| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2004: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
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
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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
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