A case of propofol toxicity: further evidence for a causal mechanism

A 5-month-old boy required sedation after a cleft lip repair. He was sedated with propofol and intermittent fentanyl, requiring escalating doses over the subsequent 48 h. On the second post-operative day he developed a metabolic acidosis followed by multiple cardiac dysrhythmias, hepatic and renal failure. Propofol was stopped. His multisystem organ failure gradually resolved after initiation of charcoal haemoperfusion. Further investigation demonstrated an abnormality in acylcarnitine metabolism, similar to that found in one previous case report.     

The mechanism of inhibitory actions of propofol on rat supraoptic neurons.

BACKGROUND: In the perioperative period, plasma osmotic pressure, systemic blood pressure, and blood volume often change dramatically. Arginine vasopressin is a key factor in the regulation of these parameters. This study was performed to evaluate the direct and the mechanism of the actions of propofol on arginine vasopressin release from magnocellular neurosecretory neurons in the rat supraoptic nucleus. METHODS: Somatodendritic arginine vasopressin release from supraoptic nucleus slice preparations was measured by radioimmunoassay. Ionic currents were measured using the whole-cell mode of the patch-clamp technique in supraoptic nucleus slice preparations or in single dissociated supraoptic nucleus neurons of the rat. RESULTS: Propofol at concentrations greater than 10(-5) M inhibited the arginine vasopressin release stimulated by potassium chloride (50 mM). This inhibition by propofol was not reversed by picrotoxin, a gamma-aminobutyric acid(A)(GABA(A)) receptor antagonist, whereas arginine vasopressin release induced by glutamate (10(-3) M) was also inhibited by propofol at a clinically relevant concentration (10(-6) M). The latter effect was reversed by picrotoxin. Propofol evoked Cl- currents at concentrations ranging 10(-6) to 10(-4) M. Propofol (10(-6) M) enhanced the GABA (10(-6) M)-induced current synergistically. Moreover, propofol (10(-6) M) prolonged the time constant of spontaneous GABA-mediated inhibitory postsynaptic currents. Furthermore, propofol (10(-5) M and 10(-4) M) reversibly inhibited voltage-gated Ca2+ currents, whereas it did not affect currents induced by glutamate (10(-3) M). CONCLUSIONS: Propofol inhibits somatodendritic arginine vasopressin release from the supraoptic nucleus, and the enhancement of GABAergic inhibitory synaptic inputs and the inhibition of voltage-gated Ca2+ entry are involved in the inhibition of arginine vasopressin release.     

Origins of cortical GABAergic neurons in the cynomolgus monkey

In human most cortical gamma-aminobutyric acidergic (GABAergic) neurons are produced in the proliferative zones of the dorsal telencephalon in contrast to rodents. We report that in cynomolgus monkey fetuses cortical GABAergic neurons are generated in the proliferative zones of the dorsal telencephalon, in addition to the proliferative region of the ventral telencephalon, the ganglionic eminence (GE), however, with a temporal delay. GABAergic neuron progenitors labeled for Mash1 and GAD65 were present mainly in the GE at embryonic days (E) 47-55, and in the entire dorsal telencephalon at E64-75. These progenitors within the dorsal telencephalon are generated locally rather than in the GE. The ventral and dorsal lineages of cortical GABAergic neurons display different laminar distribution. Early generated GABAergic neurons from the GE mostly populate the marginal zone and subplate, whereas cortical plate GABAergic neurons originate from both ventral and dorsal telencephalon. A differential regulation of the two GABA synthesizing enzymes (GAD65 and GAD67) parallels GABAergic neuron differentiation. GAD65 is preferentially expressed in GABAergic progenitors and migrating neurons, GAD67 in morphologically differentiated neurons. Therefore, the dorsal telencephalic origin of cortical GABAergic neurons is not human-specific but appears as a former event in the ascent of evolution that could provide GABAergic neurons to an expending neocortex.     

Reorganization of actin in neurons after propofol exposure

BACKGROUND: It has previously been shown that propofol in clinically relevant concentrations induces a calcium-dependent conformational change in the cytoskeleton. The aim of this study was to further clarify the effect of propofol on the actin cytoskeleton and to determine if this conformational change is mediated by the interaction between the GABA(A)-receptor and propofol. METHODS: Primary cultured cortical neurons from newborn rats were treated with propofol 3 microg x ml(-1) in a time-response titration, with and without preincubation with the GABA(A)-receptor antagonist, bicuculline. Actin-protein content was detected by Western blot analysis and the cellular content of F-actin measured by a spectrophotometric technique. RESULTS: Propofol triggers a relatively slow statistically significant increase in the intracellular F-actin content, maximum after 20-min incubation (160%+/-16.3) (mean+/-SEM) P<0.05. The propofol-induced increase in F-actin was effectively blocked by bicuculline. The increase in intracellular actin content after exposure to propofol as well as the effect of bicuculline were verified by Western blot analysis. CONCLUSION: The present study shows that propofol triggers a time-dependent change of actin. Since this reorganization can be blocked effectively by a GABA(A)-receptor antagonist, this suggests that the GABA(A)-receptor is involved in the pathway leading to cytoskeletal reorganization after propofol treatment. The actin polymerization reached its maximum after 20 min. Therefore, we believe that the propofol-induced changes might be connected with slower cellular responses such as cell-to-cell interaction and/or channel regulation.     

丙泊酚生殖毒性的研究现状

背景丙泊酚是临床常用的静脉全麻药,其安全性及是否会对接受丙泊酚麻醉的患者造成损害倍受麻醉医生关注。目的回顾近年来国内外关于丙泊酚生殖毒性方面的研究情况,总结实验方法。内容丙泊酚在动物实验研究中发现其可致未发育成熟大脑神经损伤。丙泊酚用于人工体外受精的镇痛或镇静时,卵细胞内有丙泊酚蓄积,用于孕妇的产科和非产科手术时后代是否受该药的影响还存在争议。趋向丙泊酚生殖毒性亟待更多的临床研究,用于评估全麻药对后代影响的方法还有待进一步完善。     

Three distinct families of GABAergic neurons in rat visual cortex

In the cortex inhibition is mediated predominantly by GABAergic interneurons. Although all of these neurons use the same neurotransmitter, studies in the rat frontal cortex have shown that they are molecularly and physiologically diverse. It is not known whether similar subgroups of GABAergic neurons exist in primary visual cortex and how these different inhibitory neurons are inserted into specific cortical circuits. We have used immunostaining with antibodies against gamma aminobutyric acid (GABA), parvalbumin (PV), calretinin (CR), somatostatin (SOM), calbindin (CB) and nitric oxide synthase (NOS) to probe for colocalization of known markers of GABAergic interneurons. The results show that the majority of PV (100%), SOM (89.8%) and CR (93.9%) staining neurons are GABA positive. PV immunoreactive neurons constitute a distinct group that show no overlap with CR, SOM and NOS expressing cells and only a minor overlap (5.3%) with CB. PV immunoreactive cells account for 50.8% of GABAergic neurons. A second group of SOM expressing neurons accounts for 16.9% of GABAergic cells. None of these cells colocalize PV or CR, but 1.7% of SOM neurons stain for NOS and 86.3% show CB immunoreactivity. The third distinct group of CR expressing cells accounts for 17.0% of GABAergic neurons. All of these are PV, CB, SOM and NOS negative. CB expressing neurons represent a heterogeneous group that includes GABAergic and non- GABAergic cells. Our findings indicate that GABAergic neurons in rat area 17 are organized in at least three separate families that can be identified by the expression of PV, CR and SOM. These cells account for 84.9% of GABAergic neurons. These results extend previous observations in rat frontal agranular cortex and suggest that in visual cortex the inhibitory network is composed of similar cell types.      

异丙酚对大鼠海马神经元钾离子通道的影响

目的 采用大鼠海马神经元作为研究对象,研究异丙酚对神经元的瞬间外向钾通道、延迟整流钾通道的影响,以探讨静脉麻醉药作用的可能机制。方法 在急性分离的大鼠海马锥体神经元上,利用全细胞膜片钳技术,记录瞬间外向、延迟整流两种钾离子通道的电流。研究异丙酚对这些通道电流幅度和通道动力学的作用。结果 异丙酚对上述通道电流均具有抑制作用,呈可逆性和浓度依赖性,并对离子通道的激活和失活曲线有一定的影响。异丙酚对瞬间外向钾通道和延迟整流钾通道作用的EC50分别为(71±18)和(37±18)μmol·-1,最大抑制率分别为52％±3％和32％±5％。结论 异丙酚对海马神经元上的瞬间外向钾电流、延迟整流钾电流有不同程度抑制作用。异丙酚对锥体神经元兴奋性的影响,可能与影响记忆功能有关。     

丙泊酚对布比卡因中枢及心脏毒性的治疗作用

目的 观察丙泊酚对布比卡因系统毒性的治疗作用.方法 24只雄性SD大鼠随机分为丙泊酚组(P)和对照组(C),每组12只.以肢体Ⅱ导联监测ECG;暴露大鼠股动脉,置入24G套管针监测动脉BP,同时暴露大鼠股静脉,置入24G套管针泵注0.5%布比卡因2 mg·kg-1·min-1.记录其发生抽搐、ECG出现心律失常和MAP≤40 mm Hg的时间.当MAP≤40 mm Hg时,立即停止泵注布比卡因,P组经静脉恒速泵注丙泊酚50 mg/kg(容积为5 ml/kg).而C组经静脉恒速泵注生理盐水5 ml/kg,两组均5 min内泵注完.记录大鼠出现室性心律失常、惊厥和MAP≤40 mm Hg毒性反应的时间和布比卡因累计剂量.开始复苏后每5分钟的MAP、HR和大鼠生存时间.结果 泵注布比卡因后,两组间大鼠发生心律失常、惊厥及MAP≤40 mm Hg的毒性反应时间、布比卡因的累计剂量差异均无统计学意义.与C组相比,泵注布比卡因至MAP≤40 mm Hg时应用丙泊酚处理,可显著改善大鼠的MAP和HR,明显提高大鼠的生存率(P＜0.05).结论 丙泊酚对严重的布比卡因中毒时有明显的治疗效应.     

Connectivity of GABAergic calretinin-immunoreactive neurons in rat primary visual cortex.

In rat visual cortex neurons that are immunoreactive for the calcium-binding protein calretinin (CR+) constitute a distinct family which accounts for 17% of gamma-aminobutyric acid (GABA)-expressing cells. It is not clear, however, (i) whether CR is expressed exclusively in GABAergic neurons and (ii) how CR+ neurons are incorporated into neuronal circuits of rat visual cortex. To address these questions we studied synaptic relationships of CR+ neurons with GABA+ and GABA- elements in the neuropil of rat primary visual cortex (area 17). All CR+ neurons are nonpyramidal cells with smooth or sparsely spiny and often beaded dendrites. Of all CR+ neurons, 56% are located in layers 1 and 2/3. In layer 2/3, most CR+ neurons are bipolar-shaped and have vertically oriented dendrites. Many ascending dendritic branches reach layer 1 where they run parallel to pial surface. CR+ axons are thin, highly branched near the cell body and often send descending collaterals to layers 5 and 6. Double immunofluorescence labeling revealed GABA in 94% of CR+ cell bodies in layer 2/3. Electron microscopic analysis shows that all CR+ axon terminals contain elongated vesicles and form symmetric synapses. Postembedding staining shows that 98% of CR+ terminals are GABA+. GABA-immunoreactivity is also present in somata and thick dendrites of CR+ neurons but many thin dendrites are GABA-. CR+ somata, dendrites and axon terminals are enriched in mitochondria. Somata and thick CR+ dendrites are densely innervated. At least 68% of the targets of CR+ terminals in layer 2/3 are GABA+ and > or = 50% of these are other CR+ neurons. The remainder (32%) of targets of CR+ terminals are thin dendrites of GABA- cells. In contrast, in layers 5 and 6, 60% of CR+ terminals form synapses with GABA- somatic profiles. The preferential interactions of layer 2/3 CR+ neurons with GABAergic neurons, and with CR+ neurons in particular, suggests that these cells play a role in the inhibition of inhibitory neurons of the same layer. Through these interactions CR+ cells may reduce inhibition of pyramidal cells in layers 2/3, 5 and 6 and thus disinhibit a column of neurons.     

Correlating in vivo anaesthetic effects with ex vivo receptor density data supports a GABAergic mechanism of action for propofol, but not for isoflurane

If the in vivo effects of anaesthesia are mediated through aspecific receptor system, then a relationship could exist betweenthe regional changes in brain metabolism caused by a particularagent and the underlying regional distribution of the specificreceptors affected by that agent. Positron emission tomographydata from volunteers studied while unconscious during propofol(n=8) or isoflurane (n=5) anaesthesia were used retrospectivelyto explore for evidence of relationships between regional anaestheticeffects on brain glucose metabolism and known (ex vivo) regionaldistribution patterns of human receptor binding sites. The regionalmetabolic reductions caused by propofol differed significantlyfrom those of isoflurane. Propofol’s reductions negativelycorrelated most significantly with the regional distributionof [³H]diazepam and [³H]flunitrazepam (benzodiazepine) bindingsite densities (r=–0.86, P<0.0005; r=–0.79, P<0.005,respectively) and less strongly with [³H]naloxone (opioid) bindingdensity (r=–0.69, P<0.05). Isoflurane’s reductionspositively correlated only with muscarinic (acetylcholine) bindingdensity (r=0.85, P<0.05). These findings are consistent withthe hypothesis that some of propofol’s in vivo anaestheticeffects may be mediated through a GABAergic mechanism and suggestsome of isoflurane’s in vivo effects might involve antagonismof central acetylcholine functioning. Br J Anaesth 2001; 86: 618–26     

Biochemical and electrophysiologic evidence that propofol enhances GABAergic transmission in the rat brain.

The influence of propofol, a new intravenous anesthetic agent, on brain gamma-aminobutyric acid (GABA)-ergic transmission has been investigated both in vitro and in vivo. In vitro, propofol, like benzodiazepines, 1) markedly enhanced 3H-GABA binding in cortical membrane preparations; 2) potentiated muscimol-induced stimulation of 36Cl- uptake in membrane vesicle preparations (the propofol potentiating effect was antagonized by bicuculline); and 3) inhibited 35S-TBPS binding to unwashed membrane preparations from rat cerebral cortex. Finally, propofol failed to displace 3H-flunitrazepam from its binding site, indicating that its site of action in brain is different from that of benzodiazepines. In vivo, the effect of propofol was studied using single-unit recording of the electrical activity of both nondopaminergic neurons in the pars reticulata of the substantia nigra (PR neurons) and of dopaminergic neurons in the pars compacta of the substantia nigra (DA neurons). PR neurons are known to be inhibited by GABA-mimetic drugs and benzodiazepines, whereas DA neurons are tonically inhibited by PR neurons. The intravenous administration of propofol, in a fat emulsion formulation, produced a brief dose-dependent inhibition of the firing rate of PR neurons. The dose producing 50% inhibition of the firing rate was calculated to be 1.2 +/- 0.1 mg/kg. The inhibitory effect lasted less than 5 min. Repeated injections of propofol reproduced the same inhibitory response, whereas continuous infusion (0.5 mg.kg-1.min-1) produced a persistent inhibition of neuronal firing. The inhibitory effect of propofol on PR neurons was potentiated by diazepam and reversed by picrotoxin and bicuculline but was not influenced by the benzodiazepine antagonist Ro 15-1788. These findings suggest that propofol exerts a GABA-mimetic action on PR neurons by acting on a site distinct from the benzodiazepine recognition site. Unlike benzodiazepines, propofol inhibited the firing rate of DA neurons with a potency proportional to its inhibitory effect on PR neurons. The inhibition of DA neurons was reversed by bicuculline and picrotoxin. The results suggest that propofol enhances the inhibitory control over DA neurons by strionigral GABAergic neurons.     

Quantitative chemical composition of cortical GABAergic neurons revealed in transgenic venus-expressing rats

Although neocortical GABAergic (gamma-aminobutyric acidergic) interneurons have been the focus of intense study, especially in the rat, a consensus view of the functional diversity and organization of inhibitory cortical neurons has not yet been achieved. To better analyze GABAergic neurons in the rat, we used a bacterial artificial chromosome (BAC) construct and established 2 lines of transgenic rats that coexpress Venus, a yellow fluorescent protein, with the vesicular GABA transporter. The brain GABA content from both transgenic lines was similar to the level found in wild-type rats. In the frontal cortex, Venus was expressed in >95% of GABAergic neurons, most of which also expressed at least one of 6 biochemical markers, including alpha-actitin-2, which preferentially labeled late-spiking neurogliaform cells. Taking advantage of the fact that Venus expression allows for targeted recording from all classes of nonpyramidal cells, irrespective of their somatic morphologies, we demonstrated that fast-spiking neurons, which were heterogeneous in somatic size as well as vertical dendritic projection, had relatively uniform horizontal dimensions, suggesting a cell type-specific columnar input territory. Our data demonstrate the benefits of VGAT-Venus rats for investigating GABAergic circuits, as well as the feasibility of using BAC technology in rats to label subsets of specific, genetically defined neurons.     

Nitrous oxide activates GABAergic neurons in the spinal cord in Fischer rats

BACKGROUND: Findings to date indicate that nitrous oxide exerts its antinociceptive effect by activating descending noradrenergic neurons. The mechanism whereby descending inhibitory neurons, including noradrenergic neurons, produce antinociceptive effect remains unclear. Using c-Fos protein as a marker for neuronal activation, we examined whether spinal cord neurons activated by nitrous oxide are y-aminobutyric acid-mediated (GABAergic) neurons. METHODS: Adult male Fischer (a strain in which nitrous oxide shows strong antinociceptive properties) and Lewis (a strain in which nitrous oxide lacks antinociceptive properties) rats were exposed to either air (control) or nitrous oxide. Frozen sections of the spinal cord were either stained for c-Fos or double-stained for c-Fos and glutamic acid decarboxylase (a rate-limiting enzyme for GABA synthesis) and analyzed by standard or confocal microscopy. RESULTS: In Fischer rats, 90 min of 75% N2O administration increased the number of c-Fos-positive cells in the spinal cord approximately threefold as compared with the control group. The c-Fos-positive cells induced by nitrous oxide were almost entirely colocalized with glutamic acid decarboxylase-positive cells. In contrast, exposure did not change the number of c-Fos-positive cells in the spinal cord in Lewis rats. CONCLUSIONS: Exposure to nitrous oxide activates GABAergic neurons in the spinal cord. The dose-dependence of GABAergic neuronal activation in the Fischer rats and its absence in the Lewis rat correlate with antinociceptive responses previously reported in these same circumstances. Together, we interpret these data to indicate that activation of GABAergic neurons in the spinal cord are involved in the antinociceptive action of nitrous oxide.     

异丙酚对交感神经元钠通道电流的影响

目的 研究异丙酚对交感神经元他细胞钠通道电流的影响。探讨基金上 因管扩张机制。方法 酶消化法急性分离ＳＤ大鼠（８～１２ｄ）颈上交感神经节细胞,应用全细胞膜片钳技术记录异丙酚对钠通道电流以的影响。结果 在钳制电压（Ｖｈ）～８０ｍＶ,刺激电压（Ｖｔ）０ｍＶ条件下,临床相关浓度的异丙酚（５．６μｍｏｌ／Ｌ）使钠通道电流峰值降２７．６６％（Ｐ〈０．０１）,随浓度增加,抑制作用逐渐增强（ｒ＝０．９８２。Ｐ〈     

丙泊酚诱导大鼠原代培养皮层神经元凋亡

目的探讨丙泊酚对原代培养皮层神经元凋亡的影响及可能机制。方法原代培养7d的大鼠皮层神经元,随机分为两组:对照组(给予相同容积的20%脂肪乳剂)和丙泊酚组(丙泊酚终浓度为500μmol/L),上述药物处理12h后,采用MTT法检测两组神经元存活率,Hoechst33258核染色法检测神经元的凋亡,罗丹明染色检测线粒体膜电位,Western blot法检测神经元cyt-c和cleaved-caspase-3蛋白含量。结果丙泊酚组皮层神经元存活率(54.4%±6.4%),明显低于对照组(99.8%±4.1%)(P0.05);神经元凋亡率(46.5%±5.3%),明显高于对照组(7.2%±0.9%)(P0.05),线粒体膜电位(59.6%±4.3%)明显低于对照组(99.9%±5.7%)(P0.05);cyt-c蛋白含量(0.38±0.03),明显高于对照组(0.15±0.02)(P0.05),cleaved-caspase-3蛋白含量(0.46±0.04)明显高于对照组(0.13±0.02)(P0.05)。结论丙泊酚可诱导发育期原代培养皮层神经元凋亡,其机制可能与抑制线粒体膜电位,增加cyt-c和cleaved-caspase-3蛋白含量有关。     

Actions of propofol on pontine neurons controlling arterial pressure in rats

Tonic firing of pontine neurons provides excitatory input to the vasomotor centre in the ventrolateral medulla. To increase our understanding of the actions of propofol on CNS neurons controlling the cardiovascular system, we evaluated the effects of propofol on this tonic firing of pontine neurons. The actions of propofol (doses 1?4, respectively; 24 ± 2, 40 ± 4, 65 ± 3 and 104 ± 3 mg · kg^?1 · hr^?1) on the pontine neurons were studied using eight atropinized Wistar rats. Electrical activity of renal sympathetic nerves, systemic arterial blood pressure and heart rate were recorded. Propofol decreased renal nerve activity by 3 ± 2%, 23 ± 3%, 33 ± 3% and 52 ± 4% at the four doses. Arterial pressure and heart rate decreased similarly in a dose-dependent manner. Sympathetic and cardiovascular responses to blocking neurons in the pontine reticular formation by microinjection of glycine were depressed by propofol. Renal nerve activity was decreased by 44 ± 5%, 41 ± 4%, 28 ± 3% and 13 ± 2% after pontine blockade during infusion of doses 1 to 4, respectively. Similarly, arterial pressure was decreased by 25 ± 3, 15 ± 2, 12 ± 1 and 5 ± 2 mmHg. Finally, heart rate decreased by 27 ± 6, 20 ± 4, 18 ± 4 and 13 ±5 beats per min as the propofol dose increased. The tonic firing of pontine neurons was minimally depressed by the lower two doses of propofol but higher doses did appear to depress their firing, demonstrating dose-dependence of actions of this anaesthetic. In conclusion, at light levels of propofol anaesthesia, the hypotensive effects probably relate mostly to direct actions on the heart and peripheral vasculature because central sympathetic control of the circulation is not markedly disrupted. As the depth of anaesthesia is increased, selective effects on CNS vasomotor neurons become more apparent leading to depression of excitatory pontine inputs to the vasomotor neurons in the medulla.     

Aluminum bone toxicity in immature rats exposed to simulated high altitude

Aluminum (Al) is an element to which humans are widely exposed. Chronic administration induces a negative effect on bone tissue, affecting collagen synthesis and matrix mineralization. Its toxic effects are cumulative. Hypobaric hypoxia induces stress erythropoiesis, leading to hypertrophy of the erythropoietic marrow affecting the bone. This study was designed to evaluate the risk of Al bone toxicity among immature rats maintained at simulated high altitude (SHA) by mechanical assessment of stiffness and strength, calculation of some indicators of bone material and geometrical properties, as well as blood determinations. Forty growing rats were divided into control and experimental groups whether injected with vehicle or Al, as Al(OH)₃, three times a week for 3 months. Half of each group was exposed to hypobaric conditions (HX) by placing the animals in a SHA chamber. Both treatments negatively affected structural properties of bones, decreasing the maximum capacity to withstand load, the limit elastic load and the capacity of absorbing energy in elastic conditions. Al administration significantly depressed mandible structural stiffness, although diaphyseal stiffness was not modified. Indicators of bone material intrinsic properties, elastic modulus and stress, were significantly reduced by Al or HX. Treatments increased the diaphyseal sectional bending moment of inertia, suggesting that femur, but not mandible, compensates for the decline in the material properties with an adaptation of its architecture to maintain structural properties. The different biomechanical behaviors between the two kinds of bone are probably due to their different embryological origin and specific functions, as mandible is a bone that adjusts its strength to biting forces, whereas femur is designed to support load.     

异丙酚或依托咪酯对幼龄大鼠海马神经元凋亡的影响

目的 评价异丙酚或依托咪酯对幼龄大鼠海马神经元凋亡的影响.方法 雄性SD大鼠140只,4周龄,体重40～60 g,采用随机数字表法,将大鼠随机分为7组(n=20):对照组(C组)、异丙酚50 mg/kg组(P1组)、异丙酚100 mg/kg组(P2组)、异丙酚200 mg/kg组(P3组)、依托咪酯10 mg/kg组(E1组)、依托咪酯30 mg/kg组(E2组)和依托咪酯60 mg/kg组(E3组).P1组和E1组单次腹腔注射异丙酚50 mg/kg或依托咪酯10 mg/kg;P2组、P3组、E2组和E3组首次注射异丙酚50 mg/kg或依托咪酯10 mg/kg,待大鼠有体动反应后,再每次追加异丙酚50 mg/kg或依托咪酯10 mg/kg,直至给完总量.大鼠苏醒2h时,每组取5只大鼠,抽取动脉血样进行血气分析.每组取5只大鼠,取海马CA1区,电镜下观察超微结构.每组取5只大鼠,取海马组织,采用RT-PCR法测定Survivin mRNA和Caspase-3mRNA的表达.每组取5只大鼠,取海马组织,采用Western blot法测定Survivin蛋白和Caspase-3蛋白的表达.结果 七组间pH值、PaO2、PaCO2、HCO3-、BE和SaO2比较差异无统计学意义(P＞0.05).与C组比较,P1组、P2组、E1组和E2组海马Survivin和Caspase-3的mRNA和蛋白表达差异无统计学意义(P＞0.05),P3组和E3组海马Survivin mRNA和蛋白表达下调,Caspase-3 mRNA和蛋白表达上调(P＜0.05),海马CA1区神经元出现核固缩、染色质边集及凋亡小体.结论 较大剂量异丙酚和依托咪酯可能通过抑制Survivin的表达,增强Caspase-3的活性,导致幼龄大鼠海马神经元凋亡.