Correlation between the anaesthetic effect of halothane and saturable binding in brain
Correlation between the anaesthetic effect of halothane and saturable binding in brain
复制标题
氟烷麻醉效果与脑内饱和结合的相关性
作者：
A. Evers;B. Berkowitz;D. D'avignon
挥发性麻醉剂作用的分子机制的两种理论表明，麻醉剂引起神经元膜结构的普遍扰动，可能是通过与膜脂质的非特异性相互作用1，2，或者麻醉剂结合到膜蛋白3 -5上的适当分子尺寸的位点。基于最近的发现，氟化麻醉剂可以通过19 F核磁共振（19 F-NMR）光谱6在动物组织中观察到，我们使用19 F-NMR来量化挥发性麻醉剂氟烷和大鼠脑组织之间的相互作用。稳态脑氟烷浓度被认为是吸入浓度的非线性函数，在吸入氟烷浓度高于2.5%（体积）时发生明显的脑饱和。使用自旋回波脉冲序列，发现氟烷存在于大脑中的两种不同的化学环境中，其特征在于不同的自旋-自旋-弛豫时间（T2）、化学位移和占据动力学。其中一种环境（T2=3.6ms）中的氟烷浓度在吸入氟烷浓度为2.5%时达到饱和;发现该环境的占用率与药物的麻醉作用相关。在另一种环境中（T2=43 ms），脑氟烷浓度是吸入浓度的线性函数。这些数据表明氟烷在脑内存在一个可饱和的麻醉部位，不支持麻醉剂通过非特异性膜扰动起作用的概念。
Two theories of the molecular mechanism of volatile anaesthetic action suggest either that anaesthetics cause a generalized perturbation of neuronal membrane structure, probably through a nonspecific interaction with membrane lipids1,2, or that anaesthetics bind to sets of sites of appropriate molecular dimension on membrane proteins3–5. Based on the recent finding that fluorinated anaesthetics can be observed in animal tissue by 19F nuclear magnetic resonance (19F-NMR) spectroscopy6, we have used 19F-NMR to quantify the interaction between the volatile anaesthetic halothane and rat brain tissue. Steady-state brain halothane concentration was found to be a non-linear function of inspired concentration, with apparent saturation of brain occurring at inspired halothane concentrations above 2.5% by volume. Using a spin-echo pulse sequence it was found that halothane exists in two distinct chemical environments in brain, characterized by different spin-spin –relaxation times (T2), chemical shifts and kinetics of occupancy. Halothane concentration in one of these environments (T2=3.6ms) was saturated at ∼2.5% inspired halothane; occupancy of this environment was found to correlate with the anaesthetic effect of the drug. In the other environment (T2=43 ms), brain halothane concentration was a linear function of inspired concentration. These data suggest the existence of a saturable anaesthetic site for halothane in brain and do not support the concept that anaesthetics act by nonspecific membrane perturbation.