Stereoselective loss of righting reflex in rats by isoflurane
Stereoselective loss of righting reflex in rats by isoflurane
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DOI：
10.1097/00000542-200009000-00035
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发表时间：
2000-09-01
期刊：
影响因子：
8.8
通讯作者：
Franks, NP
中科院分区：
文献类型：
--
作者：
Dickinson, R;White, I;Franks, NP
背景：尽管光学活性静脉全麻药在动物体内产生立体选择性效应已被广泛接受，但有关挥发性药物的研究情况仍很混乱。对稀有异氟烷对映体的传统研究仅限于少数动物，并产生了相互矛盾的结果。然而，通过静脉注射这些挥发性对映体，有可能在大量动物中进行研究，并获得可靠的结果，有助于确定异氟烷的分子靶点。方法：将纯异氟烷对映体在脂肪乳剂中增溶后静脉注射给药。测定了每个对映体产生翻正反射丧失的能力作为剂量的函数，并绘制了量化的剂量-反应曲线。此外，还记录了每个对映体的睡眠时间。结果：S(+)对映体产生翻正反射的能力比R(-)对映体高40+/-8%。S(+)对映体的睡眠时间比R(-)对映体的睡眠时间长约50%。结论：异氟醚的S(+)对映体比R(-)对映体更易引起大鼠翻正反射的丧失(P<；0.001)。这证实了异氟烷通过与手性位点结合而起作用的观点。观察到的立体选择性程度为从体外实验中确定哪些分子靶点最有可能在异氟烷引起的翻正反射丧失中发挥主要作用提供了有用的指导。
Background: Although it is accepted widely that optically active intravenous general anesthetics produce stereoselective effects in animals, the situation regarding volatile agents is confused. Conventional studies with scarce isoflurane enantiomers have been limited to small numbers of animals and produced conflicting results. By Injecting these volatile enantiomers intravenously, however, it is possible to study large numbers of animals and obtain reliable results that can help to identify the molecular targets for isoflurane.Methods: Pure isoflurane enantiomers were administered intravenously to rats after solubilization in a lipid emulsion. The ability of each enantiomer to produce a loss of righting reflex was determined as a function of dose, and quantal dose-response curves were constructed. In addition, sleep times were recorded with each enantiomer. Chiral gas chromatography was used to measure relative enantiomer concentrations in the brains of rats injected with racemic isoflurane.Results: The S(+)-enantiomer was 40 +/- 8% more potent than the R(-)-enantiomer at producing a loss of righting reflex. The S(+)-enantiomer induced longer sleep times (by about 50%) than did the R(-)-enantiomer. Rats anesthetized by a dose of racemic isoflurane sufficient to achieve a half-maximal effect had essentially identical brain concentrations of the two enantiomers.Conclusions: The S(+)-enantiomer of the general anesthetic isoflurane is significantly (P < 0.001) more potent than the R(-)-enantiomer at causing a loss of righting reflex in rats. This confirms the view that isoflurane acts by binding to chiral sites. The observed degree of stereoselectivity provides a useful guide for ascertaining from in vitro experiments which molecular targets are most likely to play major roles in the loss of righting reflex caused by isoflurane.