PROPOFOL ACTIVATES GABA(A) RECEPTOR-CHLORIDE IONOPHORE COMPLEX IN DISSOCIATED HIPPOCAMPAL PYRAMIDAL NEURONS OF THE RAT
PROPOFOL ACTIVATES GABA(A) RECEPTOR-CHLORIDE IONOPHORE COMPLEX IN DISSOCIATED HIPPOCAMPAL PYRAMIDAL NEURONS OF THE RAT
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DOI：
10.1097/00000542-199310000-00021
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发表时间：
1993-10-01
期刊：
影响因子：
8.8
通讯作者：
IKEMOTO, Y
中科院分区：
文献类型：
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作者：
HARA, M;KAI, Y;IKEMOTO, Y
背景异丙酚麻醉的分子机制与促进γ-氨基丁酸（GABA）介导的抑制性神经传递有关。在目前的研究中，作者研究了异丙酚对急性分离的哺乳动物中枢neurons.Methods的直接行动：海马锥体神经元的酶处理后的大鼠脑片分离。采用膜片钳技术的全细胞配置对单个神经元进行电压钳位，并通过快速给药系统进行给药。结果：在-60mV电压钳位的锥体神经元中，异丙酚诱发跨膜内向电流，该电流在高浓度麻醉剂下脱敏。随着丙泊酚剂量的增加，电流的峰值幅度呈S形增加。最小二乘拟合得到解离常数为1.2 × 10（-5）m，希尔系数为1.8，从而表明临床浓度的异丙酚诱发电流，麻醉剂协同激活通道。阈值浓度小于10（-6）M。电流的反转电位根据能斯特方程预测的氯平衡电位移动，表明电流由氯离子携带。荷包牡丹碱和士的宁抑制电流的浓度依赖性的方式，其中前者几乎是40倍，比后者更有效。丙泊酚诱导的电流与GABA诱导的电流交叉脱敏，但没有观察到这样的相互作用与甘氨酸诱导的电流。Ro 15 -1788（10（-6）M）是一种别构苯二氮卓类拮抗剂，对反应无影响。地西泮（10（-6）M）可增强丙泊酚诱导的电流，而戊巴比妥（10（-6）M和3 × 10（-5）M）对电流无影响。结论：临床相关浓度的丙泊酚可直接激活哺乳动物中枢神经元中的GABA（A）受体-氯离子载体复合物，从而增加氯离子电导，这可能有助于麻醉剂产生麻醉作用。在高浓度丙泊酚存在下，GABA（A）受体的脱敏可能导致GABA（A）抑制系统受到抑制。
Background. The molecular mechanism of propofol anesthesia has been related to facilitation of the inhibitory neurotransmission mediated by gamma-aminobutyric acid (GABA). In the current study, the authors examined the direct actions of propofol on the acutely dissociated mammalian central neurons.Methods: Hippocampal pyramidal neurons were dissociated after enzymatic treatment of the brain slices of the rat. Single neurons were voltage-clamped using the whole cell configuration of the patch clamp technique, and drugs were applied with a rapid drug-application system.Results: In the pyramidal neurons voltage-clamped at -60 mV, propofol evoked a transmembrane inward current, which desensitized at high concentrations of the anesthetic. The peak amplitude of the current increased sigmoidally with increasing doses of propofol applied. A least-squares fitting gave a dissociation constant of 1.2 x 10(-5) m and a Hill coefficient of 1.8, thereby indicating that clinical concentrations of propofol evoke the current, and that the anesthetic cooperatively activates the channel. The threshold concentration was less than 10(-6) M. The reversal potential for the current shifted according to the chloride equilibrium potential predicted by the Nernst equation, indicating that the current was carried by chloride ions. Bicuculline and strychnine suppressed the current in a concentration-dependent manner, in which the former was almost 40-fold more potent than the latter. The propofol-induced current cross-desensitized with the GABA induced current, but no such interaction was observed with the glycine-induced current. Ro15-1788 (10(-6) M), an allosteric benzodiazepine antagonist, had no effect on the response. Diazepam (10(-6) M) enhanced the propofol-induced current, but pentobarbital (10(-6) m and 3 x 10(-5) M) did not affect the current.Conclusions: Propofol at clinically relevant concentrations directly activates the GABA(A) receptor-chloride ionophore complex in the mammalian central neurons and, hence, increases the chloride conductance, which may contribute to anesthesia produced by the agent. The desensitization of the GABA(A) receptor in the presence of high concentrations of propofol may result in a suppression of the GABA(A) inhibitory system.