| Owing to the advantage of quick effect,short duration,prompt revival and surgery-free memory, Propofol (2,6-diisopropylphenol) has been widely used in general anesthesia induction and maintenance and used as a sedative agent in the intensive care unit (ICU). Many researches have been done to investigate the anesthetic mechanism of propofol, but it has not been made out very clearly today. As we know, brain is the effective organ of intravenous anesthetics, the research of cerebeal uptake and distribution of popofol is favourable to explore the mechanism of general anesthesia of popofol.The anatomic structure and distribution of central nervous systems have a certain degree of specificity, so that the anesthetic agents to play its role in the pharmacology of narcotic site also selective. The central GABAA receptor is the major inhibitory receptor in the central nervous system. It scatters in the brain, but the distribution is disequilibrium in different brain tissues and it is more intensive in some cerebral tissues. A number of studys showed that the central GABAA receptor represents an important target in mediating the anesthetic mechanism of propofol. Synaptic theory is one of the most important theories of general mechanism.The doctrine suppose that general anesthesia drugs may target on the synaptic transmission, the main function of the propofol may be on GABA receptors. GABA receptors activated can increase nervous conductance and depolarization, resulting in the anesthesia process. Basing on these researches, it can be assumed that propofol concentrations are discordant in various cerebral tissues. Therefore, the cerebral uptake and regional distribution of propofol must be investigated for the understanding of its anesthetic mechanism.1,In 1988, Upton put forward the concept of cerebral uptake and the method of mass balancing principles. By measuring the propofol concentrations in arterial and venous blood of cerebral circulation, in addition cerebral blood flow, we can calculate the feature of the cerebral uptake of propofol indirectly, but the character of regional distribution of propofol in the brain can not be revealed objectively yet by this method. To improve the research of cerebral uptake of propofol, the propofol concentrations in different parts of the brain must be detected directly by anatomical methods. Shyr and Larsson had compared the propofol distribution of brain tissues in the Sprague Dawley rat respectively. Shyr discovered that the cerebral uptake of propofol was equilibrium in different brain tissues,but Larsson discovered that the midbrain was different to the other brain function area in intaking propofol. It may be injected factor, state of brain uptake, and species of experimental animal that influence the cerebral uptake and distribution of propofol. The previous experiments used the SD rat as the experimental animal. Due to the significant differences between the mouse brain structure and function and the human brain's, it is difficult to generalize the experimental results. It is necessary to further study with a more high-grade animal. The function district and the structure of dog brain are similar with that of the human brain, and the volume and the quality of dog brain are bigger than the mouse brain's, furthermore, there has obvious anatomical landmark so as to get the obvious regional tissues in dog brain. We had measured the propofol concentrations in different cerebral tissues under different depth of anesthesia at a single bolus in dogs. Experimental results shown that the propofol concentration was highest in pons when the animal's eyes closed without stimulation and in thalamus when the eyelid reflex disappeared respectively, and lowest in hippocampus under the both anesthesia conditions.Under different depth of anesthesia at a single bolus intravenous injection of propofol, the difference of propofol concentrations between internal carotid artery and jugular vein was significant and showed that the cerebral uptake of propofol was underway. The late study indicated that at 30 min a constant rate of 70mg/(kg·h) intravenous injection of propofol, propofol was distributed dynamic evenly among regional cerebral tissues in dogs, but the thalamus constains high propofol concentration; at 50 min cerebral uptake of propofol achieved stable equilibrium state, propofol was distributed evenly in the cerebral tissues in dogs.The chief aim of this study is to mesure the propofol concentrations of different cerebral tissues bying HPLC-UV and to investigate the cerebral uptake and regional distribution of propofol under the circumstance of noxious stimulation at cerebral uptake quilibrium of propofol in dogs.Material and methods12 healthy male dogs aged 12-18 months were divided randomly into two groups (group S and C). All the experiment were scheduled during the day and fasting in diet for 12-hour were prior to experiment. The venous channel was established in the great saphenous vein of the right posterior limb. Propofol was intravenously injected respectively at a single bolus 7mg·kg-1 in group S and group C in 15 sec. after their eyelid reflex and pedal reflex disappeared, animals were fixed supinely on the platform. The constant intravenous infusion of propofol was taken at a rate of 70mg/(kg·h) to maintain anesthesia.When the infusion of propofol was at the 50th min,animals of group S were given stimulation to the end of its tail by hemostat for lmin. Animals of group C were given no stimulation.The blood samples were taken from the right internal carotid and internal jugular vein at the 51th min in group S and at the 50th min in group C. Then the animal was scarificed immediately by decapitation. The dorsal thalamus,epithalamus,metathalamus,hypothalamus,subthalamus,frontal lobe,parietal lobe,temporal lobe,hippocampus,cingulate gyrus,cerebellum,midbrai,pons,were further dissected for determination the concentrations of propofol.Propofol concentration was determined by HPLC-UV. External standard was a control article of propofol. The analysis was performed with a Shim-pack VP-ODS, 250x4.6mmID, Shim-pack GVP-ODS,10×4.6mmID and a 2996 Waters ultraviolet detector (270nm). The solvent system was purified water-methanol at flow rate of 1ml·min-1.The brain samples were extracted with acetonitrile (2ml·g-1) and homogenized and the blood samples were extracted with acetonitrile (di-volume). After being centrifuged, the supernatant was submitted to HPLC analysis. The sample volume is 20μl.Measurement data were expressed as mean±standard deviation. All data were analysed with the Statistics Package for Social Sciences (SPSS, version 13.0 for WINDOWS; SPSS Inc., Chicago, IL, USA). We used the Independent-Samples T Test,Paired-Samples T Test and Repeated Measure to test for differences. Multiple comparisons were analyzed by LSD test.Differences were considered statistically significant when P was less than 0.05.Results1.All experimental animals reached safely and quickly the condition of anesthesia and maintained a stable status.2.The propfol concentration in blood plasma:The concentration of propofol in internal carotid artery and internal jugular vein blood plasma were 6.16±1.04,6.16±0.49μg/ml (t=0.002,P=0.999) in group S and 6.17±1.00,6.16±0.99μg/ml(t=0.252,P=0.811)in group C respectively, the differences between them were not statistically significant.3. The propofol concentration in brain tissues:In group C, the propofol concentrations of the dorsal thalamus,epithalamus,metathalamus,hypothalamus,subthalamus,frontal lobe,parietal lobe,temporal lobe,hippocampus,cingulate gyrus,cerebellum,midbrain,pons were 6.12±0.50,6.08±0.67,6.08±0.89,6.21±0.73,6.12±0.51,6.08±0.31,6.05±0.63,6.12±0.70,6.09±0.58,6.06±0.97,6.08±1.04,6.03±0.99,6.11±0.75(μg/g) respectively(F=0.037, P=0.948) and no significant differences.In group S, the propofol concentrations of dorsal thalamus,epithalamus,metathalamus,hypothalamus,subthalamus,frontal lobe,parietal lobe,temporal lobe,hippocampus,cingulate gyrus,cerebellum,midbrain,pons were 8.99±0.77,6.13±1.10,6.12±1.10,6.11±0.94,9.13±0.53,6.11±0.99,6.11±0.93,6.10±0.90,6.10±0.94,6.13±0.96,6.11±1.04,6.10±0.93,6.11±0.96 (μg·g-1) respectively (F=17.207,P=0.000). The propofol concentration in the dorsal thalamus (8.99±0.77μg·g-1) and subthalamus (9.13±0.53ug/g) was higher than these any other brain tissues'(P<0.05).The propofol concentrations were no significant difference between group S and C (P> 0.05).The brain tissues concentrations of propofol exist interaction with noxious stimulus (F=10.575, P=0.000).The concentration of propofol in dorsal thalamus and subthalamus were highest under the condition of balance of the brain uptake and noxious stimulus.Conclusions1 At 50 min a constant rate of 70mg/(kg-h) intravenous injection of propofol, there is no significant differences in propofol concentration between jugular venous blood and carotid arterial blood and show whole brain uptake of propofol achieve a equilibrium state. Propofol is distributed evenly among all the region of brain tissues. 2 Under the circumstance of noxious stimulation, the propofol concentration in dorsal thalamus and subthalamus are higher than that in other cerebral regions (epithalamus,metathalamus,hypothalamus,frontal lobe,parietal lobe,temporal lobe,hippocampus,cingulate gyrus,cerebellum,midbrain,pons),which is in equilibrious distribution of propofol in the later. |
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