RESEARCH OF THE MECHANISM OF GENEKRAL ANESTHESIA-ROLE OF P-GLYCOPROTEIN

P-糖蛋白表达于血脑屏障、肠粘膜等器官的内皮细胞。在血脑屏障中表达的P-糖蛋白在体外可输出多种复合给药。静脉注射局麻药进入中枢神经系统，促进兴奋和痉挛。大脑中的局部麻醉剂也参与了心血管毒性。为了阐明P-糖蛋白在局麻药控制惊厥中的作用，我们建立了一种观察惊厥的清醒、自发呼吸的大鼠模型。实验当天，大鼠吸入氧气七氟醚麻醉。将聚乙烯导管(PE-50和SP-3)分别置入颈动脉和颈静脉。麻醉苏醒后，在t…下以4 mg/kg/分钟静脉注射利多卡因更多地监测血压和心率，直到强直/阵挛惊厥发生。在惊厥开始时，通过静脉注射硫喷妥钠处死大鼠，并从主动脉灌流大鼠的大脑。留置动脉导管取血，测定脑组织中利多卡因及其主要代谢物单乙基甘氨己内酯(MEGX)浓度。使用相同的实验方案来测量外消旋布比卡因(布比卡因)的惊厥效力。根据我们先前的研究测定利多卡因和布比卡因的血药浓度。我们发展了一种新的简单测定脑匀浆中局麻药浓度的新方法。利多卡因的诱导力不受P-糖蛋白奎尼丁的影响。奎尼丁不改变惊厥剂量和布比卡因在脑内的浓度，但显著降低惊厥开始时布比卡因的血浆浓度。这些结果表明，P-糖蛋白参与控制布比卡因在大脑中的浓度，而不是利多卡因。较少

P-glycoprotein is expressed in endothelial cells in the blood brain barrier (BBB), intestinal mucosa and various other organs. P-glycoprotein expressed in BBB exports various compound administered extracorporeally. Intravenously administered local anesthetics are delivered to the central nervous system, promoting excitation and convulsion. Local anesthetics in the brain are also involved in the cardiovascular toxicity. For elucidating the role of P-glycoprotein for controlling convulsions by local anesthetics, we have developed an awake, spontaneously breathing rat model for observing convulsions.Male Sprague-Dawley rats aged 9-10 weeks and weighing 350-400g were housed 12 hour dark and light cycle. On the day of experiment, rat was anesthetized with inhalational sevoflurane in oxygen. Polyethylene catheters (PE-50 and SP-3) were inserted into carotid artery and cervical vein, respectively. After emergence from anesthesia, lidocaine was intravenously administered at 4 mg/kg/min under t … More he monitoring of blood pressure and heart rate until tonic/clonic convulsions occurred. At the onset of convulsions, rats were killed by intravenous administration of thiopental and the brain was perfused from the aorta. Blood sample was obtained from the indwelling arterial catheter and plasma and brain concentrations of lidocaine and its primary metabolite, monoethylglycinexylidide (MEGX) were measured. The same experimental protocol was used for measuring the convulsive potency of racemic bupivacaine (bupivacaine). Plasma concentrations of lidocaine and bupivacaine were measured according to our previous study. We have developed a new method for simple measurement of the concentration of local anesthetics in brain homogenates.Convulsant potency of lidocaine was not affected by pretreatment of a P-glycoprotein, quinidine. Convulsive dose and the concentration of bupivacaine in the brain were not changed by quinidine ; however, plasma concentration of bupivacaine at the onset of convulsinsions was significantly decreased by quinidine. These results suggest that P-glycoprotein is involved in controlling the concentration of bupivacaine, but not lidocaine, in the brain. Less