地氟醚预处理对局灶性脑缺血再灌注损伤保护作用的研究
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摘要
当今脑血管疾病在世界范围内仍为第三大死因，因此这方面的研究一直是目前医学研究热点之一。脑卒中一旦发生，严重影响患者生存质量，甚至危及生命。虽然脑卒中的治疗措施很多，如中医、西医等方法，但其疗效都不尽人意。因此，脑卒中重在预防，贵在预防。近几年来，在脑保护研究领域兴起的药物预处理方法实质上是一种预防措施。一些麻醉药预处理的脑保护作用已被研究证实。地氟醚预处理是否诱导脑缺血耐受作用的产生及其机制等方面的研究尚未见报道。本实验采用大鼠局灶性脑缺血模型，首次应用DWI磁共振技术评估缺血再灌注24h脑梗死容积，旨在探讨：(1)重复地氟醚预处理是否诱导产生延迟性脑缺血耐受作用；(2)单次短时间地氟醚预处理诱导急性脑缺血耐受的可行性；(3)腺苷A_1受体拮抗剂对地氟醚预处理诱导急性脑缺血耐受的影响。
实验一：目的 探讨地氟醚预处理对脑局灶性缺血损伤的影响。方法采用大脑中动脉阻闭(middle cerebral artery occlusion，MCAO)模型，将30只雄性SD大鼠随机分成3组：对照组(C组，n=10)，动物不接受任何处理；地氟醚组(Des组，n=10)，动物每天接受1h的地氟醚预处理(5.7％地氟醚，94％O_2)，连续5 d：吸O_2组(O_2组，n=10)，动物每天接受吸
第四军巴大学硕士学位论文
94％O。lh行预处理，连续 5 d。所有动物均在大脑中动脉阻闭 120 in后
恢复再灌注，观察再灌注后24 h动物神经行为学改变及脑梗死容积。结
果 再灌注后 24 h神经行为学评分 D：S组明显低于 C组和 O。组仔＜0刀 1）：
24 h脑梗死容积C组为2761 士155 石3 mm3刀。组为253．84土门．39…3，
Des组 59．56130．37。’，Des组明显低于对照组（P＜0．of）。结论重复地
氟醚预处理可诱导延迟性脑缺血耐受，对大鼠局灶性脑缺血损伤产生保护
作用。
实验二：目的探讨单次短时间地氟醚预处理诱导急性脑缺血耐受的
可行性。摊30只雄性SD大鼠口80～3209），随机分为三组：对照组a
grOOp，fi习 只），动物不接受任何处理：吸氧气组＊北roup，p习 只），动
物接受lh吸氧预处理四4％氧气）；地氟醚组①es gToup，n习 只），动物接
受lh的地氟醚预处理＊．7％地氟醚）。所有动物均采用右侧颈动脉丝线栓
塞大脑中动脉致局灶性脑缺血 120min，观察再灌注后 24h动物神经行为
学改变及脑梗死容积（TTC染色法和核磁共振检测）。结果直肠温度、PH。
PaO。、PaCO。、血压及血糖在预处理期间三组无明显差异。再灌注后 24 h
神经行为学评分地氟醚组明显低于吸氧组和对照组仔奶刀5）；地氟醚组
24h脑梗死容积（TI’C：323．44土50．12…’；DWI：281．48土35．16＊＊3）明显
低于吸氧组（hC：427．96上87．26＊＊’；DWI：386．70t27＊6＊＊’）和对只
组（h C：498土43．88一’；D WWL 402．53t28．14 nil’），后两组梗死容积
无显著性差异（P＞0刀5）。结论单次短时间地氟醚预处理可通过诱导急性脑
缺血耐受而产生脑保护作用。
实验三 目的 探讨腺昔AI受体桔抗剂对地氟醚短时预处理诱导急性
脑缺血耐受的影响。摊：36只雄性SD大鼠椭0～3209），随机分为6
组（＋＝6）：生理盐水＋地氟醚组（S ALALmE＋D＋S组），二甲亚矾＋地氟醚组
（DMSO＋DCS组），腺昔AI受体桔抗剂＋地氟醚组（DPCPX＋DCS组），生
理盐水＋氧气组（SALINE＋OZ组），二甲亚矾＋氧气组（DMSO＋OZ组），腺
2
第囚军巴大学田士学位沦文
昔 AI受体桔抗剂＋氧气组（DPCPX＋OZ组）。地氟醚预处理＊刀 MAC，60drifl）
或吸氧预处理前30ban分别经腹腔注射生理盐水2．snl．－Mrag，DMSO
2．Sill．－rareg和DPCPX lm叭g。预处理结束＊后，所有动物均采用右侧颈动
脉丝线栓塞大脑中动脉，致局灶性脑缺血 120drin，观察髓注后 24h动
物神经行为学改变及脑梗死容积懈量方法同实验二卜结果直肠温度
PaO。、PaCO。、血压及血糖在预处理期间三组间无明显差异。再灌后24h
神经行为学评分及脑梗死容积DPCPX＋Des组明显高于SALWE＋Des组和
＊＊SO十＊es组，与吸氧预处理各组元明显差异：吸氧预处理3组间也无
显著性差异。结论腺昔山受体阻滞剂DPCPX可消除短时地氟醚预处理
诱导的急性脑缺血耐受作用。
Nowdays cerebrovascular diseases still are the third cause for death in the whole world, therefore the study in this field has been an important aspect of medical research. Once stroke occurs, it often leads to neurologic deficit which seriously influence the quality of life and even threaten the life of patients. Although many protective treatment measures, such as Chinese medical science and western medicine, against brain ischemia damage have been found, few of them show satisfactory curative effect. Therefore, prevention measures are gradually emphasized in the treatment of brain ischemia. Recently, a lot of studies have focused on preconditioning measures of brain ischemia . Some anesthetics have been proved to have preconditioning effect on brain ischemia. However, whether desflurane preconditioning can induce brain ischemic tolerance has not been reported. In this study, we evaluated the effects of desflurane preconditioning of neuroprotection against middle cerebral artery occlusion injury in rat with diffusion -weighted MR imaging for the first time. The present study was designed to evaluate the following objectives in a rat middle cerebral artery occlusion (MCAO) model. (1) To investigate if desflurane preconditioning induces ischemic tolerance
against neuronal injury produced by MCAO in rats.(2) To investigate if once short-duration desflurane preconditioning induces ischemic tolerance against brain injury produced by MCAO in rats.(3) To investigate the effects of DPCPX, an adenosine receptor antagonist, on the brain ischemic tolerance induced by preconditioning with once short-duration desflurane. Experiment 1:
AIM To investigate if desflurane preconditioning induces delayed ischemic tolerance against neuronal damage produced by MCAO in rats. METHODS Thirty male Sprague-Dawley (SD) rats weighing 280-320g were randomly divided into three groups: control group (C), without pretreatment; desflurane preconditioning group (Des), inhalation of 5.7% desflurane mixing with 94% O2 lh per day for 5d;oxygen preconditioning group (Oi), inhalation of 94%O2 1h per day for 5d. Right MCAO (120min) was induced by a 3-0 nylon thread with round tip inserted cranially into right internal carotid artery. The neurologic deficit score (NDS) was evaluated 24h after reperfusion and the infarct volume was determined 24h after reperfusion. RESULTS The NDS of Des group was lower than other two groups (P<0.01). The infarct volume of C, O2 and Des group was (276.10+155.63) mm3, (253.84+174.39) mm3 and (59.56+30.37) mm3 respectively. The difference between Des group and C group was significant (P<0.01). CONCLUSION Desflurane pretreatment was able to induce delayed ischemic tolerance against neuronal injury produced by transient MCAO in rats. Experiment 2:
AIM To investigate if once short-duration desflurane preconditioning induces acute ischemic tolerance against brain injury produced by MCAO in rats. Methods Thirty male SD rats weighing 280-320 g were randomized into three
groups: control group (C), without pretreatment; oxygen-inhaling group (O2), with inhaling 94% O2 1h; desflurane preconditioning group, inhalation of 5.7% desflurane mixing with 94% O2 1h, n=10, (Des). Each animal was then subjected to 2-hour MCAO by the intraluminal suture technique. The NDS were evaluated 24h after reperfusion and the infarct volume were measured with diffusion-weighted imaging (DWI) and TTC staining at 24 hours of reperfusion. Results Rectal temperature, PH, PaO2, PaCO2, blood pressure and blood glucose were controlled and not different among groups during preconditioning. The NDS of Des group was lower than those of other two groups at 24 hours of reperfusion. The infarct volume was smaller in Des group(TTC:323.44+50.12 mm3 ;DWI:281.48+35.16mm3) compared with O2 group (TTC:427.96+87.26 mm3 ;DWI:386.70+27.86 mm3) and control group (TTC:498+43.88 mm3;DWI: 402.53+28.14 mm3), but the infarct volume was no significant difference between O2 group and control group (P>0.05). Conclusions Once short-duration desflurane pretrea
实验一：目的 探讨地氟醚预处理对脑局灶性缺血损伤的影响。方法采用大脑中动脉阻闭(middle cerebral artery occlusion，MCAO)模型，将30只雄性SD大鼠随机分成3组：对照组(C组，n=10)，动物不接受任何处理；地氟醚组(Des组，n=10)，动物每天接受1h的地氟醚预处理(5.7％地氟醚，94％O_2)，连续5 d：吸O_2组(O_2组，n=10)，动物每天接受吸
第四军巴大学硕士学位论文
94％O。lh行预处理，连续 5 d。所有动物均在大脑中动脉阻闭 120 in后
恢复再灌注，观察再灌注后24 h动物神经行为学改变及脑梗死容积。结
果 再灌注后 24 h神经行为学评分 D：S组明显低于 C组和 O。组仔＜0刀 1）：
24 h脑梗死容积C组为2761 士155 石3 mm3刀。组为253．84土门．39…3，
Des组 59．56130．37。’，Des组明显低于对照组（P＜0．of）。结论重复地
氟醚预处理可诱导延迟性脑缺血耐受，对大鼠局灶性脑缺血损伤产生保护
作用。
实验二：目的探讨单次短时间地氟醚预处理诱导急性脑缺血耐受的
可行性。摊30只雄性SD大鼠口80～3209），随机分为三组：对照组a
grOOp，fi习 只），动物不接受任何处理：吸氧气组＊北roup，p习 只），动
物接受lh吸氧预处理四4％氧气）；地氟醚组①es gToup，n习 只），动物接
受lh的地氟醚预处理＊．7％地氟醚）。所有动物均采用右侧颈动脉丝线栓
塞大脑中动脉致局灶性脑缺血 120min，观察再灌注后 24h动物神经行为
学改变及脑梗死容积（TTC染色法和核磁共振检测）。结果直肠温度、PH。
PaO。、PaCO。、血压及血糖在预处理期间三组无明显差异。再灌注后 24 h
神经行为学评分地氟醚组明显低于吸氧组和对照组仔奶刀5）；地氟醚组
24h脑梗死容积（TI’C：323．44土50．12…’；DWI：281．48土35．16＊＊3）明显
低于吸氧组（hC：427．96上87．26＊＊’；DWI：386．70t27＊6＊＊’）和对只
组（h C：498土43．88一’；D WWL 402．53t28．14 nil’），后两组梗死容积
无显著性差异（P＞0刀5）。结论单次短时间地氟醚预处理可通过诱导急性脑
缺血耐受而产生脑保护作用。
实验三 目的 探讨腺昔AI受体桔抗剂对地氟醚短时预处理诱导急性
脑缺血耐受的影响。摊：36只雄性SD大鼠椭0～3209），随机分为6
组（＋＝6）：生理盐水＋地氟醚组（S ALALmE＋D＋S组），二甲亚矾＋地氟醚组
（DMSO＋DCS组），腺昔AI受体桔抗剂＋地氟醚组（DPCPX＋DCS组），生
理盐水＋氧气组（SALINE＋OZ组），二甲亚矾＋氧气组（DMSO＋OZ组），腺
2
第囚军巴大学田士学位沦文
昔 AI受体桔抗剂＋氧气组（DPCPX＋OZ组）。地氟醚预处理＊刀 MAC，60drifl）
或吸氧预处理前30ban分别经腹腔注射生理盐水2．snl．－Mrag，DMSO
2．Sill．－rareg和DPCPX lm叭g。预处理结束＊后，所有动物均采用右侧颈动
脉丝线栓塞大脑中动脉，致局灶性脑缺血 120drin，观察髓注后 24h动
物神经行为学改变及脑梗死容积懈量方法同实验二卜结果直肠温度
PaO。、PaCO。、血压及血糖在预处理期间三组间无明显差异。再灌后24h
神经行为学评分及脑梗死容积DPCPX＋Des组明显高于SALWE＋Des组和
＊＊SO十＊es组，与吸氧预处理各组元明显差异：吸氧预处理3组间也无
显著性差异。结论腺昔山受体阻滞剂DPCPX可消除短时地氟醚预处理
诱导的急性脑缺血耐受作用。
Nowdays cerebrovascular diseases still are the third cause for death in the whole world, therefore the study in this field has been an important aspect of medical research. Once stroke occurs, it often leads to neurologic deficit which seriously influence the quality of life and even threaten the life of patients. Although many protective treatment measures, such as Chinese medical science and western medicine, against brain ischemia damage have been found, few of them show satisfactory curative effect. Therefore, prevention measures are gradually emphasized in the treatment of brain ischemia. Recently, a lot of studies have focused on preconditioning measures of brain ischemia . Some anesthetics have been proved to have preconditioning effect on brain ischemia. However, whether desflurane preconditioning can induce brain ischemic tolerance has not been reported. In this study, we evaluated the effects of desflurane preconditioning of neuroprotection against middle cerebral artery occlusion injury in rat with diffusion -weighted MR imaging for the first time. The present study was designed to evaluate the following objectives in a rat middle cerebral artery occlusion (MCAO) model. (1) To investigate if desflurane preconditioning induces ischemic tolerance
against neuronal injury produced by MCAO in rats.(2) To investigate if once short-duration desflurane preconditioning induces ischemic tolerance against brain injury produced by MCAO in rats.(3) To investigate the effects of DPCPX, an adenosine receptor antagonist, on the brain ischemic tolerance induced by preconditioning with once short-duration desflurane. Experiment 1:
AIM To investigate if desflurane preconditioning induces delayed ischemic tolerance against neuronal damage produced by MCAO in rats. METHODS Thirty male Sprague-Dawley (SD) rats weighing 280-320g were randomly divided into three groups: control group (C), without pretreatment; desflurane preconditioning group (Des), inhalation of 5.7% desflurane mixing with 94% O2 lh per day for 5d;oxygen preconditioning group (Oi), inhalation of 94%O2 1h per day for 5d. Right MCAO (120min) was induced by a 3-0 nylon thread with round tip inserted cranially into right internal carotid artery. The neurologic deficit score (NDS) was evaluated 24h after reperfusion and the infarct volume was determined 24h after reperfusion. RESULTS The NDS of Des group was lower than other two groups (P<0.01). The infarct volume of C, O2 and Des group was (276.10+155.63) mm3, (253.84+174.39) mm3 and (59.56+30.37) mm3 respectively. The difference between Des group and C group was significant (P<0.01). CONCLUSION Desflurane pretreatment was able to induce delayed ischemic tolerance against neuronal injury produced by transient MCAO in rats. Experiment 2:
AIM To investigate if once short-duration desflurane preconditioning induces acute ischemic tolerance against brain injury produced by MCAO in rats. Methods Thirty male SD rats weighing 280-320 g were randomized into three
groups: control group (C), without pretreatment; oxygen-inhaling group (O2), with inhaling 94% O2 1h; desflurane preconditioning group, inhalation of 5.7% desflurane mixing with 94% O2 1h, n=10, (Des). Each animal was then subjected to 2-hour MCAO by the intraluminal suture technique. The NDS were evaluated 24h after reperfusion and the infarct volume were measured with diffusion-weighted imaging (DWI) and TTC staining at 24 hours of reperfusion. Results Rectal temperature, PH, PaO2, PaCO2, blood pressure and blood glucose were controlled and not different among groups during preconditioning. The NDS of Des group was lower than those of other two groups at 24 hours of reperfusion. The infarct volume was smaller in Des group(TTC:323.44+50.12 mm3 ;DWI:281.48+35.16mm3) compared with O2 group (TTC:427.96+87.26 mm3 ;DWI:386.70+27.86 mm3) and control group (TTC:498+43.88 mm3;DWI: 402.53+28.14 mm3), but the infarct volume was no significant difference between O2 group and control group (P>0.05). Conclusions Once short-duration desflurane pretrea
引文
1. Animates E, Tsai YC, Gerhold TD, Kamath SH, Davies IR, Sokoll MD. A comparison of the effect of halothane on N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor-mediated excitatory synaptic transmission in the hippocampus. Anesth Analg, 1996; 82:843～847
2. Bai D, Pennefather PS, Mac Donald IF, Orser BA. The general anesthetic propofol slows deactivation and desensitization of GABA (A) receptors. J Neurosci, 1999; 19:10635～10646
3. Bederson JB, Germano IM, Guarino L. Cortical blood flow and cerebral perfusion pressure in a new noncraniotomy model of subarachnoid hemorrhage in the rat. Stroke, 1995;26:1086-1091.
4. Boutros A, Wang J, Capuano C. Isoflurane and halothane increase adenosine triphosphate preservation, but do not provide additive recovery of function after ischemia, in preconditioning rat hearts. Anesthesiology, 1997;Jan; 86(1): 109～117
5. Cason BA, Gamperl AK, Slocum RE, Hickey RF. Anesthetic induced preconditioning: previous administration of isoflurane decreases myocardial infarct size in rabbits. Anesthesiology, 1997, 87:1182～1190
6. Cope DK, Impastato WK, Cohen MV, Downey JM. Volatile anesthetics protect the ischemic rabbit myocardium from infarction. Anesthesiology, 1997;Mar; 86(3): 699～709
7. Eger EI II. New in haled anesthetics. Anesthesiology, 1994, 80:906
8. Garcia JH. A reliable method to occlusion a middle cerebral artery in wistar rats. Stroke, 1993,2 4(9):1423.
9. Gel man S, Fowler KC, Smith LR. Regional blood flow during isoflurane and halothane anesthesia. Anesth Analg, 1984; 63:557～565
10. Haghighi SS, Sirintrapnn SJ, Johnson JC, Keller BP, Oro JJ. Suppression of spinal and cortical somatosensory evoked potentials by desflurane anesthesia. J Neurosurg Anesthesiol, 1996, Apr;8(2): 148～153
11. Heurteaux C, Lauvitzen I, Widmann C. Lanzdunski M. Essential role of adenosine, adensoine A1 receptor, and ATP-sensitive K~+ channels in cerebral ischemic preconditioning, Pharmacology 1995(92): 4666～4670
12. Hoffman WE, Charbel FT, Edelman G, Ausman JI. Thiopental and desflurane treatment for brain protection. Neurosurgery, 1998 Nov; 43(5):1050～1053
13. Hudgins WR, Garcia JH. The effect of electrocautery, atmospheric exposure, and surgical retraction on the permeability of the blood-brain barrier. Stroke. 1970; 1: 375～380.
14. Ismaeil MS, Tkachenko I, Gamperl AK, Hickey RF, Cason BA. Mechanisms of isoflurane-induced myocardial preconditioning in rabbits. Anesthesiology, 1999, 90:812-821
15. Kawamura S, Yasui N, Shirasawa M, Fukasawa H. Rat middle cerebral artery occlusion using an intraluminal thread technique. Acta Neurochir(Wien). 1991; 109:126～132.
16. Kawasaki M, Hirotak, Roth SH; Ito Y. The effects of general anesthetics on excitatory and inhibitory synaptic transmission in area CA1 of the rat hippocampus in vitro. Anesth Analg, 1999; 88:676～680
17. Kersten JR, Schmeling TJ, Pegel PS, Gross GJ, Warltier DC. Isoflurane mimics ischemic reconditioning via activation of K~+(ATP) channels: reduction of myocardial infarct size with an acute memory phase. Anesthesiology, 1997, 87:361-370
18. Kitagawa K, Matsumoto M, Tagaya M, Hata, R, Ueda H, Niinobe M, Handa N, Fukunaga R, Kimura K, Mikoshiba K, Kamada T. "Ischemic tolerance" phenomenon found in the brain. Brain Res. 1990; 528:21～24.
19. Koizumi JI, Yoshida Y, Nakazawa T, et al. Experimental studies of ischaemia brain edema. 1. A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischaemia area. Jap J Stroke, 1986,8(1): 1～8.
20. Kuge Y, Minemalsu K, Yamaguchi T, et al. Nylon monofilament for intraluminal
middle cerebral artery occlusion in rats. Stroke, 1995, 26(9): 1655-1657
21. Laing RJ, Jakubowski J, L aing RW. Middle cerebral artery occlusion without craniectomy in rats which method works best? Stroke, 1993, 24(2):294～298.
22. Lee SR, Cheun JK. Propofol administration reduces hippocampal neuronal damage induced by kainic acid in rats. Neurol Res, 1999; 21: 225～228
23. Longa ZE, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke, 1989,20:84-91
24. Lynch C 3rd. Anesthetic preconditioning: not just for the heart? Anesthesiology, 1999 Sep; 91(3): 606-608
25. Mastronardi P, Cafiero T. Rational use of opioids. Minerva Anestesiol, 2001; 67(4): 332-337.
26. Matta BF, Heath KJ, Tipping K, Summors AC. Direct cerebral vasodilatory effects of sevoflurane and isoflurane. Anesthesiology, 1999; 91: 677-680
27. Memezawa H, Smith ML, Siesjo BK. Penumbral tissues salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke, 1992, 23: 552～559.
28. Memezawa H, Zhao Q, Smith ML, Siesjo "BK. Hyperthermia nullifies the ameliorating effect of dizocilpine maleate (MK-801) in focal cerebral ischemia. Brain Res. 1995; 670:48 -52.
29. Minematsu K, Fisher M, Davis MA, et al. Diffusion- weighted magnetic resonance imaging: rapid and quantitative detection of focal brain ischemia[J]. Neurology, 1992, 42(3): 235.
30. Miura T, Tsuchida A. Adenosine and preconditioning revisited. Clin, Exp. pharmacol. Physiol. 1999, 26:92-99
31. Moseley ME, Cohen Y, Mintorovitch J, et al. Early detection of regional cerebral ischemia in cats: comparison of diffusion-and T2-weighted MRI
and spectroscopy. Magnet Reson Med, 1990,14:330
32. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation, 1986, 74:1124-1136
33. Novalija E, Fujita S, Kampine JP, Stowe DE Sevoflurane mimics ischemic preconditioning effects on coronary flow and nitric oxide release in isolated hearts. Anesthesiology, 1999, 91:701-712
34. Olessen SP. Leakiness of rat microvessels to fluorescent probes following craniotomy. Acta Physiol Scand. 1987; 130: 63～68.
35. P. K. Von Iubitz, J.M. Dambrosia, O. Kempski, D.J. Redmond, Cyclohexyl adeosine protects against neuronal death following ischemia in the CA1 region of gerbil hippocampus. Stroke, 1992; 19:1133-1139
36. Penta de peppo A, Polisca P, Tomai F, De Paulis R, Turani F, Zapancich E, Sommariva L, Pasqualetti P, Cniariello L. Recovery of LV contractility in man is enhanced by preischemic administration of enflurane. Ann Thorac Surg, 1999, Jul; 68(1):112～118
37. Phillis JW. The effective A_1 and A_2 adenosine receptor antagonists on cerebral ischemic injury in the gerbil, Brain Res. 1995 DEC 24;705(1-2): 79～84
38. Rabb CH. Nylon monofilament for intraluminal middle cerebral artery occlusion in rats. Stroke. 1996; 27:151. Letter.
39. Ridenour TR, Warner DS, Todd MM, Gionet TX. Comparative effects of propofol and halothane on outcome from temporary middle cerebral artery occlusion in the rat. Anaesthesiology, 1992; 76:807-812
40. Riepe MW, Ludolph AC. Chemical preconditioning: a cytoprotective strategy. Mol Cell Biochem, 1997, 174:249～254
41. Robert SE, Stefan Z, Edwin H, et al. A critical reevaluation of the intraluminal thread model of focal cerebral ischemia. Stroke, 1998, 29:2162-2170.
42. Roscoe AK, Christensen JD, Lynch C 3rd. Isoflurane, but not halothane,
induces protection of human myocardium via adenosine A1 receptors and adenosine triphosphate-sensitive potassium channels. Anesthesiology, 2000; 92 (6);1692～1701
43. Saidman LJ. The rate of desflurare in the practice of anesthesia. Anesthesiology, 1991, 74:399
44. Shimoji K, Takahata Y, Fujiwara N, et al. Effects of pentobarbital and ketamine on brain injury- induced anti-ischemic activity. Brain Res, 1987, 408:385-388
45. Siley RM, Wrnstein E, Matleo RS, Pantuck EJ, Pantuck CB. Desflurane and isoflurane in surgical patient: comparison of emergence time. Anesthesiology, 1991, 74:425
46. Singer M, Chong J, Lu D, et al. Diffusion-weighted MRI in acute subcortical infarction. Stroke, 1998,29(1): 133～136.
47. Takahata Y, Shimoji K. Brain injury improves survival of mice following brain ischema. Brain Res, 1986,381:368～371
48. Tatlisumak T, Takano K, Carano RA, Miller LP, Foster AC, Fisher M. Delayed treatment with an adenosine kinase inhibitor, GP683, attenuates infarct size in rats with temporary middle cerebral artery occlusion. Stroke, 1998, 29:1952-1958
49. Toller WG, Montgomery MW, Pagel PS, Hettrick DA, Warltier DC, Kersten JR. Isoflurane-enhanced recovery of canine stunned myocardium:role for protein kinase C? Anesthesiology, 1999 Sep; 91(3): 713～722
50. Tomai F, De Panlis R, Penta de Peppo A, Colagrande L, Caprara E, Polisca, De Matteis G, Ghini AS, Forlani S, Colella D, Chiariello L. Beneficial impact of isoflurane during cornary bypass surgery on troponin I release. G Ital Cardiol, 1999;Sep; 29(9): 1007～1014
51. Tsai YC, Huang SJ, Lai YY, Chang CL, Cheng JT. Propofol does not reduce infarct volume in rats undergoing permanent middle cerebral artery occlusion. Acta Anaesthesiol Sin, 1994; 32:99～104
52. Udolphi K. A, Schubert P, Parkinson F.E, Fredholm B.B. Adenosine and brain ischemia, Cere brovasc. Brain Metab. Rev. 1992(4): 346-369
53. Van Everdingen KJ, van der Grond J, Kappelle LJ, et al. Diffusion-weighted magnetic resonance imaging in acute stroke. Stroke, 1998, 29(9): 1783～1790.
54. Wantch S, Caa J, Siewerl B, et al. Acute human stroke studied by whole brain echo planar diffusion- weighted magnetic resonance imaging. Ann Neurol, 1995,37:231
55. Warach s, Chien D, Li W, et al. Fast magnetic resonance diffusion-weighted imaging of acute human stroke. Neurology, 1992, 42:1717～1723.
56. Yamasaki T, Nakakimura K, Matumoto M, Xiong L, Ishikawa T, Sakabe T. Effects of graded suppression of the EEG with propofol on the neurological outcome following incomplete cerebral ischemia in rats. Eur J Anesthesiol, 1999; 16:320～329
57．安宁豫，孟祥辉，高元桂．急性脑梗塞弥散加权MRI与病理对照实验研究．中国医学影像学杂志，1999；7(4)：278～281
58．安宁豫，孟祥辉，高元桂．弥散加权MRI评价经动脉溶栓治疗急性脑梗塞实验研究．中国医学影像学杂志，2000；8(5)：366～369
59．蔡葵，陈涓，陈敏等．磁共振弥散成像对超急性中风患者诊断的价值．中国医学影像技术，2000；16(7)：543～546
60．陈伯銮，李德馨．麻醉药对脑功能和脑代谢的影响和脑保护．国外医学麻醉学与复苏分册，2003；24(1)：1～2
61．段光明，张剑宁．脑缺血预适应的研究进展．国外医学脑血管疾病分册，2000；8(5)：276～277
62．高新明，常业恬，徐军美等．地氟醚预处理对缺血再灌注心肌的保护作用．中华麻醉学杂志，1999；19(9)：546～549
63．韩鸿宾，王简，毛传万等．扩散成像在脑缺血性中风中的诊断价值研究．实用放射学杂志，2002；18(1)：1～3
64．韩鸿宾，谢敬霞．MR扩散与灌注成像在脑缺血诊断中的应用．中华放
射学杂志，1998；32(6)：364～369
65．胡胜，熊利泽，陈绍洋，郑玉，路志红，刘艳红．地氟醚顶处理对大鼠局灶脑缺血损伤的保护作用．第四军医大学学报，2002；23(15)：1382～1384
66．李东亮，程晓红，沈虹等．大鼠大脑中动脉可逆性阻塞的实验研究[J]．动物学报，1993；39(2)：176
67．李胜．大鼠大脑中动脉区局灶性脑缺血模型．国外医学脑血管疾病分册，1998；6(1)：3～6
68．李志欣．磁共振功能成像对脑缺血半暗带的研究进展．国外医学临床放射学分册，2002；25(2)：71～74
69．林顺发，庄伟端．磁共振扩散成像诊断急性脑梗死．卒中与神经疾病，2000；7(2)：113～114
70．刘俊杰，赵俊，主编．现代麻醉学，第二版．北京：人民卫生出版社，1996；274-276
71．刘鸣．卒中防治的研究证据——预防进展更加令人鼓舞．国外医学脑血管疾病分册，2001；9(4)：195
72．刘璇，朱兴旋．药物筛选中脑缺血模型的应用．中国药理学通报，1998；14(5)：399～401
73．刘艳红，熊利泽，陈绍洋，郑玉，路志红，胡胜．钠离子通道在异氟醚预处理诱导的脑保护中的作用．第四军医大学学报，2002；23(15)；1366～1368
74．彭章龙，杭燕南，孙大金．地氟醚、七氟醚和异氟醚预处理对心肌缺血／再灌注损伤的保护作用．中华麻醉学杂志，2002；22(11)：676～680
75．沈顺姬，陈嘉峰．大鼠局灶性脑缺血模型的建立．中风与神经疾病杂志，2002；19(4)：246～247
76．王琦，徐荣天，李松柏等．MR弥散加权成像对超急性期脑梗塞的临床研究．中国医学影像技术，2002；18(7)：640～641
77．王耀明，童萼塘，肖学宏．MRI评价改进的大鼠可逆性局灶性脑缺血模型．卒中与神经疾病，1999；6(3)：171～173
78．吴丽娥，刘鸣．功能性磁共振对急性脑梗死诊断及溶栓治疗的价值．
脑与神经疾病杂志，2002；10(4)：253～255
79．肖小华，黄如训，吕衍春，李玲，梁康福，殷梅，罗柏宁，苏镇培，孟悛非．磁共振弥散／罐注加权成像确认局灶脑缺血半暗带的实验研究．中国神经精神疾病杂志，2000；26(3)：148～151
80．肖学宏，孔祥泉，江利，王耀明，徐海波，李丽云，唐岳枫．急性脑缺血及再灌注磁共振扩散加权成像的特点．中华放射学杂志，1999；33(10)：662～666．
81．熊利泽，朱正华，董海龙，胡文能，侯立朝．异氟醚预处理对大鼠局灶性脑血损伤的保护作用．中华麻醉学杂志，2000；12：730～732
82．徐军美，常业恬，李李等．地氟醚预处理对缺血／再灌注心肌的保护作用．中华麻醉学杂志，1999；19(11)：646～649
83．徐军美，胡冬煦，常业恬等．吸人麻醉药预处理对兔心肌缺血再灌注中心肌细胞调亡的影响．中华麻醉学杂志，2002；22(8)：483～485
84．杨渊，张苏明．脑缺血的病理生理研究进展：半暗带、基因表达与神经元保护．国外医学物理学与康复学分册，2003；23(1)：1～2
85．郁丽娜，谢俊然，段满林．缺血再灌注损伤的病理生理临床表现和预防．国外医学麻醉学与复苏分册，2002；23(1)：5～8
86．朱波．中枢神经系统缺血缺氧损伤模型．国外医学麻醉学与复苏分册，2002；23(1)：17～20
2. Bai D, Pennefather PS, Mac Donald IF, Orser BA. The general anesthetic propofol slows deactivation and desensitization of GABA (A) receptors. J Neurosci, 1999; 19:10635～10646
3. Bederson JB, Germano IM, Guarino L. Cortical blood flow and cerebral perfusion pressure in a new noncraniotomy model of subarachnoid hemorrhage in the rat. Stroke, 1995;26:1086-1091.
4. Boutros A, Wang J, Capuano C. Isoflurane and halothane increase adenosine triphosphate preservation, but do not provide additive recovery of function after ischemia, in preconditioning rat hearts. Anesthesiology, 1997;Jan; 86(1): 109～117
5. Cason BA, Gamperl AK, Slocum RE, Hickey RF. Anesthetic induced preconditioning: previous administration of isoflurane decreases myocardial infarct size in rabbits. Anesthesiology, 1997, 87:1182～1190
6. Cope DK, Impastato WK, Cohen MV, Downey JM. Volatile anesthetics protect the ischemic rabbit myocardium from infarction. Anesthesiology, 1997;Mar; 86(3): 699～709
7. Eger EI II. New in haled anesthetics. Anesthesiology, 1994, 80:906
8. Garcia JH. A reliable method to occlusion a middle cerebral artery in wistar rats. Stroke, 1993,2 4(9):1423.
9. Gel man S, Fowler KC, Smith LR. Regional blood flow during isoflurane and halothane anesthesia. Anesth Analg, 1984; 63:557～565
10. Haghighi SS, Sirintrapnn SJ, Johnson JC, Keller BP, Oro JJ. Suppression of spinal and cortical somatosensory evoked potentials by desflurane anesthesia. J Neurosurg Anesthesiol, 1996, Apr;8(2): 148～153
11. Heurteaux C, Lauvitzen I, Widmann C. Lanzdunski M. Essential role of adenosine, adensoine A1 receptor, and ATP-sensitive K~+ channels in cerebral ischemic preconditioning, Pharmacology 1995(92): 4666～4670
12. Hoffman WE, Charbel FT, Edelman G, Ausman JI. Thiopental and desflurane treatment for brain protection. Neurosurgery, 1998 Nov; 43(5):1050～1053
13. Hudgins WR, Garcia JH. The effect of electrocautery, atmospheric exposure, and surgical retraction on the permeability of the blood-brain barrier. Stroke. 1970; 1: 375～380.
14. Ismaeil MS, Tkachenko I, Gamperl AK, Hickey RF, Cason BA. Mechanisms of isoflurane-induced myocardial preconditioning in rabbits. Anesthesiology, 1999, 90:812-821
15. Kawamura S, Yasui N, Shirasawa M, Fukasawa H. Rat middle cerebral artery occlusion using an intraluminal thread technique. Acta Neurochir(Wien). 1991; 109:126～132.
16. Kawasaki M, Hirotak, Roth SH; Ito Y. The effects of general anesthetics on excitatory and inhibitory synaptic transmission in area CA1 of the rat hippocampus in vitro. Anesth Analg, 1999; 88:676～680
17. Kersten JR, Schmeling TJ, Pegel PS, Gross GJ, Warltier DC. Isoflurane mimics ischemic reconditioning via activation of K~+(ATP) channels: reduction of myocardial infarct size with an acute memory phase. Anesthesiology, 1997, 87:361-370
18. Kitagawa K, Matsumoto M, Tagaya M, Hata, R, Ueda H, Niinobe M, Handa N, Fukunaga R, Kimura K, Mikoshiba K, Kamada T. "Ischemic tolerance" phenomenon found in the brain. Brain Res. 1990; 528:21～24.
19. Koizumi JI, Yoshida Y, Nakazawa T, et al. Experimental studies of ischaemia brain edema. 1. A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischaemia area. Jap J Stroke, 1986,8(1): 1～8.
20. Kuge Y, Minemalsu K, Yamaguchi T, et al. Nylon monofilament for intraluminal
middle cerebral artery occlusion in rats. Stroke, 1995, 26(9): 1655-1657
21. Laing RJ, Jakubowski J, L aing RW. Middle cerebral artery occlusion without craniectomy in rats which method works best? Stroke, 1993, 24(2):294～298.
22. Lee SR, Cheun JK. Propofol administration reduces hippocampal neuronal damage induced by kainic acid in rats. Neurol Res, 1999; 21: 225～228
23. Longa ZE, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke, 1989,20:84-91
24. Lynch C 3rd. Anesthetic preconditioning: not just for the heart? Anesthesiology, 1999 Sep; 91(3): 606-608
25. Mastronardi P, Cafiero T. Rational use of opioids. Minerva Anestesiol, 2001; 67(4): 332-337.
26. Matta BF, Heath KJ, Tipping K, Summors AC. Direct cerebral vasodilatory effects of sevoflurane and isoflurane. Anesthesiology, 1999; 91: 677-680
27. Memezawa H, Smith ML, Siesjo BK. Penumbral tissues salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke, 1992, 23: 552～559.
28. Memezawa H, Zhao Q, Smith ML, Siesjo "BK. Hyperthermia nullifies the ameliorating effect of dizocilpine maleate (MK-801) in focal cerebral ischemia. Brain Res. 1995; 670:48 -52.
29. Minematsu K, Fisher M, Davis MA, et al. Diffusion- weighted magnetic resonance imaging: rapid and quantitative detection of focal brain ischemia[J]. Neurology, 1992, 42(3): 235.
30. Miura T, Tsuchida A. Adenosine and preconditioning revisited. Clin, Exp. pharmacol. Physiol. 1999, 26:92-99
31. Moseley ME, Cohen Y, Mintorovitch J, et al. Early detection of regional cerebral ischemia in cats: comparison of diffusion-and T2-weighted MRI
and spectroscopy. Magnet Reson Med, 1990,14:330
32. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation, 1986, 74:1124-1136
33. Novalija E, Fujita S, Kampine JP, Stowe DE Sevoflurane mimics ischemic preconditioning effects on coronary flow and nitric oxide release in isolated hearts. Anesthesiology, 1999, 91:701-712
34. Olessen SP. Leakiness of rat microvessels to fluorescent probes following craniotomy. Acta Physiol Scand. 1987; 130: 63～68.
35. P. K. Von Iubitz, J.M. Dambrosia, O. Kempski, D.J. Redmond, Cyclohexyl adeosine protects against neuronal death following ischemia in the CA1 region of gerbil hippocampus. Stroke, 1992; 19:1133-1139
36. Penta de peppo A, Polisca P, Tomai F, De Paulis R, Turani F, Zapancich E, Sommariva L, Pasqualetti P, Cniariello L. Recovery of LV contractility in man is enhanced by preischemic administration of enflurane. Ann Thorac Surg, 1999, Jul; 68(1):112～118
37. Phillis JW. The effective A_1 and A_2 adenosine receptor antagonists on cerebral ischemic injury in the gerbil, Brain Res. 1995 DEC 24;705(1-2): 79～84
38. Rabb CH. Nylon monofilament for intraluminal middle cerebral artery occlusion in rats. Stroke. 1996; 27:151. Letter.
39. Ridenour TR, Warner DS, Todd MM, Gionet TX. Comparative effects of propofol and halothane on outcome from temporary middle cerebral artery occlusion in the rat. Anaesthesiology, 1992; 76:807-812
40. Riepe MW, Ludolph AC. Chemical preconditioning: a cytoprotective strategy. Mol Cell Biochem, 1997, 174:249～254
41. Robert SE, Stefan Z, Edwin H, et al. A critical reevaluation of the intraluminal thread model of focal cerebral ischemia. Stroke, 1998, 29:2162-2170.
42. Roscoe AK, Christensen JD, Lynch C 3rd. Isoflurane, but not halothane,
induces protection of human myocardium via adenosine A1 receptors and adenosine triphosphate-sensitive potassium channels. Anesthesiology, 2000; 92 (6);1692～1701
43. Saidman LJ. The rate of desflurare in the practice of anesthesia. Anesthesiology, 1991, 74:399
44. Shimoji K, Takahata Y, Fujiwara N, et al. Effects of pentobarbital and ketamine on brain injury- induced anti-ischemic activity. Brain Res, 1987, 408:385-388
45. Siley RM, Wrnstein E, Matleo RS, Pantuck EJ, Pantuck CB. Desflurane and isoflurane in surgical patient: comparison of emergence time. Anesthesiology, 1991, 74:425
46. Singer M, Chong J, Lu D, et al. Diffusion-weighted MRI in acute subcortical infarction. Stroke, 1998,29(1): 133～136.
47. Takahata Y, Shimoji K. Brain injury improves survival of mice following brain ischema. Brain Res, 1986,381:368～371
48. Tatlisumak T, Takano K, Carano RA, Miller LP, Foster AC, Fisher M. Delayed treatment with an adenosine kinase inhibitor, GP683, attenuates infarct size in rats with temporary middle cerebral artery occlusion. Stroke, 1998, 29:1952-1958
49. Toller WG, Montgomery MW, Pagel PS, Hettrick DA, Warltier DC, Kersten JR. Isoflurane-enhanced recovery of canine stunned myocardium:role for protein kinase C? Anesthesiology, 1999 Sep; 91(3): 713～722
50. Tomai F, De Panlis R, Penta de Peppo A, Colagrande L, Caprara E, Polisca, De Matteis G, Ghini AS, Forlani S, Colella D, Chiariello L. Beneficial impact of isoflurane during cornary bypass surgery on troponin I release. G Ital Cardiol, 1999;Sep; 29(9): 1007～1014
51. Tsai YC, Huang SJ, Lai YY, Chang CL, Cheng JT. Propofol does not reduce infarct volume in rats undergoing permanent middle cerebral artery occlusion. Acta Anaesthesiol Sin, 1994; 32:99～104
52. Udolphi K. A, Schubert P, Parkinson F.E, Fredholm B.B. Adenosine and brain ischemia, Cere brovasc. Brain Metab. Rev. 1992(4): 346-369
53. Van Everdingen KJ, van der Grond J, Kappelle LJ, et al. Diffusion-weighted magnetic resonance imaging in acute stroke. Stroke, 1998, 29(9): 1783～1790.
54. Wantch S, Caa J, Siewerl B, et al. Acute human stroke studied by whole brain echo planar diffusion- weighted magnetic resonance imaging. Ann Neurol, 1995,37:231
55. Warach s, Chien D, Li W, et al. Fast magnetic resonance diffusion-weighted imaging of acute human stroke. Neurology, 1992, 42:1717～1723.
56. Yamasaki T, Nakakimura K, Matumoto M, Xiong L, Ishikawa T, Sakabe T. Effects of graded suppression of the EEG with propofol on the neurological outcome following incomplete cerebral ischemia in rats. Eur J Anesthesiol, 1999; 16:320～329
57．安宁豫，孟祥辉，高元桂．急性脑梗塞弥散加权MRI与病理对照实验研究．中国医学影像学杂志，1999；7(4)：278～281
58．安宁豫，孟祥辉，高元桂．弥散加权MRI评价经动脉溶栓治疗急性脑梗塞实验研究．中国医学影像学杂志，2000；8(5)：366～369
59．蔡葵，陈涓，陈敏等．磁共振弥散成像对超急性中风患者诊断的价值．中国医学影像技术，2000；16(7)：543～546
60．陈伯銮，李德馨．麻醉药对脑功能和脑代谢的影响和脑保护．国外医学麻醉学与复苏分册，2003；24(1)：1～2
61．段光明，张剑宁．脑缺血预适应的研究进展．国外医学脑血管疾病分册，2000；8(5)：276～277
62．高新明，常业恬，徐军美等．地氟醚预处理对缺血再灌注心肌的保护作用．中华麻醉学杂志，1999；19(9)：546～549
63．韩鸿宾，王简，毛传万等．扩散成像在脑缺血性中风中的诊断价值研究．实用放射学杂志，2002；18(1)：1～3
64．韩鸿宾，谢敬霞．MR扩散与灌注成像在脑缺血诊断中的应用．中华放
射学杂志，1998；32(6)：364～369
65．胡胜，熊利泽，陈绍洋，郑玉，路志红，刘艳红．地氟醚顶处理对大鼠局灶脑缺血损伤的保护作用．第四军医大学学报，2002；23(15)：1382～1384
66．李东亮，程晓红，沈虹等．大鼠大脑中动脉可逆性阻塞的实验研究[J]．动物学报，1993；39(2)：176
67．李胜．大鼠大脑中动脉区局灶性脑缺血模型．国外医学脑血管疾病分册，1998；6(1)：3～6
68．李志欣．磁共振功能成像对脑缺血半暗带的研究进展．国外医学临床放射学分册，2002；25(2)：71～74
69．林顺发，庄伟端．磁共振扩散成像诊断急性脑梗死．卒中与神经疾病，2000；7(2)：113～114
70．刘俊杰，赵俊，主编．现代麻醉学，第二版．北京：人民卫生出版社，1996；274-276
71．刘鸣．卒中防治的研究证据——预防进展更加令人鼓舞．国外医学脑血管疾病分册，2001；9(4)：195
72．刘璇，朱兴旋．药物筛选中脑缺血模型的应用．中国药理学通报，1998；14(5)：399～401
73．刘艳红，熊利泽，陈绍洋，郑玉，路志红，胡胜．钠离子通道在异氟醚预处理诱导的脑保护中的作用．第四军医大学学报，2002；23(15)；1366～1368
74．彭章龙，杭燕南，孙大金．地氟醚、七氟醚和异氟醚预处理对心肌缺血／再灌注损伤的保护作用．中华麻醉学杂志，2002；22(11)：676～680
75．沈顺姬，陈嘉峰．大鼠局灶性脑缺血模型的建立．中风与神经疾病杂志，2002；19(4)：246～247
76．王琦，徐荣天，李松柏等．MR弥散加权成像对超急性期脑梗塞的临床研究．中国医学影像技术，2002；18(7)：640～641
77．王耀明，童萼塘，肖学宏．MRI评价改进的大鼠可逆性局灶性脑缺血模型．卒中与神经疾病，1999；6(3)：171～173
78．吴丽娥，刘鸣．功能性磁共振对急性脑梗死诊断及溶栓治疗的价值．
脑与神经疾病杂志，2002；10(4)：253～255
79．肖小华，黄如训，吕衍春，李玲，梁康福，殷梅，罗柏宁，苏镇培，孟悛非．磁共振弥散／罐注加权成像确认局灶脑缺血半暗带的实验研究．中国神经精神疾病杂志，2000；26(3)：148～151
80．肖学宏，孔祥泉，江利，王耀明，徐海波，李丽云，唐岳枫．急性脑缺血及再灌注磁共振扩散加权成像的特点．中华放射学杂志，1999；33(10)：662～666．
81．熊利泽，朱正华，董海龙，胡文能，侯立朝．异氟醚预处理对大鼠局灶性脑血损伤的保护作用．中华麻醉学杂志，2000；12：730～732
82．徐军美，常业恬，李李等．地氟醚预处理对缺血／再灌注心肌的保护作用．中华麻醉学杂志，1999；19(11)：646～649
83．徐军美，胡冬煦，常业恬等．吸人麻醉药预处理对兔心肌缺血再灌注中心肌细胞调亡的影响．中华麻醉学杂志，2002；22(8)：483～485
84．杨渊，张苏明．脑缺血的病理生理研究进展：半暗带、基因表达与神经元保护．国外医学物理学与康复学分册，2003；23(1)：1～2
85．郁丽娜，谢俊然，段满林．缺血再灌注损伤的病理生理临床表现和预防．国外医学麻醉学与复苏分册，2002；23(1)：5～8
86．朱波．中枢神经系统缺血缺氧损伤模型．国外医学麻醉学与复苏分册，2002；23(1)：17～20