Srivastava K, Hatanaka T, Katayama K, Koizumi T
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Japan.
Biol Pharm Bull. 1999 Mar;22(3):288-94. doi: 10.1248/bpb.22.288.
We have previously reported that brain sensitivity to thiopental with respect to electroencephalogram (EEG) is enhanced in uranyl acetate pretreated renal dysfunction rats. The results were attributed to pharmacodynamic factors. In this study, in vivo EEG and in vitro binding studies for gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex were performed to investigate the mechanism of the enhanced effect of thiopental. The receptor binding properties in the brain membrane from normal and renal dysfunction rats were examined using [3H]tertbutylbicycloorthobenzoate (TBOB), [3H]flunitrazepam and [3H]muscimol. The effect of plasma dialysate from normal (ND) and renal dysfunction rats (RDD) on the thiopental induced EEG and receptor binding were also examined to confirm the role of endogenous compounds. The intrinsic receptor binding characteristics of various sites and their allosteric interaction with thiopental was similar in membrane preparations from normal and renal dysfunction rats. However, RDD, when compared to ND, enhanced the EEG induced by thiopental. At the receptor level, RDD significantly enhanced the thiopental induced inhibition of TBOB. No difference was found between the influence of ND and RDD on the interaction between thiopental and flunitrazepam or muscimol binding. These results showed that the thiopental induced allosteric inhibition of TBOB binding was potentiated by some endogenous compounds in RDD and suggests that this action might be the mechanism, at least in part, for the increased sensitivity of thiopental in renal dysfunction rats.
我们之前报道过，在醋酸铀预处理的肾功能不全大鼠中，大脑对硫喷妥钠的脑电图（EEG）敏感性增强。结果归因于药效学因素。在本研究中，进行了体内EEG和γ-氨基丁酸（GABA）-苯二氮䓬受体复合物的体外结合研究，以探讨硫喷妥钠增强作用的机制。使用[3H]叔丁基双环邻苯二甲酸酯（TBOB）、[3H]氟硝西泮和[3H]蝇蕈醇检测正常大鼠和肾功能不全大鼠脑膜中的受体结合特性。还检测了正常大鼠（ND）和肾功能不全大鼠（RDD）的血浆透析液对硫喷妥钠诱导的EEG和受体结合的影响，以确认内源性化合物的作用。正常大鼠和肾功能不全大鼠的膜制剂中，各部位的内在受体结合特性及其与硫喷妥钠的变构相互作用相似。然而，与ND相比，RDD增强了硫喷妥钠诱导的EEG。在受体水平，RDD显著增强了硫喷妥钠诱导的TBOB抑制作用。ND和RDD对硫喷妥钠与氟硝西泮或蝇蕈醇结合相互作用的影响未发现差异。这些结果表明，RDD中的一些内源性化合物增强了硫喷妥钠诱导的TBOB结合变构抑制作用，提示这一作用可能至少部分是肾功能不全大鼠中硫喷妥钠敏感性增加的机制。
