Hara M, Kai Y, Ikemoto Y
Department of Dental Anesthesiology, Faculty of Dentistry, Kyushu University, Fukuoka, Japan.
Anesthesiology. 1994 Oct;81(4):988-94. doi: 10.1097/00000542-199410000-00026.
Activation of the gamma-aminobutyric acidA (GABAA) receptor-ionophore complex has been reported as a possible molecular mechanism of the anesthetic action of propofol. Augmentation of GABA-induced inhibitory transmission has also been suggested as a mechanism. Because data describing this latter mechanism in mammalian neurons are few, we have examined the effects of propofol on the GABA response in central neurons of the rat.
Hippocampal pyramidal neurons were dissociated after enzyme treatment of the rat brain slices. The neurons were voltage-clamped with the whole cell configuration of the patch clamp technique. Neurotransmitters and drugs were applied using the "Y-tube" method, which exchanges the extracellular solutions around the neuron within 10-20 ms and makes it possible to obtain the peak response before desensitization develops.
In pyramidal neurons voltage-clamped at -60 mV, GABA induced an inward current. Propofol (10(-6) M) augmented the current and shifted the concentration-response curve for GABA to the left without affecting the maximum response. A low concentration of the anesthetic (10(-6) M) reduced the dissociation constant for GABA from 8.2 x 10(-6) to 4.2 x 10(-6) M without a significant effect on the Hill coefficient. Coapplication of propofol at a higher concentration (5 x 10(-6) M) also shifted the GABA dose-response curve to the left, reducing the dissociation constant to 2.8 x 10(-6) M. Potentiation by propofol was not associated with a change in the reversal potential for the GABA response and was not voltage-dependent. The inhibitory glycine response was not affected by propofol (10(-6) M or 5 x 10(-6) M).
Propofol at clinically relevant concentrations enhances the inhibitory GABAA receptor-mediated response in mammalian central neurons. The enhancement may result in reduced excitability of the neuronal network and may, consequently, contribute to the anesthetic action of the agent.
据报道，γ-氨基丁酸A（GABAA）受体-离子载体复合物的激活是丙泊酚麻醉作用的一种可能分子机制。也有人提出增强γ-氨基丁酸（GABA）诱导的抑制性传递是一种机制。由于描述哺乳动物神经元中后一种机制的数据很少，我们研究了丙泊酚对大鼠中枢神经元GABA反应的影响。
用酶处理大鼠脑片后分离出海马锥体细胞。采用膜片钳技术的全细胞模式对神经元进行电压钳制。使用“Y形管”方法施加神经递质和药物，该方法可在10 - 20毫秒内交换神经元周围的细胞外溶液，并能够在脱敏发生前获得峰值反应。
在钳制电压为-60 mV的锥体细胞中，GABA诱导内向电流。丙泊酚（10⁻⁶ M）增强了该电流，并使GABA的浓度-反应曲线向左移动，而不影响最大反应。低浓度麻醉剂（10⁻⁶ M）使GABA的解离常数从8.2×10⁻⁶降至4.2×10⁻⁶ M，而对希尔系数无显著影响。更高浓度（5×10⁻⁶ M）的丙泊酚共同应用也使GABA剂量-反应曲线向左移动，将解离常数降至2.8×10⁻⁶ M。丙泊酚的增强作用与GABA反应的反转电位变化无关，且不依赖电压。抑制性甘氨酸反应不受丙泊酚（10⁻⁶ M或5×10⁻⁶ M）影响。
临床相关浓度的丙泊酚增强了哺乳动物中枢神经元中抑制性GABAA受体介导的反应。这种增强可能导致神经元网络兴奋性降低，从而可能有助于该药物的麻醉作用。
