麻醉药作用机制及其保护作用与离子通道的研究进展

神经药理学报 ›› 2013, Vol. 3 ›› Issue (4): 39-46.

麻醉药作用机制及其保护作用与离子通道的研究进展

李英杰, 杨宝学

天然药物及仿生药物国家重点实验室，北京大学基础医学院药理学系，北京，中国，100191

出版日期:2013-08-26 发布日期:2014-06-27
通讯作者: 杨宝学，男，教授，博士，博士生导师；研究方向：药理学；Tel：+86-010-82805622，E-mail: baoxue@bjmu.edu.cn
作者简介:李英杰，男，硕士研究生；研究方向：药理学；Tel：+86-010-82805559，E-mail: liyingjiecuihuimei@163.com
基金资助:
国家自然科学基金项目(No.30870921、No 81170632、No 81261160507)，科技部国际科技合作与交流专项项目（No.2012DFA11070），教育部高等学校博士学科点专项科研基金项目(No.20100001110047)

Anesthetic Mechanism, Its Protective Effect and Ion Channels

LI Ying-jie，YANG Bao-xue

State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China, 100191

Online:2013-08-26 Published:2014-06-27
Contact: 杨宝学，男，教授，博士，博士生导师；研究方向：药理学；Tel：+86-010-82805622，E-mail: baoxue@bjmu.edu.cn
About author:李英杰，男，硕士研究生；研究方向：药理学；Tel：+86-010-82805559，E-mail: liyingjiecuihuimei@163.com
Supported by:
国家自然科学基金项目(No.30870921、No 81170632、No 81261160507)，科技部国际科技合作与交流专项项目（No.2012DFA11070），教育部高等学校博士学科点专项科研基金项目(No.20100001110047)

摘要/Abstract

摘要： 麻醉药广泛应用于临床各类手术中，但其麻醉作用机制至今仍不清楚。随着更多新技术的应用，发现麻醉药的作用机制主要与增强GABAA-R通道，抑制N-甲基-D-门冬氨酸和神经元烟碱乙酰胆碱受体通道的功能以及抑制电压门控离子通道开放等有关。同时麻醉药的脏器保护作用也与离子通道有关，主要通过激活钾离子通道，抑制钙离子内流等途径实现。该文将从这两方面综述麻醉药与离子通道的关系。

关键词: 麻醉药, &, gamma, -氨基丁酸受体通道, N-甲基-D-门冬氨酸受体通道, 神经元烟碱乙酰胆碱受体通道, 电压门控离子通道

Abstract: Anesthetics have been widely used in clinical surgeries, but their detailed mechanisms are still unclear. With the application of some new techniques, it is found that the ion channels are involved in anesthetic mechanisms, such as the suppression of N-methyl-D-aspartate channel and neuronal nicotinic acetylcholine receptors, inhibition of opening the voltage-gated ion channels function, and enhancing the GABAA-R channels. In addition, the protective effects of anesthetics on organs are also related with ion channels, which can be realized via activating potassium channels, attenuating calcium influx and so on. This article reviews the relationship between the anesthetics and ion channels in these two aspects.

Key words: anesthetic, gamma aminobutyric acid receptor（GABAA-R）channel, N-methyl-D-aspartic acid（NMDA）receptor channel, neuronal nicotinic acetylcholine receptors（n-AChRs) , voltage-gated ion channel（VGIC）

中图分类号:

R964

李英杰, 杨宝学. 麻醉药作用机制及其保护作用与离子通道的研究进展[J]. 神经药理学报, 2013, 3(4): 39-46.

LI Ying-jie，YANG Bao-xue. Anesthetic Mechanism, Its Protective Effect and Ion Channels[J]. Acta Neuropharmacologica, 2013, 3(4): 39-46.

参考文献

[1]   Franks N P, Lieb W R. Molecular and cellular mechanisms of general anaesthesia[J]. Nature, 1994, 367(6464): 607-614.

[2]   Krasowski M D, Harrison N L. General anaesthetic actions on ligand-gated ion channels[J]. Cell Mol Life Sci, 1999, 55(10): 1278-1303.

[3]   Julien Dine, Claudia Kuhne, Jan M Deussing, et al. Optogenetic evocation of field inhibitory postsynaptic potentials in hippocampal slices: a simple and reliable approach for studying pharmacological effects on GABAA and GABAB receptor-mediated neurotransmission[J]. Front Cell Neurosci, 2014, 8:2.

[4]   Andrew Jenkins, Nicholas P Franks, William R Lieb. Effects of temperature and volatile anesthetics on GABAA receptors[J]. Anesthesiology, 1999, 90(2): 484-491.

[5]   Jason A Campagna, Keith W Miller, Stuart A Forman. Mechanisms of actions of inhaled anesthetics[J]. N Engl J Med, 2003, 348(21): 2110-2124.

[6]   Lecker I, Yin Y, Wang D S, et al. Potentiation of GABAA receptor activity by volatile anaesthetics is reduced by α5 GABAA receptor-preferring inverse agonists[J]. Br J Anaesth, 2013, 110(Suppl 1): i73-i81.

[7]   Sebel L E, Richardson J E, Singh S P, et al. Additive effects of sevoflurane and propofol on gamma-aminobutyric acid receptor function[J]. Anesthesiology, 2006, 104(6): 1176-1183.

[8]   Gyulai F E, Mintun M A, Firestone L L. Dose-dependent enhancement of in vivo GABAA-benzodiazepine receptor binding by isoflurane[J]. Anesthesiology, 2001 ,95(3) :585-593.

[9]   Christine M Sandiego, Jin Xiao, Tim Mulnix, et al. Awake nonhuman primate brain PET imaging with minimal head restraint: evaluation of GABAA-benzodiazepine binding with 11C-flumazenil in awake and anesthetized animals[J]. J Nucl Med, 2013, 54(11): 1962-1968.

[10] Mitsutaka Sugimura, Shigeo Kitayama, Katsuya Morita, et al. Effects of volatile and intravenous anesthetics on the uptake of GABA, glutamate and dopamine by their transporters heterologously expressed in COS cells and in rat brain synaptosomes[J]. Toxicol Lett, 2001, 123(1): 69-76.

[11] Robert I Westphalen, No-Bong Kwak, Keir Daniels, et al. Regional differences in the effects of isoflurane on neurotransmitter release[J]. Neuropharmacology, 2011, 61(4): 699-706.

[12] Hapfelmeier G, Haseneder R, Eder M, et al. Isoflurane slows inactivation kinetics of rat recombinant α2β2γ1L GABAA receptors: enhancement of GABAergic transmission despite an open-channel block[J]. Neurosci Lett, 2001, 307(2): 97-100.

[13] Scott P Armstrong, Paul J Banks, Thomas J Mckitrick, et al. Identification of two mutations (F758W and F758Y) in the N-methyl-D-aspartate receptor glycine-binding site that selectively prevent competitive inhibition by xenon without affecting glycine binding[J]. Anesthesiology, 2012, 117(1): 38-47.

[14] Dickinson R, Peterson B K, Banks P, et al. Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor by the anesthetics xenon and isoflurane: evidence from molecular modeling and electrophysiology[J]. Anesthesiology, 2007, 107(5): 756-767.

[15] Cheng-Gong, Joan J Kendig. Enflurane directly depresses glutamate AMPA and NMDA currents in mouse spinal cord motor neurons independent of actions on GABAA or glycine receptors[J]. Anesthesiology, 2000, 93(4): 1075-1084.

[16] Megumi Yamashita, Takashi Mori, Keiichi Nagata, et al. Isoflurane modulation of neuronal nicotinic acetylcholine receptors expressed in human embryonic kidney cells[J]. Anesthesiology, 2005, 102(1): 76-84.

[17] Cui Tan-xing, Christian G Canlas, Xu Y, et al. Anesthetic effects on the structure and dynamics of the second transmembrane domains of nAChR α4β2[J]. Biochim Biophys Acta, 2010, 1798(2): 161-166.

[18] Vasyl Bondarenko, Victor E Yushmanov, Xu Y, et al. NMR study of general anesthetic interaction with nAChR β2 subunit[J]. Biophys J, 2008, 94(5): 1681-1688.

[19] David Mowrey, Esmael J Haddadian, Liu Lu-tian, et al. Unresponsive correlated motion in α7 nAChR to halothane binding explains its functional insensitivity to volatile anesthetics[J]. J Phys Chem B, 2010, 114(22): 7649-7655.

[20] David D Mowrey, Liu Qiang, Vasyl Bondarenko, et al. Insights into distinct modulation of α7 and α7β2 nicotinic acetylcholine receptors by the volatile anesthetic isoflurane[J]. J Biol Chem, 2013, 288(50): 35793-35800.

[21] Karl F Herold, Hugh C Hemmings. Sodium channels as targets for volatile anesthetics[J]. Front Pharmacol, 2012, 3: 50.

[22] Toru Yokoyama, Kouichiro Minami, Yuka Sudo, et al. Effects of sevoflurane on voltage-gated sodium channel Na(v)1.8, Na(v)1.7, and Na(v)1.4 expressed in Xenopus oocytes[J]. J Anesth, 2011, 25(4): 609-613.

[23] Michiaki Yamakage, Akiyoshi Namiki. Calcium channels--basic aspects of their structure, function and gene encoding; anesthetic action on the channels--a review[J]. Can J Anaesth, 2002, 49(2): 151-164.

[24] Bruce E Herring, Xie Zheng, Jeremy Marks, et al. Isoflurane inhibits the neurotransmitter release machinery[J]. J Neurophysiol, 2009, 102(2): 1265-1273.

[25] Veit-Simon Eckle, Michael R Digruccio, Victor N Uebele, et al. Inhibition of T-type calcium current in rat thalamocortical neurons by isoflurane[J]. Neuropharmacology, 2012, 63(2): 266-273.

[26] Mansoureh Eghbali, Peter W Gage, Bryndis Birnir. Effects of propofol on GABAA channel conductance in rat-cultured hippocampal neurons[J]. Eur J Pharmacol, 2003, 468(2): 75-82.

[27] Yue Lan, Michal Pawlowski, Shlomo S Dellal, et al. Robust photoregulation of GABAA receptors by allosteric modulation with a propofol analogue[J]. Nat Commun, 2012, 3: 1095.

[28] Jenkins A, Franks N P, Lieb W R. Effects of temperature and volatile anesthetics on GABAA receptors[J]. Anesthesiology, 1999, 90(2): 484-491.

[29] Grace M S Yip, Chen Zi-wei, Christopher J Edge, et al. A propofol binding site on mammalian GABAA receptors identified by photolabeling[J]. Nat Chem Biol, 2013, 9(11): 715-720.

[30] Malin Jonsson Fagerlund, Johanna Sjodin, Michael A Dabrowski, et al. Reduced efficacy of the intravenous anesthetic agent AZD3043 at GABAA receptors with β2 (N289M) and β3 (N290M) point-mutations[J]. Eur J Pharmacol, 2012, 694(1-3): 13-19.

[31] Francois-Xavier Lapebie, Celine Kennel, Laurent Magy, et al. Potential side effect of propofol and sevoflurane for anesthesia of anti-NMDA-R encephalitis[J]. BMC Anesthesiol, 2014, 14(1): 5.

[32] Yoshinori Kotani, Masamitsu Shimazawa, Shinichi Yoshimura, et al. The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties[J]. CNS Neurosci Ther, 2008, 14(2):95-106.

[33] Seth Kingston, Mao Li-min, Yang Lu, et al. Propofol inhibits phosphorylation of N-methyl-D-aspartate receptor NR1 subunits in neurons[J]. Anesthesiology, 2006, 104(4): 763-769.

[34] Gretchen L Snyder, Stacey Galdi, Joseph P Hendrick, et al. General anesthetics selectively modulate glutamatergic and dopaminergic signaling via site-specific phosphorylation in vivo[J]. Neuropharmacology, 2007, 53(5): 619-630.

[35] Lingamaneni R, Birch M L, Hemmings H J. Widespread inhibition of sodium channel-dependent glutamate release from isolated nerve terminals by isoflurane and propofol[J]. Anesthesiology, 2001, 95(6): 1460-1466.

[36] Wei Ou-yang, Wang Gang, Hugh J Hemmings. Isoflurane and propofol inhibit voltage-gated sodium channels in isolated rat neurohypophysial nerve terminals[J]. Mol Pharmacol, 2003, 64(2): 373-381.

[37] Shirasaka T, Yoshimura Y, Qiu D L, et al. The effects of propofol on hypothalamic paraventricular nucleus neurons in the rat[J]. Anesth Analg, 2004, 98(4): 1017-1023.

[38] Belouchi N E, Roux E, Savineau J P, et al. Interaction of extracellular albumin and intravenous anaesthetics, etomidate and propofol, on calcium signalling in rat airway smooth muscle cells[J]. Fundam Clin Pharmacol, 2000, 14(4): 395-400.

[39] Shigemura T, Hatakeyama N, Shibuya N, et al. Effects of propofol on contractile response and electrophysiological properties in single guinea-pig ventricular myocyte[J]. Pharmacol Toxicol, 1999, 85(3): 111-114.

[40] Kristen M Coates, Pamela Flood. Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant α7 and α4β2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes[J]. Br J Pharmacol, 2001, 134(4): 871-879.

[41] Orser B A, Pennefather P S, Macdonald J F. Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors[J]. Anesthesiology, 1997, 86(4): 903-917.

[42] Kristen M Coates, Pamela Flood. Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant α7 and α4β2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes[J]. Br J Pharmacol, 2001, 134(4): 871-879.

[43] Vasyl Bondarenko, David D Mowrey, Tommy S Tillman, et al. NMR structures of the human α7 nAChR transmembrane domain and associated anesthetic binding sites[J]. Biochim Biophys Acta, 2014, 1838(5): 1389-1395.

[44] Reckziegel G, Friederich P, Urban B W. Ketamine effects on human neuronal Na+ channels[J]. Eur J Anaesthesiol, 2002, 19(9): 634-640.

[45] Donald D Denson, Douglas C Eaton. Ketamine inhibition of large conductance Ca2+-activated K+ channels is modulated by intracellular Ca2+[J]. Am J Physiol, 1994, 267(5 Pt 1): C1452-C1458.

[46] Donald D Denson, Pascal Duchatelle, Douglas C Eaton. The effect of racemic ketamine on the large conductance Ca2+-activated potassium (BK) channels in GH3 cells[J]. Brain Res, 1994, 638(1-2): 61-68.

[47] Coates K M, Mather L E, Johnson R, et al. Thiopental is a competitive inhibitor at the human alpha7 nicotinic acetylcholine receptor[J]. Anesth Analg, 2001, 92(4): 930-933.

[48] Andoh T, Furuya R, Oka K, et al. Differential effects of thiopental on neuronal nicotinic acetylcholine receptors and P2X purinergic receptors in PC12 cells[J]. Anesthesiology, 1997, 87(5): 1199-1209.

[49] Yang Y, Si J Q, Fan C, et al. Effects of ropivacaine on GABA-activated currents in isolated dorsal root ganglion neurons in rats[J]. Chinese J Applied Physiology, 2013, 29(3): 263-266.

[50] Koji Hara, Takeyoshi Sata. The effects of the local anesthetics lidocaine and procaine on glycine and gamma-aminobutyric acid receptors expressed in Xenopus oocytes[J]. Anesth Analg, 2007, 104(6): 1434-1439.

[51] Masahiro Sugimoto, Ichiro Uchida, Sakae Fukami, et al. The alpha and gamma subunit-dependent effects of local anesthetics on recombinant GABAA receptors[J]. Eur J Pharmacol, 2000, 401(3): 329-337.

[52] Hahnenkamp K, Durieux M E, Hahnenkamp A, et al. Local anaesthetics inhibit signalling of human NMDA receptors recombinantly expressed in Xenopus laevis oocytes: role of protein kinase C[J]. Br J Anaesth, 2006, 96(1): 77-87.

[53] Carsten Gronwald, Vladimir Vegh, Markus W Hollmann, et al. The inhibitory potency of local anesthetics on NMDA receptor signalling depends on their structural features[J]. Eur J Pharmacol, 2012, 674(1): 13-19.

[54] Harry A Fozzard, Michael F Sheets, Dorothy A Hanck. The sodium channel as a target for local anesthetic drugs[J]. Front Pharmacol, 2011, 2: 68.

[55] Melissa H Kelley, Noriko Taguchi, Ardalan Ardeshiri, et al. Ischemic insult to cerebellar Purkinje cells causes diminished GABAA receptor function and allopregnanolone neuroprotection is associated with GABAA receptor stabilization[J]. J Neurochem, 2008, 107(3): 668-678.

[56] Warner D S. Isoflurane neuroprotection: a passing fantasy, again?[J]. Anesthesiology, 2000, 92(5): 1226-1228.

[57] Ito H, Watanabe Y, Isshiki A, et al. Neuroprotective properties of propofol and midazolam, but not pentobarbital, on neuronal damage induced by forebrain ischemia, based on the GABAA receptors[J]. Acta Anaesthesiol Scand, 1999, 43(2): 153-162.

[58] Richard J Mcmurtrey, Zuo Zhi-yi. Isoflurane preconditioning and postconditioning in rat hippocampal neurons[J]. Brain Res, 2010, 1358: 184-190.

[59] Ding Zhong-yang, Zhang Jia-ming, Xu Jing-yu, et al. Propofol administration modulates AQP-4 expression and brain edema after traumatic brain injury[J]. Cell Biochem Biophys, 2013, 67(2): 615-622.

[60] Jae Hoon Lee, Cui Hui-song, Seo Kyung Shin, et al. Effect of propofol post-treatment on blood-brain barrier integrity and cerebral edema after transient cerebral ischemia in rats[J]. Neurochem Res, 2013, 38(11): 2276-2286.

[61] Cui W Y, Tian A Y, Bai T. Protective effects of propofol on endotoxemia-induced acute kidney injury in rats[J]. Clin Exp Pharmacol Physiol, 2011, 38(11): 747-754.

[62] Jenny B W Li, Huang Xin-yang, Roger S Zhang, et al. Decomposition of slide helix contributions to ATP-dependent inhibition of Kir6.2 channels[J]. J Biol Chem, 2013, 288(32): 23038-23049.

[63] Yao Yuan-yuan, Zhu Man-hua, Zhang Feng-jiang, et al. Activation of Akt and cardioprotection against reperfusion injury are maximal with only five minutes of sevoflurane postconditioning in isolated rat hearts[J]. J Zhejiang Univ Sci B, 2013, 14(6): 511-517.

[64] Amjad Kiani, Mohsen Mirmohammad Sadeghi, Gharipour M, et al. Preconditioning by isoflurane as a volatile anesthetic in elective coronary artery bypass surgery[J]. ARYA Atheroscler, 2013, 9(3): 192-197.

[65] Li Dong-liang, Huang Bin, Liu Jiang-dong, et al. Decreased brain K(ATP) channel contributes to exacerbating ischemic brain injury and the failure of neuroprotection by sevoflurane post-conditioning in diabetic rats[J]. PLoS One, 2013, 8(8): e73334.

[66] Zaugg M, Wang L, Zhang L, et al. Choice of anesthetic combination determines Ca2+ leak after ischemia-reperfusion injury in the working rat heart: favorable versus adverse combinations[J]. Anesthesiology, 2012, 116(3): 648-657.

[67] Kojima A, Kitagawa H, Omatsu-Kanbe M, et al. Presence of store-operated Ca2+ entry in C57BL/6J mouse ventricular myocytes and its suppression by sevoflurane[J]. Br J Anaesth, 2012, 109(3): 352-360.

[68] Akiko Kojima, Hirotoshi Kitagawa, Mariko Omatsu-Kanbe, et al. Sevoflurane protects ventricular myocytes against oxidative stress-induced cellular Ca2+ overload and hypercontracture[J]. Anesthesiology, 2013, 119(3): 606-620.