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

p -糖蛋白在血脑屏障（BBB）内皮细胞、肠黏膜和其他器官中表达。血脑屏障中表达的p -糖蛋白输出体外给药的各种化合物。静脉注射局麻药到中枢神经系统，促进兴奋和抽搐。脑内局部麻醉剂也与心血管毒性有关。为了阐明p -糖蛋白在局部麻醉药控制惊厥中的作用，我们建立了一个清醒、自主呼吸的大鼠模型来观察惊厥。9 ~ 10周龄、体重350 ~ 400g的雄性Sprague-Dawley大鼠进行12小时的明暗循环饲养。实验当天，大鼠吸入性七氟醚含氧麻醉。PE-50和SP-3聚乙烯导管分别插入颈动脉和颈静脉。麻醉苏醒后，以4mg /kg/min的速度静脉注射利多卡因，并监测血压和心率，直至出现强直性/阵挛性惊厥。惊厥发作时，通过静脉注射硫喷妥钠杀死大鼠，并从主动脉灌注大鼠脑。留置动脉导管取血，测定血浆和脑内利多卡因及其主要代谢物甘氨酸乙酯（MEGX）的浓度。同样的实验方案用于测量外消旋布比卡因（布比卡因）的惊厥效力。利多卡因和布比卡因的血药浓度根据我们之前的研究测定。我们开发了一种简单测量脑匀浆中局麻药浓度的新方法。利多卡因的惊厥效力不受p -糖蛋白奎尼丁预处理的影响。奎尼丁不影响大鼠惊厥剂量和脑内布比卡因浓度；然而，在惊厥发作时，奎尼丁显著降低了布比卡因的血浆浓度。这些结果表明p -糖蛋白参与控制大脑中布比卡因的浓度，而不是利多卡因的浓度。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