.
Effects of thiopental and its optical isomers on nicotinic acetylcholine receptors.
复制标题
硫喷妥钠及其旋光异构体对烟碱乙酰胆碱受体的影响。
作者：
D. Downie;N. Franks;W. R. Lieb
背景
除γ-氨基丁酸A（GABAA）受体外，硫喷妥钠麻醉作用的主要分子靶点尚未确定。神经元烟碱乙酰胆碱受体（nAChR）与GABAA受体密切相关，因此也可能是主要靶点。如果是这样的话，它们可能被手术浓度（EC 50 = 25 μ m）的硫喷妥钠显著抑制，并显示与全身麻醉相同的立体选择性。
方法
神经元α 4 β 2，神经元α 7和肌肉alphaetagammadelta nAChRs在非洲爪蟾卵母细胞中表达。使用双电极电压钳技术在-70 mV处测量乙酰胆碱激活的峰值电流。外消旋硫喷妥钠和它的两个光学异构体应用和不预孵育，并在高和低浓度的乙酰胆碱。
结果
抑制所有三个nAChR增强预孵育硫喷妥钠，一个协议，模仿体内的药理学情况。使用该方案，高浓度的乙酰胆碱进一步增强了抑制作用，硫喷妥钠对神经元α 4 β 2、神经元α 7和肌肉α γ δ nAChR的IC 50分别为18 +/- 2、34 +/- 4和20 +/- 2 μ m（平均值+/- SEM），希尔系数接近1。无论是神经元α 7还是肌肉alphaetagammadelta nAChR之间的光学异构体的硫喷妥钠分化。然而，R（+）-硫喷妥钠在抑制神经元α 4 β 2 nAChR方面明显比S（-）异构体更有效;有趣的是，这与它们用于全身麻醉的立体选择性完全相反。
结论
中枢神经元和外周肌肉nAChR可以在手术EC 50浓度下被硫喷妥钠显著抑制，但没有立体选择性或与全身麻醉相反。因此，nAChR可能不是产生硫喷妥钠麻醉的关键靶点，尽管nAChR可能在该药物产生的副作用中起作用。
BACKGROUND
With the exception of gamma-aminobutyric acidA (GABAA) receptors, the major molecular targets underlying the anesthetizing actions of thiopental have yet to be established. Neuronal nicotinic acetylcholine receptors (nAChRs) are closely related to GABAA receptors and hence might also be major targets. If so, they might be expected to be substantially inhibited by surgical concentrations (EC50 = 25 micrometer) of thiopental and to display the same stereoselectivity as does general anesthesia.
METHODS
Neuronal alpha4beta2, neuronal alpha7 and muscle alphabetagammadelta nAChRs were expressed in Xenopus oocytes. Peak acetylcholine-activated currents were measured at -70 mV using the two-electrode voltage clamp technique. Racemic thiopental and its two optical isomers were applied with and without preincubation and at high and low concentrations of acetylcholine.
RESULTS
Inhibition of all three nAChRs was enhanced by preincubation with thiopental, a protocol that mimics the pharmacologic situation in vivo. Using this protocol, inhibition was further enhanced by high concentrations of acetylcholine, with IC50 = 18 +/- 2, 34 +/- 4, and 20 +/- 2 micrometer (mean +/- SEM) thiopental for the neuronal alpha4beta2, neuronal alpha7 and muscle alphabetagammadelta nAChRs, respectively, with Hill coefficients near unity. Neither the neuronal alpha7 nor the muscle alphabetagammadelta nAChR differentiated between the optical isomers of thiopental. However, R(+)-thiopental was significantly more effective than the S(-) isomer at inhibiting the neuronal alpha4beta2 nAChR; interestingly, this is diametrically opposite to their stereoselectivity for general anesthesia.
CONCLUSIONS
Both central neuronal and peripheral muscle nAChRs can be substantially inhibited by thiopental at surgical EC50 concentrations but with either no stereoselectivity or one opposite to that for general anesthesia. Thus, nAChRs are probably not crucial targets for producing thiopental anesthesia, although nAChRs may play a part in the side effects produced by this agent.
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3.6
作者：
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通讯作者：
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DOI：
--
发表时间：
1994-11
期刊：
The Journal of pharmacology and experimental therapeutics
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DOI：
--
发表时间：
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期刊：
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影响因子：
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影响因子：
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