精制清开灵抗实验性脑缺血的血管保护机制研究
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摘要
近年来,以发展保护“血管系统(vasculature)”的方法来改善中风疗效的观点成为西方学者关注的热点,其中,以内皮型一氧化氮合酶(eNOS)为靶点的治疗措施为治疗脑缺血损伤拓展出了新的思路和途径。研究缺血后血管损伤的病理生理过程,发展能够提供血管保护的治疗措施有着重要的意义,有可能成为缺血性中风病治疗的新方向。
现代医学重视“血管系统”的学术动向与缺血性中风“毒损脑络”病机假说及“解毒通络”治法不谋而合。用于急性期中风治疗已逾二十年的清开灵注射液是由古方安宫牛黄丸改制而成,具有清热解毒、化痰通络、醒神开窍的功效,对中风病的临床疗效显著。国家重点基础研究发展规划(973)项目“清开灵注射液多环节阻抑脑缺血级联反应药效物质与作用机理研究”(课题号G1999054404)利用指纹图谱识别清开灵注射液的组分,通过对其细胞毒性、整体动物毒性研究排查,以清开灵注射液中胆酸、栀子苷、黄芩苷、珍珠母水解液四个有效组分研制而成了增效减毒的新型注射液——精制清开灵。
本部分工作以线栓法复制大鼠持久性大脑中动脉栓塞(PMCAO)模型,观察精制清开灵及其组分在持久性脑缺血急性期与亚急性期是否能够阻抑脑缺血后血管损伤和促进血管修复,从而发挥脑保护作用。具体包括以下两部分内容及相关实验:
第一部分,以eNOS为着眼点,观察PMCAO 2-72h大鼠脑组织eNOS的表达规律及精制清开灵对其影响,探讨精制清开灵对缺血性中风后血管系统损伤与修复过程的干预趋势。
第二部分选择PMCAO 72h这一时段,深入研究精制清开灵及其组分的脑保护作用与它们对血管系统损伤和保护相关指标的干预作用,具体包括五个内容:精制清开灵及其组分对PMCAO 72h大鼠的脑保护作用;精制清开灵及其各组分对PMCAO 72h大鼠脑组织eNOS表达的影响;精制清开灵及其各组分对PMCAO 72h大鼠脑组织血管生成素-1,2(Ang-1,2)及其受体Tie-2表达的影响;精制清开灵及其组分对PMCAO 72h大鼠血清肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、基质金属蛋白酶-2(MMP-2)和基质金属蛋白酶-9(MMP-9)含量的影响。本部分实验在观察精制清开灵及其组分对血管系统损伤与保护相关指标干预作用的同时,着重比较精制清开灵与其各组分对上述指标作用的异同并进行相关性分析,希望能够揭示精制清开灵注射液方剂配伍的部分机制,并探讨中风病“毒损脑络”病机及“解毒通络”治法的现代生物学基础。
各部分实验结果如下:
一、PMCAO 2-72h大鼠脑组织eNOS表达规律及精制清开灵对其影响PMCAO 2-72h,模型组大鼠脑组织eNOS表达较假手术组大鼠反应性增高。PMCAO后2小时,精制清开灵治疗组大鼠脑缺血半暗带eNOS表达即较模型组动物升高,至PMCAO后72小时仍维持这一趋势。
二、精制清开灵及其组分对PMCAO 72h大鼠的脑保护作用
观察PMCAO 72h精制清开灵及其组分胆酸、栀子苷、黄芩苷、珍珠母水解液的脑保护效果,可知:⑴栀子苷和精制清开灵具有良好的阻抑血浆vWF含量病理性升高的作
Ischemic stroke is a common disease of middle-aged and aged people. Jeopardizing people’s health because of its high attack rate, recurrence rate, mutilation rate and mortality rate, ischemic stroke has been the third main cause of death and has attracted great attention of the medical science circle. In recent years, scholars of western countries has shown solicitudes for methods of protecting vasculature to improve curative effect of stroke. Among these methods, therapeutic measures targeting eNOS has provided new idea and pathway to the treatment of ischemic stroke. It is of great importance to study patho-physiology process of the vascular damage after stroke and to develop therapeutic measures of protecting vasculature, maybe it will be a new direction for the treatment of ischemic stroke.
Interestingly, this academic trends partly coincides with the new rising hypothesis of‘toxin hurts brain collaterals’and the therapeusis of‘removing toxin and dredging collaterals’. Qing Kai Ling(QKL) injection is a multicomponent injection derived from Angongniuhuang pills. The effects of QKL injection include clearing heat and removing toxin, dissipating phlegm and dredging collaterals, awaking mind and opening orifice, etc. The injection had been proved to had good effects since it was extensively used to treat acute stroke in 1980s. The research of“Study on the effective substances and functionary mechanisms of Qing Kai Ling injection in blocking cascade of cerebral ischemia damage”, which was funded by National Basic Research Program of China (973 Program, G1999054404), clarified the effective substances of QKL injection in blocking cascade of cerebral ischemia damage, and presented an important innovation of Traditional Chinese Medicine (TCM) prescription, namely, the combination of effective ingredients of Chinese materia medica. And according to the theory, a kind of new chinese medical prescription--Refined Qing Kai Ling (RQKL) injection was invented.
We copied permanent middle cerebral artery occlusion (PMCAO) model of rats using filament method. And we explored whether RQKL injection and its individual ingredients manifested neuroprotective effects by inhibiting injury of vasculature and facilitating recovery of vasculature. Studies were performed as follows in two parts:
First part, using the techniques of immunohistochemistry and western blots, we examined expression of eNOS in brain tissue of rats undergone PMCAO from 2-72 hours and investigated whether RQKL’s cerebroprotective effects were correlated with the expression of eNOS under ischemic condition.
Second part, we further explored the relationship between cerebroprotective effects of RQKL and its individual ingredients and their different influences on harmful and beneficial targets of vasculature, and the part of work can be further divided into four individual experiments:
1. Cerebroprotective effects of RQKL and its individual ingredients on rats after 72 hours
现代医学重视“血管系统”的学术动向与缺血性中风“毒损脑络”病机假说及“解毒通络”治法不谋而合。用于急性期中风治疗已逾二十年的清开灵注射液是由古方安宫牛黄丸改制而成,具有清热解毒、化痰通络、醒神开窍的功效,对中风病的临床疗效显著。国家重点基础研究发展规划(973)项目“清开灵注射液多环节阻抑脑缺血级联反应药效物质与作用机理研究”(课题号G1999054404)利用指纹图谱识别清开灵注射液的组分,通过对其细胞毒性、整体动物毒性研究排查,以清开灵注射液中胆酸、栀子苷、黄芩苷、珍珠母水解液四个有效组分研制而成了增效减毒的新型注射液——精制清开灵。
本部分工作以线栓法复制大鼠持久性大脑中动脉栓塞(PMCAO)模型,观察精制清开灵及其组分在持久性脑缺血急性期与亚急性期是否能够阻抑脑缺血后血管损伤和促进血管修复,从而发挥脑保护作用。具体包括以下两部分内容及相关实验:
第一部分,以eNOS为着眼点,观察PMCAO 2-72h大鼠脑组织eNOS的表达规律及精制清开灵对其影响,探讨精制清开灵对缺血性中风后血管系统损伤与修复过程的干预趋势。
第二部分选择PMCAO 72h这一时段,深入研究精制清开灵及其组分的脑保护作用与它们对血管系统损伤和保护相关指标的干预作用,具体包括五个内容:精制清开灵及其组分对PMCAO 72h大鼠的脑保护作用;精制清开灵及其各组分对PMCAO 72h大鼠脑组织eNOS表达的影响;精制清开灵及其各组分对PMCAO 72h大鼠脑组织血管生成素-1,2(Ang-1,2)及其受体Tie-2表达的影响;精制清开灵及其组分对PMCAO 72h大鼠血清肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、基质金属蛋白酶-2(MMP-2)和基质金属蛋白酶-9(MMP-9)含量的影响。本部分实验在观察精制清开灵及其组分对血管系统损伤与保护相关指标干预作用的同时,着重比较精制清开灵与其各组分对上述指标作用的异同并进行相关性分析,希望能够揭示精制清开灵注射液方剂配伍的部分机制,并探讨中风病“毒损脑络”病机及“解毒通络”治法的现代生物学基础。
各部分实验结果如下:
一、PMCAO 2-72h大鼠脑组织eNOS表达规律及精制清开灵对其影响PMCAO 2-72h,模型组大鼠脑组织eNOS表达较假手术组大鼠反应性增高。PMCAO后2小时,精制清开灵治疗组大鼠脑缺血半暗带eNOS表达即较模型组动物升高,至PMCAO后72小时仍维持这一趋势。
二、精制清开灵及其组分对PMCAO 72h大鼠的脑保护作用
观察PMCAO 72h精制清开灵及其组分胆酸、栀子苷、黄芩苷、珍珠母水解液的脑保护效果,可知:⑴栀子苷和精制清开灵具有良好的阻抑血浆vWF含量病理性升高的作
Ischemic stroke is a common disease of middle-aged and aged people. Jeopardizing people’s health because of its high attack rate, recurrence rate, mutilation rate and mortality rate, ischemic stroke has been the third main cause of death and has attracted great attention of the medical science circle. In recent years, scholars of western countries has shown solicitudes for methods of protecting vasculature to improve curative effect of stroke. Among these methods, therapeutic measures targeting eNOS has provided new idea and pathway to the treatment of ischemic stroke. It is of great importance to study patho-physiology process of the vascular damage after stroke and to develop therapeutic measures of protecting vasculature, maybe it will be a new direction for the treatment of ischemic stroke.
Interestingly, this academic trends partly coincides with the new rising hypothesis of‘toxin hurts brain collaterals’and the therapeusis of‘removing toxin and dredging collaterals’. Qing Kai Ling(QKL) injection is a multicomponent injection derived from Angongniuhuang pills. The effects of QKL injection include clearing heat and removing toxin, dissipating phlegm and dredging collaterals, awaking mind and opening orifice, etc. The injection had been proved to had good effects since it was extensively used to treat acute stroke in 1980s. The research of“Study on the effective substances and functionary mechanisms of Qing Kai Ling injection in blocking cascade of cerebral ischemia damage”, which was funded by National Basic Research Program of China (973 Program, G1999054404), clarified the effective substances of QKL injection in blocking cascade of cerebral ischemia damage, and presented an important innovation of Traditional Chinese Medicine (TCM) prescription, namely, the combination of effective ingredients of Chinese materia medica. And according to the theory, a kind of new chinese medical prescription--Refined Qing Kai Ling (RQKL) injection was invented.
We copied permanent middle cerebral artery occlusion (PMCAO) model of rats using filament method. And we explored whether RQKL injection and its individual ingredients manifested neuroprotective effects by inhibiting injury of vasculature and facilitating recovery of vasculature. Studies were performed as follows in two parts:
First part, using the techniques of immunohistochemistry and western blots, we examined expression of eNOS in brain tissue of rats undergone PMCAO from 2-72 hours and investigated whether RQKL’s cerebroprotective effects were correlated with the expression of eNOS under ischemic condition.
Second part, we further explored the relationship between cerebroprotective effects of RQKL and its individual ingredients and their different influences on harmful and beneficial targets of vasculature, and the part of work can be further divided into four individual experiments:
1. Cerebroprotective effects of RQKL and its individual ingredients on rats after 72 hours
引文
1.Dirnagl U,Iadecola C,Moskowitz MA.Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci.1999 Sep;22(9):391-397.
2.Gladstone DJ,Black SE,Hakim AM.Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke. 2002 Aug;33(8):2123-2136.
3.Cipolla MJ,McCall AL,Lessov N.Reperfusion decreases myogenic reactivity and alters middle cerebral artery function after focal cerebral ischemia in rats. Stroke. 1997;28:176-180.
4.Fagan SC,Hess DC,Hohnadel EJ.Targets for vascular protection after acute ischemic stroke. Stroke. 2004 Sep;35(9):2220-2225. Epub 2004 Jul 29.
5.Lammert E,Cleaver O,Melton D.Induction of pancreatic differentiation by signals from blood vessels. Science.2001;294:564-567.
6.Matsumoto K, Yoshitomi H, Rossant J. Liver organogenesis promoted by endothelial cells prior to vascular function. Science. 2001;294:559-563.
7.Cipolla MJ,Curry AB.Middle cerebral artery function after stroke: the threshold duration of reperfusion for myogenic activity. Stroke. 2002;33:2094-2099.
8.Cipolla MJ,Lessov N,Hammer ES.Threshold duration of ischemia for myogenic tone in middle cerebral arteries: effect on vascular smooth muscle actin. Stroke. 2001;32:1658-1664.
9.Cipolla MJ,Lessov N,Clark WM.Postischemic attenuation of cerebral artery reactivity is increased in the presence of tissue plasminogen activator. Stroke. 2000;31:940-945.
10.Kontos HA.Oxygen radicals in cerebral ischemia: the 2001 Willis Lecture. Stroke. 2001;32:2712-2716.
11.Weisbrot-Lefkowitz M,Reuhl K,Perry B. Overexpression of human glutathione peroxidase protects transgenic mice against focal cerebral ischemia/reperfusion damage. Brain Res Mol Brain Res.1998;53:333-338.
12.Murakami K,Kondo T,Kawase M.Mitochondrial susceptibility to oxidative stress exacerbates cerebral infarction that follows permanent focal cerebral ischemia in mutant mice with manganese superoxide dismutase deficiency. J Neurosci.1998;18:205-213.
13.Clark WM,Rinker LG,Lessov NS.Efficacy of antioxidant therapies in transient focal ischemia in mice. Stroke.2001;32:1000-1004.
14.De La Cruz JP,Guerrero A,Gonzalez-Correa JA. Antioxidant effect of acetylsalicylic and salicylic acid in rat brain slices subjected to hypoxia. J Neurosci Res.2004;75:280-290.
15.Matsuo Y,Mihara S,Ninomiya M.Protective effect of endothelin type A receptor antagonist on brain edema and injury after transient middle cerebral artery occlusion in rats. Stroke. 2001;32:2143-2148.
16.Zhang Z, Chopp M.Vascular endothelial growth factor and angiopoietins in focal cerebral ischemia. Trends Cardiovasc Med. 2002;12:62-66.
17.Yancopoulos GD,Davis S,Gale NW.Vascular-specific growth factors and blood vessel formation. Nature.2000;407:242-248.
18.Gursoy-Ozdemir Y,Bolay H,Saribas O. Role of endothelial nitric oxide generation and peroxynitrite formation in reperfusion injury after focal cerebral ischemia. Stroke. 2000;31:1974-1980.
19.Matthias Endres,Ulrich Laufs,James K.Targeting eNOS for stroke protection.Trends in Neurosciences.2004;27:283-289.
20. Zhang ZG,Zhang L,Croll SD.Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice. Neuroscience. 2002;113:683-687.
21.Hayashi T,Noshita N,Sugawara T.Temporal profile of angiogenesis and expression of related genes in the brain after ischemia.J Cereb Blood Flow Metab. 2003;23:166-180.
22.Sairanen T,Carpen O,Karjalainen-Lindsberg ML. Evolution of cerebral tumor necrosis factor-alpha production during human ischemic stroke. Stroke. 2001;32:1750-1758.
23.Vila N,Castillo J,Davalos A. Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke. 2000;31:2325-2329.
24.Tilton RG,Berens KL.Functional role for selectins in the pathogenesis of cerebral ischemia. Drug News Perspect. 2002;15:351-357.
25.Hess DC,Howard E,Cheng C.Hypertonic mannitol loading of NF-kB transcription factor decoys in human brain microvascular endothelial cells blocks upregulation of ICAM-1 editorial comment. Stroke. 2000;31:1179-1186.
26.Mocco J,Choudhri T,Huang J.HuEP5C7 as a humanized monoclonal anti-E/P-selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke. Circ Res. 2002;91:907-914.
27.D’Ambrosio AL, Pinsky DJ, Connolly ES.The role of the complement cascade in ischemia/reperfusion injury: implications for neuroprotection.Mol Med. 2001;7:367-382.
28.Di Napoli M.Systemic complement activation in ischemic stroke. Stroke.2001;32:1443-1448.
29.Rosenberg GA,Cunningham LA,Wallace J.Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res.2001;893:104-112.
30.Chang DI, Hosomi N, Lucero J.Activation systems for latent matrix metalloproteinase-2 are upregulated immediately after focal cerebral ischemia. J Cereb Blood Flow Metab. 2003;23:1408-1419.
31.del Zoppo GJ, Schmid-Schonbein GW, Mori E. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke. 1991;22:1276-1283.
32.Iadecola C. Bright and dark sides of nitric oxide in ischemic brain injury.Trends Neurosci. 1997;20:132-139.
33.Lerouet D, Beray-Berthat V, Palmier B.Changes in oxidative stress, iNOS activity and neutrophil infiltration in severe transient focal cerebral ischemia in rats. Brain Res. 2002;958:166-175.
34.Zhu DY, Deng Q, Yao HH.Inducible nitric oxide synthase expression in the ischemic core and penumbra after transient focal cerebral ischemia in mice. Life Sci. 2002;71:1985-1996.
35.Croll SD, Wiegand SJ.Vascular growth factors in cerebral ischemia. Mol Neurobiol. 2001;23:121-135.
36.Ay H, Ay I, Koroshetz WJ. Potential usefulness of basic fibroblast growth factor as a treatment for stroke. Cerebrovasc Dis.1999;9:131-135.
37.Beck H, Acker T, Wiessner C.Expression of angiopoietin-1, angiopoietin-2, and tie receptors after middle cerebral artery occlusion in the rat. Am J Pathol. 2000;157:1473-1483.
38.Lin TN, Wang CK, Cheung WM.Induction of angiopoietin and tie receptor mRNA expression after cerebral ischemia-reperfusion.J Cereb Blood Flow Metab. 2000;20:387-395.
39.Servos S, Zachary I, Martin JF.VEGF modulates NO production: the basis of a cytoprotective effect? Cardiovasc Res. 1999;41:509-510.
40.Tsurumi Y, Murohara T, Krasinski K.Reciprocal relation between VEGF and NO in the regulation of endothelial integrity. Nat Med.1997;3:879-886.
41.Wheeler-Jones C,Abu-Ghazaleh R,Cospedal R.Vascular endothelial growth factor stimulates prostacyclin production and activation of cytosolic phospholipase A2 in endothelial cells via p42/p44 mitogen-activated protein kinase. FEBS Lett. 1997;420:28-32.
42.Chen J,Zhu RL,Nakayama M.Expression of the apoptosis-effector gene, Bax, is upregulated in vulnerable hippocampal CA1 neurons following global ischemia. J Neurochem. 1996;67:64-71.
43.Hara A,Iwai T,Niwa M.Immunohistochemical detection of Bax and Bcl-2 proteins in gerbil hippocampus following transient forebrain ischemia. Brain Res. 1996;711:249-253.
44.Abid MR,Guo S,Minami T.Vascular endothelial growth factor activates PI3K/Akt/Forkhead signaling in endothelial cells. Arterioscler Thromb Vasc Biol.2004;24:294-300.
45.Zachary I. VEGF signaling: integration and multi-tasking in endothelial cell biology. Biochem Soc Trans. 2003;31:1171-1177.
46.Cai J, Ahmad S, Jiang WG.Activation of vascular endothelial growth factor receptor-1 sustains angiogenesis and Bcl-2 expression via the phosphatidylinositol 3-kinase pathway in endothelial cells. Diabetes. 2003;52:2959-2968.
47.Gladstone DJ,Black SE,Hakim AM.Toward wisdom from failure:lessons from neuroprotective stroke trials and new therapeutic directions.Stroke. 2002;33:2123-2136.
48.Jonas S,Aiyagari V,Vieira D.The failure of neuronal protective agents versus the success of thrombolysis in the treatment of ischemic stroke. The predictive value of animal models. Ann N Y Acad Sci. 2001;939:257-267.
49.George SJ.Therapeutic potential of matrix metalloproteinase inhibitors in atherosclerosis. Expert Opin Investig Drugs. 2000;9:993-1007.
1.Furchgott RF, Zawadzki JV.The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.Nature, November 27, 1980; 288(5789): 373-376.
2.Loscalzo J. Nitric oxide and vascular disease. N.Engl. J. Med. 1995 Jul 27;333(4):251-253.
3.Rudic RD, Sessa WC. Nitric oxide in endothelial dysfunction and vascular remodeling: clinical correlates and experimental links. Am J Hum Genet. 1999 Mar;64(3):673-677.
4.Iadecola C. Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci. 1997 Mar;20(3):132-139.
5.Samdani AF, Dawson TM, Dawson VL. Nitric oxide synthase in models of focal ischemia. Stroke. 1997 Jun;28(6):1283-1288.
6.Huang PL, Huang Z, Mashimo H. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995 Sep 21;377(6546):239-242.
7.Fleming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol. 2003 Jan;284(1):R1-12.
8.Fulton D, Gratton JP, Sessa WC. Post-translational control of endothelial nitric oxide synthase: why isn't calcium/calmodulin enough? J Pharmacol Exp Ther. 2001 Dec;299(3):818-824.
9.Laufs U, Endres M, Stagliano N. Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J Clin Invest. 2000 Jul;106(1):15-24.
10.Huang Z, Huang PL, Ma J. Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. J Cereb Blood Flow Metab. 1996 Sep;16(5):981-987.
11.Dalkara T, Morikawa E, Panahian N.Blood flow-dependent functional recovery in a rat model of focal cerebral ischemia. Am J Physiol. 1994 Aug;267(2 Pt 2):H678-683.
12.Murohara T, Asahara T, Silver M. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest. 1998 Jun 1;101(11):2567-2578.
13.Aicher A, Heeschen C, Mildner-Rihm C. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med. 2003 Nov;9(11):1370-6. Epub 2003 Oct 12.
14.Dimmeler S, Aicher A, Vasa M. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest. 2001 Aug;108(3):391-397.
15.Laufs U, Werner N, Link A. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation. 2004 Jan 20;109(2):220-226. Epub 2003 Dec 22.
16.Zhang ZG, Zhang L, Jiang Q. Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res. 2002 Feb 22;90(3):284-288.
17.Laufs U. Beyond lipid-lowering: effects of statins on endothelial nitric oxide. Eur J Clin Pharmacol. 2003 Mar;58(11):719-731. Epub 2003 Feb 18.
18.Hernandez-Perera O,Perez-Sala D,Navarro-Antolin J.Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest. 1998 Jun 15;101(12):2711-2719.
19.Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem. 1998 Sep 11;273(37):24266-71.
20.Endres M,Laufs U, Huang Z.Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8880-8885.
21.Yamada M, Huang Z, Dalkara T. Endothelial nitric oxide synthase-dependent cerebral blood flow augmentation by L-arginine after chronic statin treatment. J Cereb Blood Flow Metab. 2000 Apr;20(4):709-717.
22.Sironi L, Cimino M, Guerrini U. Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage. Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):322-327.
23.Kawashima S, Yamashita T, Miwa Y. HMG-CoA reductase inhibitor has protective effects against stroke events in stroke-prone spontaneously hypertensive rats. Stroke. 2003 Jan;34(1):157-163.
24.Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002 Jul 6;360(9326):7-22.
25.Jonsson N, Asplund K. Does pretreatment with statins improve clinical outcome after stroke? A pilot case-referent study. Stroke. 2001 May;32(5):1112-1115.
26.O'Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation. 1997 Mar 4;95(5):1126-1131.
27.Waters,D.D, Gregory G. Schwartz .Effects of Atorvastatin on Stroke in Patients With Unstable Angina or Non-Q-Wave Myocardial Infarction: A Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Substudy. Circulation, Sep 2002; 106: 1690-1695.
28.Heeschen C, Hamm CW, Laufs U. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation. 2002 Mar 26;105(12):1446-1452.
29.Gertz K, Laufs U, Lindauer U, Nickenig G. Withdrawal of statin treatment abrogates stroke protection in mice. Stroke. 2003 Feb;34(2):551-557.
30.Hafezi-Moghadam A, Simoncini T, Yang E. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med. 2002 May;8(5):473-479.
31.Limbourg FP, Huang Z, Plumier JC. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J Clin Invest. 2002 Dec;110(11):1729-1738.
32.Stead LG, Rowe BH. Evidence-based emergency medicine/systematic review abstract. Corticosteroid treatment for acute ischemic stroke. Ann Emerg Med. 2003 Jul;42(1):150-152.
33.Chambliss KL, Shaul PW. Estrogen modulation of endothelial nitric oxide synthase. Endocr Rev. 2002 Oct;23(5):665-686.
34. Simoncini T, Hafezi-Moghadam A, Brazil DP. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature. 2000 Sep 28;407(6803):538-541.
35.Simoncini T, Genazzani AR, Liao JK. Nongenomic mechanisms of endothelial nitric oxide synthase activation by the selective estrogen receptor modulator raloxifene. Circulation. 2002 Mar 19;105(11):1368-1373.
36.Hurn PD, Brass LM. Estrogen and stroke: a balanced analysis. Stroke. 2003 Feb;34(2):338-341.
37.Prorock AJ, Hafezi-Moghadam A, Laubach VE, Liao JK, Ley K. Vascular protection by estrogen in ischemia-reperfusion injury requires endothelial nitric oxide synthase. Am J Physiol Heart Circ Physiol. 2003 Jan;284(1):H133-40. Epub 2002 Sep 05.
38.Wassertheil-Smoller S, Hendrix SL, Limacher M. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA. 2003 May 28;289(20):2673-2684.
39.Fukai T, Siegfried MR, Ushio-Fukai M. Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. J Clin Invest. 2000 Jun;105(11):1631-1639.
40.Kojda G, Cheng YC, Burchfield J. Dysfunctional regulation of endothelial nitric oxidesynthase (eNOS) expression in response to exercise in mice lacking one eNOS gene. Circulation. 2001 Jun 12;103(23):2839-2844.
41.Endres M, Gertz K, Lindauer U. Mechanisms of stroke protection by physical activity. Mechanisms of stroke protection by physical activity. Ann Neurol. 2003 Nov;54(5):582-590.
42.Hambrecht R, Adams V, Erbs S. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation. 2003 Jul 1;107(25):3152-3158. Epub 2003 Jun 16.
43.Wallerath T, Deckert G, Ternes T. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation. 2002 Sep 24;106(13):1652-1658.
44.Benito S, Lopez D, Saiz MP. A flavonoid-rich diet increases nitric oxide production in rat aorta. Br J Pharmacol. 2002 Feb;135(4):910-916.
45.Huang SS, Tsai MC, Chih CL. Resveratrol reduction of infarct size in Long-Evans rats subjected to focal cerebral ischemia. Life Sci. 2001 Jul 20;69(9):1057-1065.
46.Vasquez-Vivar J, Kalyanaraman B, Martasek P. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9220-9225.
47.Kuzkaya N, Weissmann N, Harrison DG. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem. 2003 Jun 20;278(25):22546-22554. Epub 2003 Apr 10.
48.Landmesser U, Dikalov S, Price SR. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest. 2003 Apr;111(8):1201-1209.
49.Wassmann S, Laufs U, Baumer AT. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol. 2001 Mar;59(3):646-654.
50.Lee CD, Folsom AR, Blair SN. Physical activity and stroke risk: a meta-analysis. Stroke. 2003 Oct;34(10):2475-2481. Epub 2003 Sep 18.
51.Di Castelnuovo A, Rotondo S, Iacoviello L. Meta-analysis of wine and beer consumption in relation to vascular risk. Circulation. 2002 Jun 18;105(24):2836-2844.
1.王永炎,杨宝琴,黄启福,络脉络病与病络,北京中医药大学学报,2003(04),P6-7。
2.陈以国,络脉与微循环的再认识,中医函授通讯,1998(04),P35-36。
3.张建斌,王玲玲,对《内经》中病理性络脉的分析,江苏中医,2001(10),P45-47。
4.刘绍能,刘为民,络脉病证治探讨,中医药研究,2002(04),P2-4。
5. 王永炎 , 关于提高脑血管疾病疗效难点的思考 , 中国中西医结合杂志 , 1997 (2),P195-196。
6.李澎涛,王永炎,黄启福,“毒损脑络”病机假说的形成及其理论与实践意义,北京中医药大学学报,2001(01),P4-9+19。
7.唐启盛,“浊毒痹阻脑络”对老年期痴呆的影响,北京中医药大学学报,1997(06),P25-26。
8. 高 颖 , 谢 颖 桢 , 王 永 炎 , 试 论 浊 毒 在 血 管 性 痴 呆 发 病 中 的 作 用 , 中 国 中 医 急症,2000(06),P31-32。
9. 宋福印 , 王永炎 , 黄启福 , 试论毒损脑络与糖尿病性脑病 , 北京中医药大学学报,2000(05),P10-11。
10.雷燕,黄启福,王永炎,论瘀毒阻络是络病形成的病理基础,北京中医药大学学报,1999(02),P9-12。
11.雷燕,郝钰,邱全瑛,黄启福,王永美,复圣散对血管内皮细胞活性及其与中性粒细胞粘附作用的影响,中国病理生理杂志,1999(05),P57。
12.杨友竹,糖尿病与自由基,日本医学介绍,1994(07),P298-299。
13.Chien S, Li S, Shyy YJ.Effects of mechanical forces on signal transduction and gene expression in endothelial cells.Hypertension. 1998 Jan;31(1 Pt 2):162-169.
14.Downey GP, Waddell TK, Fukushima T, Sue-A-Quan A. Current techniques in cell and molecular biology.J Crit Care. 1995 Sep;10(3):136-149.
15.Jennings GL, Chin-Dusting JP, Kingwell BA, Dart AM, Cameron J, Esler M, Lewis TV.Modulation of vascular function by diet and exercise.Clin Exp Hypertens. 1997 Jul-Aug;19(5-6):727-737.
16.Marks GS, Brien JF, Nakatsu K, McLaughlin BE.Does carbon monoxide have a physiological function?Trends Pharmacol Sci.1991 May;12(5):185-188.
17.李岩,赵雁,黄启福,王永炎,中医络病的现代认识,北京中医药大学学报,2002(03),P5-9。
1.Faraci FM, Brian JE. Nitric oxide and the cerebral circulation. Stroke. 1994 Mar;25(3):692-703.
2.Dalkara T, Moskowitz MA. The complex role of nitric oxide in the pathophysiology of focal cerebral ischemia.Brain Pathol. 1994 Jan;4(1):49-57.
3.Moro MA, Cardenas A, Hurtado O, Leza JC, Lizasoain I. Role of nitric oxide after brain ischaemia. Cell Calcium. 2004 Sep-Oct;36(3-4):265-275.
4.Jiang MH, Kaku T, Hada J, Hayashi Y. Different effects of eNOS and nNOS inhibition on transient forebrain ischemia. Brain Res. 2002 Aug 9;946(1):139-147.
5.Chen SH, Cheung RT. Neuropeptide Y and its receptor analogs differentially modulate the immunoreactivity for neuronal or endothelial nitric oxide synthase in the rat brain following focal ischemia with reperfusion. J Biomed Sci. 2005;12(2):267-278.
6.Huang Z, Huang PL, Ma J, Meng W, Ayata C, Fishman MC, Moskowitz MA.Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine.J Cereb Blood Flow Metab. 1996 Sep;16(5):981-987.
7.GUO Xinfeng,LAI Shilong, Meta - analysis of Qingkailing Injection for Treating Acute Stroke,Journal of Guangzhou University of Traditional Chinese Medicine,2000Mar;17(01):9-14.
8.Zhu XL, Zhang N, Li PT, Jiang YF, Xu Y. Protective effect of jasminoidin on cascade of damage of cerebral ischemia in rats. Zhongguo Zhong Yao Za Zhi. 2004 Nov;29(11):1065-1068.
9.E.Z. Longa, P.R.Weinstein,S.Carlson,R Cummins.Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 20 (1989) 84-91.
10.Iadecola C, Pelligrino DA, Moskowitz MA, Lassen NA. Nitric oxide synthase inhibition and cerebrovascular regulation.J Cereb Blood Flow Metab. 1994 Mar;14(2):175-192.
11.Leker RR, Teichner A, Ovadia H, Keshet E, Reinherz E, Ben-Hur T. Expression of endothelial nitric oxide synthase in the ischemic penumbra: relationship to expression of neuronal nitric oxide synthase and vascular endothelial growth factor. Brain Res. 2001 Aug 3;909(1-2):1-7.
12.Babaei S, Teichert-Kuliszewska K, Zhang Q, Jones N, Dumont DJ, Stewart DJ.Angiogenicactions of angiopoietin-1 require endothelium-derived nitric oxide.Am J Pathol.2003 Jun;162(6):1927-1936.
13.Zhang R, Wang L, Zhang L, Chen J, Zhu Z, Zhang Z, Chopp M. Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat. Circ Res. 2003 Feb 21;92(3):308-313.
14.Chen J, Zacharek A, Zhang C, Jiang H, Li Y, Roberts C, Lu M, Kapke A, Chopp M. Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. J Neurosci. 2005 Mar 2;25(9):2366-2375.
15.Rikitake Y, Kim HH, Huang Z, Seto M, Yano K, Asano T, Moskowitz MA, Liao JK. Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection.Stroke. 2005 Oct;36(10):2251-7. Epub 2005 Sep 1.
16.Osuka K, Watanabe Y, Usuda N, Nakazawa A, Tokuda M, Yoshida J.Modification of endothelial NO synthase through protein phosphorylation after forebrain cerebral ischemia/reperfusion. Stroke. 2004 Nov;35(11):2582-2586. Epub 2004 Sep 16.
17.Zhang ZG, Chopp M, Zaloga C, Pollock JS, Foerstermann U. Cerebral endothelial nitric oxide synthase expression after focal cerebral ischemia in rats. Stroke. 1993;24:2016-2022.
18.Zhang ZG, Chopp M, Bailey F, Malinski T. Nitric oxide changes in the rat brain after transient middle cerebral artery occlusion. J Neurol Sci.1995;128:22-27.
19.Gajkowska B, Mossakowski MJ. Endothelial nitric oxide synthase in vascular endothelium of rat hippocampus after ischemia: evidence and significance. Folia Neuropathol. 1997;35:171-180.
20.Beasley TC, Bari F, Thore C, Thrikawala N, Louis TM, Busija DW.Cerebral ischemia/reperfusion increases endothelial nitric oxide synthase levels by an indomethacin sensitive mechanism. J Cereb Blood Flow Metab. 1998;18:88-96.
21.Veltkamp R, Rajapakse N, Robins G, Puskar M, Shimizu K, Busija D. Transient focal ischemia increases endothelial nitric oxide synthase in cerebral blood vessels. Stroke. 2002 Nov;33(11):2704-2710.
22.Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage.Sironi L, Cimino M, Guerrini U, Calvio AM, Lodetti B, Asdente M, Balduini W, Paoletti R, Tremoli E. Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):322-327.
23.Tomimoto H, Nishimura M, Suenega T, Nakamura S, Akiguchi I, Wakita H, Kimura J, Mayer B. Distribution of nitric oxide synthase in the human cerebral blood vessels and brain tissues. J Cereb Blood Flow Metab.1994;14:930-938.
24.Hashiguchi A, Yano S, Morioka M, Hamada J, Ushio Y, Takeuchi Y, Fukunaga K. Up-regulation of endothelial nitric oxide synthase via phosphatidylinositol 3-kinase pathway contributes to ischemic tolerance in the CA1 subfield of gerbil hippocampus.J Cereb Blood Flow Metab. 2004 Mar;24(3):271-279.
25.Lo EH, Hara H, Rogowska J, Trocha M, Pierce AR, Huang PL, Fishman MC, Wolf GL,Moskowitz MA.Temporal correlation mapping analysis of the hemodynamic penumbra in mutant mice deficient in endothelial nitric oxide synthase gene expression. Stroke. 1996 Aug;27(8):1381-1385.
1.Bederson JB, Pitts LH, Tsuji M,et al. Rat middle cerebral artry occlusion: evaluation of the model and development of neurologic examination [J]. Stroke, 1986,17:472-476.
2.Eller T, Brauer P, Alber J, Significance and guantitatine analysis of von willebrand factor in human platelets. Thromb Res,1992,65(4-5):631-640.
3.张九莲,罗琳,缺血性脑血管疾病患者 10 项分子标志物测定的意义。齐齐哈尔医学院学报,2000,21(5):503-504。
4.Chambless LE, Shahar E, Sharett AR, Association of transient ischemia attack/stroke symptoms assessed by standardized questionaire and algorithm with cerebral vascular risk factors and carotid artery wall thickness[J].Am J Pidemiol, 1996, 144(9):857-866.
5.Botker HE,Ingerslev J.Plasma concentrations of von Willebrand factor in patients with anginapectoris secondary to coronary.atherosclerosis or cardiac syndrome.ThrombRes, 2000, 97(6):519-523.
6.Kumari M,Marmot M,Brunner E.Social determinants of von willebrand factor:the Whitehall II study. Arterioscler Thromb Vasc Biol,2000;20(7):1842-1847.
7.Verlmuyten K.Detection of neuron specific enolase concentration in cerebrospinal fluid from patients with neurological disorders by means of a sensitive enzyme immunoassay.Clin Chim Acta,1990,187:69-78.
8.Barone FC,Clark RK,Price WJ,Neuron-specific enolase increases in cerebral and systemic circulation following focal ischemia. Brain Res,1993,623(1):77-82.
9.Hatfield RH,Mckeman RM .CSF neuron-specific enolase as a quantitative marker of neuronal damage in rat stroke model [J]. Brain Res,1992;577:249-252.
10.张忱,李刚,徐亚萍,等。大鼠局灶性脑缺血再灌注模型的再灌注时间窗。中日友好医院学报,2000,14(5):255-259。
1.Endres M, Laufs U, Liao JK, Moskowitz MA. Targeting eNOS for stroke protection. Trends Neurosci. 2004 May;27(5):283-289.
2.Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK.Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase.Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8880-8885.
3.Cimino M, Balduini W, Carloni S, Gelosa P, Guerrini U, Tremoli E, Sironi L.Neuroprotective Effect of Simvastatin in Stroke: A Comparison Between Adult andNeonatal Rat Models of Cerebral Ischemia. Neurotoxicology. 2005 May 26; [Epub ahead of print]
4.Asahi M, Huang Z, Thomas S, Yoshimura S, Sumii T, Mori T, Qiu J, Amin-Hanjani S, Huang PL, Liao JK, Lo EH, Moskowitz MA. Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. J Cereb Blood Flow Metab. 2005 Jun;25(6):722-729.
5.Limbourg FP, Huang Z, Plumier JC. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J Clin Invest. 2002 Dec;110(11):1729-1738.
6.Prorock AJ, Hafezi-Moghadam A, Laubach VE, Liao JK, Ley K. Vascular protection by estrogen in ischemia-reperfusion injury requires endothelial nitric oxide synthase. Am J Physiol Heart Circ Physiol. 2003 Jan;284(1):H133-40. Epub 2002 Sep 05.
7.Sasaki Y, Noguchi T, Yamamoto E, Giddings JC, Ikeda K, Yamori Y, Yamamoto J. Effects of Ginkgo biloba extract (EGb 761) on cerebral thrombosis and blood pressure in stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol.2002 Nov;29(11):963-967.
8.Zhu XL, Zhang N, Li PT, Jiang YF, Xu Y. Protective effect of jasminoidin on cascade of damage of cerebral ischemia in rats. Zhongguo Zhong Yao Za Zhi. 2004 Nov;29(11):1065-1068.
9.Gajkowska B, Mossakowski MJ. Endothelial nitric oxide synthase in vascular endothelium of rat hippocampus after ischemia: evidence and significance. Folia Neuropathol. 1997;35:171-180.
10.Beasley TC, Bari F, Thore C, Thrikawala N, Louis TM, Busija DW.Cerebral ischemia/reperfusion increases endothelial nitric oxide synthase levels by an indomethacin sensitive mechanism. J Cereb Blood Flow Metab. 1998;18:88-96.
11.Bredt DS.Endogenous nitric oxide synthesis: biological functions and pathophysiology.Free Radic Res.1999 Dec;31(6):577-596.
12.Moro MA, Cardenas A, Hurtado O, Leza JC, Lizasoain I. Role of nitric oxide after brain ischaemia. Cell Calcium. 2004 Sep-Oct;36(3-4):265-275.
13.Jiang MH, Kaku T, Hada J, Hayashi Y. Different effects of eNOS and nNOS inhibition on transient forebrain ischemia. Brain Res. 2002 Aug 9;946(1):139-147.
14.Zhang ZG, Chopp M, Zaloga C, Pollock JS, Foerstermann U. Cerebral endothelial nitric oxide synthase expression after focal cerebral ischemia in rats. Stroke. 1993;24:2016-2022.
15.Sironi L, Cimino M, Guerrini U, Calvio AM, Lodetti B, Asdente M, Balduini W, Paoletti R, Tremoli E.Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage. Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):322-327.
16.Leker RR, Teichner A, Ovadia H, Keshet E, Reinherz E, Ben-Hur T. Expression of endothelial nitric oxide synthase in the ischemic penumbra: relationship to expression ofneuronal nitric oxide synthase and vascular endothelial growth factor. Brain Res. 2001 Aug 3;909(1-2):1-7.
17.Veltkamp R, Rajapakse N, Robins G, Puskar M, Shimizu K, Busija D. Transient focal ischemia increases endothelial nitric oxide synthase in cerebral blood vessels. Stroke. 2002 Nov;33(11):2704-2710.
18.Qizilbash N, Duffy S, Prentice CR, Boothby M, Warlow C. Von Willebrand factor and risk of ischemic stroke. Neurology. 1997 Dec;49(6):1552-1556.
19.Kumari M, Marmot M, Brunner E. Social determinants of von willebrand factor: the Whitehall II study. Arterioscler Thromb Vasc Biol. 2000 Jul;20(7):1842-1847.
1.Maisonpierre PC, Suri C, Jones PF.Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997 Jul 4;277(5322):55-60.
2.Yancopoulos GD, Klagsbrun M, Folkman J. Vasculogenesis, angiogenesis, and growth factors: ephrins enter the fray at the border. Cell. 1998 May 29;93(5):661-664.
3.Valable S, Bellail A, Lesne S. Angiopoietin-1-induced PI3-kinase activation prevents neuronal apoptosis. FASEB J. 2003 Mar;17(3):443-445. Epub 2003 Jan 02.
4.Yancopoulos GD, Davis S, Gale NW.Vascular-specific growth factors and blood vessel formation. Nature. 2000 Sep 14;407(6801):242-248.
5.Suri C, McClain J, Thurston G. Increased vascularization in mice overexpressing angiopoietin-1. Science. 1998 Oct 16;282(5388):468-471.
6.Jones N, Dumont DJ.The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R. Oncogene. 1998 Sep 3;17(9):1097-1108.
7.Korpelainen EI, Karkkainen M, Gunji Y. Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response. Oncogene. 1999 Jan 7;18(1):1-8.
8.Pettersson A, Nagy JA, Brown LF. Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Lab Invest. 2000 Jan;80(1):99-115.
9.Zhang ZG, Zhang L, Tsang W. Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia. J Cereb Blood Flow Metab. 2002 Apr;22(4):379-392.
10.Lin TN, Wang CK, Cheung WM. Induction of angiopoietin and Tie receptor mRNA expression after cerebral ischemia-reperfusion. J Cereb Blood Flow Metab. 2000 Feb;20(2):387-395.
11.Beck H, Acker T, Wiessner C. Expression of angiopoietin-1, angiopoietin-2, and tie receptors after middle cerebral artery occlusion in the rat. Am J Pathol. 2000 Nov;157(5):1473-1483.
12.Zhang ZG, Zhang L, Croll SD. Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice. Neuroscience. 2002;113(3):683-687.
13.Chen JX, Lawrence ML, Cunningham G, Christman BW, Meyrick B.HSP90 and Akt modulate Ang-1-induced angiogenesis via NO in coronary artery endothelium.J Appl Physiol. 2004 Feb;96(2):612-620. Epub 2003 Oct 10.
1.Jiang X,Namura S,Nagata I.Matrix metalloproteinase inhibitor KB7785 attenuate brain damage resulting from permanent focal cerebral ischemia in mice.Neurosci Lett,2001,305(1):41-44.
2.Heo JH, Lucero J, Abumiya T,et al.Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab,1999 ,19(6):624-33.
3.Schobitz B,De Kloet ER,Holsboer F,Gene expression and function of interleukin 1,interleukin 6 and tumor necrosis factor in the brain.Prog Neurobiol,1994,44(4):397-432.
4.Fajardo LE,Kwan hh,Kowalski J,et al..Dual role of tumor necrosis factor-alpha in angiogenesis.Am J Pathol,1992,140(3):539-544.
5.Liu T,Clark RK,McDonnell PC.Tumor necrosis factor-alpha expression in ischemic neurons. Stroke,1994,25(7):1481-1488.
6.Gong C,Qin Z,Betz AL,Cellular localization of tumor necrosis factor alpha following focal cerebral ischemia in mice. Brain Res,1998,801(1-2):1-8.
7.Gregersen R,Lambertsen K,Finsen B,Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab,2000,20(1):53-65.
8.Zhang Z,Chopp M,Goussev A,Cerebral vessels express interleukin -1beta after focal cerebral ischemia. Brain Res,1998,784(1-2):210-217.
9.Davies CA,Loddick SA,Toulmond S,The progression and topographic distribution of interleukin-1beta expression after permanent middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab,1999,19(1):87-98.
10.Legos JJ,Whitmore RG,Erhardt JA,Quantitative changes in interleukin proteins following focal stroke in the rat. Neurosci Lett,2000,282(3):189-192.
11.Stroemer RP,Rothwell NJ,Exacerbation of ischemic brain damage by localized striatal injection of interleukin-1beta in the rat. J Cereb Blood Flow Metab,1998 Aug;18(8):833-839.
12.Saliba E,Henrot A,Inflammatory mediators and neonatal brain damage. Biol Neonate,2001,79(3-4):224-227.
13.Rosenberg GA,Estrada EY,Dencoff JE.Matrix metalloproteinase and TIMPs are associated with blood brain barrier opening after reperfusion in rat brain.Stroke,1998,29(10):2189-2195.
14.Rosenberg GA, Cunningham LA, Wallace J, Alexander S, Estrada EY, Grossetete M, Razhagi A, Miller K, Gearing A.Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures[J].Brain Res.2001 Mar 2;893(1-2):104-112.
15.Gasche Y, Fujimura M, Morita-Fujimura Y,et al.Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood-brainbarrier dysfunction. J Cereb Blood Flow Metab,1999,19(9):1020-1028.
16.Fujimura M, Gasche Y, Morita-Fujimura Y,et al.Early appearance of activated matrix metalloproteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion.Brain Res,1999,842(1):92-100.
17.Asahi M,Wang X,Mori T,et al.Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci,2001,21(19):7724-7732.
[1]《中医执业助理医师考试指导及习题集》编委,华夏出版社出版,2004年4月第一版,标准书号:ISBN 7-5080-2955-03.
[2]《络病学基础与临床研究》常务编委,中国科学技术出版社出版,2005年10月第一版,标准书号:ISBN 7-5046-4951-4/R.1131.
2.Gladstone DJ,Black SE,Hakim AM.Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke. 2002 Aug;33(8):2123-2136.
3.Cipolla MJ,McCall AL,Lessov N.Reperfusion decreases myogenic reactivity and alters middle cerebral artery function after focal cerebral ischemia in rats. Stroke. 1997;28:176-180.
4.Fagan SC,Hess DC,Hohnadel EJ.Targets for vascular protection after acute ischemic stroke. Stroke. 2004 Sep;35(9):2220-2225. Epub 2004 Jul 29.
5.Lammert E,Cleaver O,Melton D.Induction of pancreatic differentiation by signals from blood vessels. Science.2001;294:564-567.
6.Matsumoto K, Yoshitomi H, Rossant J. Liver organogenesis promoted by endothelial cells prior to vascular function. Science. 2001;294:559-563.
7.Cipolla MJ,Curry AB.Middle cerebral artery function after stroke: the threshold duration of reperfusion for myogenic activity. Stroke. 2002;33:2094-2099.
8.Cipolla MJ,Lessov N,Hammer ES.Threshold duration of ischemia for myogenic tone in middle cerebral arteries: effect on vascular smooth muscle actin. Stroke. 2001;32:1658-1664.
9.Cipolla MJ,Lessov N,Clark WM.Postischemic attenuation of cerebral artery reactivity is increased in the presence of tissue plasminogen activator. Stroke. 2000;31:940-945.
10.Kontos HA.Oxygen radicals in cerebral ischemia: the 2001 Willis Lecture. Stroke. 2001;32:2712-2716.
11.Weisbrot-Lefkowitz M,Reuhl K,Perry B. Overexpression of human glutathione peroxidase protects transgenic mice against focal cerebral ischemia/reperfusion damage. Brain Res Mol Brain Res.1998;53:333-338.
12.Murakami K,Kondo T,Kawase M.Mitochondrial susceptibility to oxidative stress exacerbates cerebral infarction that follows permanent focal cerebral ischemia in mutant mice with manganese superoxide dismutase deficiency. J Neurosci.1998;18:205-213.
13.Clark WM,Rinker LG,Lessov NS.Efficacy of antioxidant therapies in transient focal ischemia in mice. Stroke.2001;32:1000-1004.
14.De La Cruz JP,Guerrero A,Gonzalez-Correa JA. Antioxidant effect of acetylsalicylic and salicylic acid in rat brain slices subjected to hypoxia. J Neurosci Res.2004;75:280-290.
15.Matsuo Y,Mihara S,Ninomiya M.Protective effect of endothelin type A receptor antagonist on brain edema and injury after transient middle cerebral artery occlusion in rats. Stroke. 2001;32:2143-2148.
16.Zhang Z, Chopp M.Vascular endothelial growth factor and angiopoietins in focal cerebral ischemia. Trends Cardiovasc Med. 2002;12:62-66.
17.Yancopoulos GD,Davis S,Gale NW.Vascular-specific growth factors and blood vessel formation. Nature.2000;407:242-248.
18.Gursoy-Ozdemir Y,Bolay H,Saribas O. Role of endothelial nitric oxide generation and peroxynitrite formation in reperfusion injury after focal cerebral ischemia. Stroke. 2000;31:1974-1980.
19.Matthias Endres,Ulrich Laufs,James K.Targeting eNOS for stroke protection.Trends in Neurosciences.2004;27:283-289.
20. Zhang ZG,Zhang L,Croll SD.Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice. Neuroscience. 2002;113:683-687.
21.Hayashi T,Noshita N,Sugawara T.Temporal profile of angiogenesis and expression of related genes in the brain after ischemia.J Cereb Blood Flow Metab. 2003;23:166-180.
22.Sairanen T,Carpen O,Karjalainen-Lindsberg ML. Evolution of cerebral tumor necrosis factor-alpha production during human ischemic stroke. Stroke. 2001;32:1750-1758.
23.Vila N,Castillo J,Davalos A. Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke. 2000;31:2325-2329.
24.Tilton RG,Berens KL.Functional role for selectins in the pathogenesis of cerebral ischemia. Drug News Perspect. 2002;15:351-357.
25.Hess DC,Howard E,Cheng C.Hypertonic mannitol loading of NF-kB transcription factor decoys in human brain microvascular endothelial cells blocks upregulation of ICAM-1 editorial comment. Stroke. 2000;31:1179-1186.
26.Mocco J,Choudhri T,Huang J.HuEP5C7 as a humanized monoclonal anti-E/P-selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke. Circ Res. 2002;91:907-914.
27.D’Ambrosio AL, Pinsky DJ, Connolly ES.The role of the complement cascade in ischemia/reperfusion injury: implications for neuroprotection.Mol Med. 2001;7:367-382.
28.Di Napoli M.Systemic complement activation in ischemic stroke. Stroke.2001;32:1443-1448.
29.Rosenberg GA,Cunningham LA,Wallace J.Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res.2001;893:104-112.
30.Chang DI, Hosomi N, Lucero J.Activation systems for latent matrix metalloproteinase-2 are upregulated immediately after focal cerebral ischemia. J Cereb Blood Flow Metab. 2003;23:1408-1419.
31.del Zoppo GJ, Schmid-Schonbein GW, Mori E. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke. 1991;22:1276-1283.
32.Iadecola C. Bright and dark sides of nitric oxide in ischemic brain injury.Trends Neurosci. 1997;20:132-139.
33.Lerouet D, Beray-Berthat V, Palmier B.Changes in oxidative stress, iNOS activity and neutrophil infiltration in severe transient focal cerebral ischemia in rats. Brain Res. 2002;958:166-175.
34.Zhu DY, Deng Q, Yao HH.Inducible nitric oxide synthase expression in the ischemic core and penumbra after transient focal cerebral ischemia in mice. Life Sci. 2002;71:1985-1996.
35.Croll SD, Wiegand SJ.Vascular growth factors in cerebral ischemia. Mol Neurobiol. 2001;23:121-135.
36.Ay H, Ay I, Koroshetz WJ. Potential usefulness of basic fibroblast growth factor as a treatment for stroke. Cerebrovasc Dis.1999;9:131-135.
37.Beck H, Acker T, Wiessner C.Expression of angiopoietin-1, angiopoietin-2, and tie receptors after middle cerebral artery occlusion in the rat. Am J Pathol. 2000;157:1473-1483.
38.Lin TN, Wang CK, Cheung WM.Induction of angiopoietin and tie receptor mRNA expression after cerebral ischemia-reperfusion.J Cereb Blood Flow Metab. 2000;20:387-395.
39.Servos S, Zachary I, Martin JF.VEGF modulates NO production: the basis of a cytoprotective effect? Cardiovasc Res. 1999;41:509-510.
40.Tsurumi Y, Murohara T, Krasinski K.Reciprocal relation between VEGF and NO in the regulation of endothelial integrity. Nat Med.1997;3:879-886.
41.Wheeler-Jones C,Abu-Ghazaleh R,Cospedal R.Vascular endothelial growth factor stimulates prostacyclin production and activation of cytosolic phospholipase A2 in endothelial cells via p42/p44 mitogen-activated protein kinase. FEBS Lett. 1997;420:28-32.
42.Chen J,Zhu RL,Nakayama M.Expression of the apoptosis-effector gene, Bax, is upregulated in vulnerable hippocampal CA1 neurons following global ischemia. J Neurochem. 1996;67:64-71.
43.Hara A,Iwai T,Niwa M.Immunohistochemical detection of Bax and Bcl-2 proteins in gerbil hippocampus following transient forebrain ischemia. Brain Res. 1996;711:249-253.
44.Abid MR,Guo S,Minami T.Vascular endothelial growth factor activates PI3K/Akt/Forkhead signaling in endothelial cells. Arterioscler Thromb Vasc Biol.2004;24:294-300.
45.Zachary I. VEGF signaling: integration and multi-tasking in endothelial cell biology. Biochem Soc Trans. 2003;31:1171-1177.
46.Cai J, Ahmad S, Jiang WG.Activation of vascular endothelial growth factor receptor-1 sustains angiogenesis and Bcl-2 expression via the phosphatidylinositol 3-kinase pathway in endothelial cells. Diabetes. 2003;52:2959-2968.
47.Gladstone DJ,Black SE,Hakim AM.Toward wisdom from failure:lessons from neuroprotective stroke trials and new therapeutic directions.Stroke. 2002;33:2123-2136.
48.Jonas S,Aiyagari V,Vieira D.The failure of neuronal protective agents versus the success of thrombolysis in the treatment of ischemic stroke. The predictive value of animal models. Ann N Y Acad Sci. 2001;939:257-267.
49.George SJ.Therapeutic potential of matrix metalloproteinase inhibitors in atherosclerosis. Expert Opin Investig Drugs. 2000;9:993-1007.
1.Furchgott RF, Zawadzki JV.The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.Nature, November 27, 1980; 288(5789): 373-376.
2.Loscalzo J. Nitric oxide and vascular disease. N.Engl. J. Med. 1995 Jul 27;333(4):251-253.
3.Rudic RD, Sessa WC. Nitric oxide in endothelial dysfunction and vascular remodeling: clinical correlates and experimental links. Am J Hum Genet. 1999 Mar;64(3):673-677.
4.Iadecola C. Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci. 1997 Mar;20(3):132-139.
5.Samdani AF, Dawson TM, Dawson VL. Nitric oxide synthase in models of focal ischemia. Stroke. 1997 Jun;28(6):1283-1288.
6.Huang PL, Huang Z, Mashimo H. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995 Sep 21;377(6546):239-242.
7.Fleming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol. 2003 Jan;284(1):R1-12.
8.Fulton D, Gratton JP, Sessa WC. Post-translational control of endothelial nitric oxide synthase: why isn't calcium/calmodulin enough? J Pharmacol Exp Ther. 2001 Dec;299(3):818-824.
9.Laufs U, Endres M, Stagliano N. Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J Clin Invest. 2000 Jul;106(1):15-24.
10.Huang Z, Huang PL, Ma J. Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. J Cereb Blood Flow Metab. 1996 Sep;16(5):981-987.
11.Dalkara T, Morikawa E, Panahian N.Blood flow-dependent functional recovery in a rat model of focal cerebral ischemia. Am J Physiol. 1994 Aug;267(2 Pt 2):H678-683.
12.Murohara T, Asahara T, Silver M. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest. 1998 Jun 1;101(11):2567-2578.
13.Aicher A, Heeschen C, Mildner-Rihm C. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med. 2003 Nov;9(11):1370-6. Epub 2003 Oct 12.
14.Dimmeler S, Aicher A, Vasa M. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest. 2001 Aug;108(3):391-397.
15.Laufs U, Werner N, Link A. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation. 2004 Jan 20;109(2):220-226. Epub 2003 Dec 22.
16.Zhang ZG, Zhang L, Jiang Q. Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res. 2002 Feb 22;90(3):284-288.
17.Laufs U. Beyond lipid-lowering: effects of statins on endothelial nitric oxide. Eur J Clin Pharmacol. 2003 Mar;58(11):719-731. Epub 2003 Feb 18.
18.Hernandez-Perera O,Perez-Sala D,Navarro-Antolin J.Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest. 1998 Jun 15;101(12):2711-2719.
19.Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem. 1998 Sep 11;273(37):24266-71.
20.Endres M,Laufs U, Huang Z.Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8880-8885.
21.Yamada M, Huang Z, Dalkara T. Endothelial nitric oxide synthase-dependent cerebral blood flow augmentation by L-arginine after chronic statin treatment. J Cereb Blood Flow Metab. 2000 Apr;20(4):709-717.
22.Sironi L, Cimino M, Guerrini U. Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage. Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):322-327.
23.Kawashima S, Yamashita T, Miwa Y. HMG-CoA reductase inhibitor has protective effects against stroke events in stroke-prone spontaneously hypertensive rats. Stroke. 2003 Jan;34(1):157-163.
24.Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002 Jul 6;360(9326):7-22.
25.Jonsson N, Asplund K. Does pretreatment with statins improve clinical outcome after stroke? A pilot case-referent study. Stroke. 2001 May;32(5):1112-1115.
26.O'Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation. 1997 Mar 4;95(5):1126-1131.
27.Waters,D.D, Gregory G. Schwartz .Effects of Atorvastatin on Stroke in Patients With Unstable Angina or Non-Q-Wave Myocardial Infarction: A Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Substudy. Circulation, Sep 2002; 106: 1690-1695.
28.Heeschen C, Hamm CW, Laufs U. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation. 2002 Mar 26;105(12):1446-1452.
29.Gertz K, Laufs U, Lindauer U, Nickenig G. Withdrawal of statin treatment abrogates stroke protection in mice. Stroke. 2003 Feb;34(2):551-557.
30.Hafezi-Moghadam A, Simoncini T, Yang E. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med. 2002 May;8(5):473-479.
31.Limbourg FP, Huang Z, Plumier JC. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J Clin Invest. 2002 Dec;110(11):1729-1738.
32.Stead LG, Rowe BH. Evidence-based emergency medicine/systematic review abstract. Corticosteroid treatment for acute ischemic stroke. Ann Emerg Med. 2003 Jul;42(1):150-152.
33.Chambliss KL, Shaul PW. Estrogen modulation of endothelial nitric oxide synthase. Endocr Rev. 2002 Oct;23(5):665-686.
34. Simoncini T, Hafezi-Moghadam A, Brazil DP. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature. 2000 Sep 28;407(6803):538-541.
35.Simoncini T, Genazzani AR, Liao JK. Nongenomic mechanisms of endothelial nitric oxide synthase activation by the selective estrogen receptor modulator raloxifene. Circulation. 2002 Mar 19;105(11):1368-1373.
36.Hurn PD, Brass LM. Estrogen and stroke: a balanced analysis. Stroke. 2003 Feb;34(2):338-341.
37.Prorock AJ, Hafezi-Moghadam A, Laubach VE, Liao JK, Ley K. Vascular protection by estrogen in ischemia-reperfusion injury requires endothelial nitric oxide synthase. Am J Physiol Heart Circ Physiol. 2003 Jan;284(1):H133-40. Epub 2002 Sep 05.
38.Wassertheil-Smoller S, Hendrix SL, Limacher M. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA. 2003 May 28;289(20):2673-2684.
39.Fukai T, Siegfried MR, Ushio-Fukai M. Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. J Clin Invest. 2000 Jun;105(11):1631-1639.
40.Kojda G, Cheng YC, Burchfield J. Dysfunctional regulation of endothelial nitric oxidesynthase (eNOS) expression in response to exercise in mice lacking one eNOS gene. Circulation. 2001 Jun 12;103(23):2839-2844.
41.Endres M, Gertz K, Lindauer U. Mechanisms of stroke protection by physical activity. Mechanisms of stroke protection by physical activity. Ann Neurol. 2003 Nov;54(5):582-590.
42.Hambrecht R, Adams V, Erbs S. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation. 2003 Jul 1;107(25):3152-3158. Epub 2003 Jun 16.
43.Wallerath T, Deckert G, Ternes T. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation. 2002 Sep 24;106(13):1652-1658.
44.Benito S, Lopez D, Saiz MP. A flavonoid-rich diet increases nitric oxide production in rat aorta. Br J Pharmacol. 2002 Feb;135(4):910-916.
45.Huang SS, Tsai MC, Chih CL. Resveratrol reduction of infarct size in Long-Evans rats subjected to focal cerebral ischemia. Life Sci. 2001 Jul 20;69(9):1057-1065.
46.Vasquez-Vivar J, Kalyanaraman B, Martasek P. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9220-9225.
47.Kuzkaya N, Weissmann N, Harrison DG. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem. 2003 Jun 20;278(25):22546-22554. Epub 2003 Apr 10.
48.Landmesser U, Dikalov S, Price SR. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest. 2003 Apr;111(8):1201-1209.
49.Wassmann S, Laufs U, Baumer AT. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol. 2001 Mar;59(3):646-654.
50.Lee CD, Folsom AR, Blair SN. Physical activity and stroke risk: a meta-analysis. Stroke. 2003 Oct;34(10):2475-2481. Epub 2003 Sep 18.
51.Di Castelnuovo A, Rotondo S, Iacoviello L. Meta-analysis of wine and beer consumption in relation to vascular risk. Circulation. 2002 Jun 18;105(24):2836-2844.
1.王永炎,杨宝琴,黄启福,络脉络病与病络,北京中医药大学学报,2003(04),P6-7。
2.陈以国,络脉与微循环的再认识,中医函授通讯,1998(04),P35-36。
3.张建斌,王玲玲,对《内经》中病理性络脉的分析,江苏中医,2001(10),P45-47。
4.刘绍能,刘为民,络脉病证治探讨,中医药研究,2002(04),P2-4。
5. 王永炎 , 关于提高脑血管疾病疗效难点的思考 , 中国中西医结合杂志 , 1997 (2),P195-196。
6.李澎涛,王永炎,黄启福,“毒损脑络”病机假说的形成及其理论与实践意义,北京中医药大学学报,2001(01),P4-9+19。
7.唐启盛,“浊毒痹阻脑络”对老年期痴呆的影响,北京中医药大学学报,1997(06),P25-26。
8. 高 颖 , 谢 颖 桢 , 王 永 炎 , 试 论 浊 毒 在 血 管 性 痴 呆 发 病 中 的 作 用 , 中 国 中 医 急症,2000(06),P31-32。
9. 宋福印 , 王永炎 , 黄启福 , 试论毒损脑络与糖尿病性脑病 , 北京中医药大学学报,2000(05),P10-11。
10.雷燕,黄启福,王永炎,论瘀毒阻络是络病形成的病理基础,北京中医药大学学报,1999(02),P9-12。
11.雷燕,郝钰,邱全瑛,黄启福,王永美,复圣散对血管内皮细胞活性及其与中性粒细胞粘附作用的影响,中国病理生理杂志,1999(05),P57。
12.杨友竹,糖尿病与自由基,日本医学介绍,1994(07),P298-299。
13.Chien S, Li S, Shyy YJ.Effects of mechanical forces on signal transduction and gene expression in endothelial cells.Hypertension. 1998 Jan;31(1 Pt 2):162-169.
14.Downey GP, Waddell TK, Fukushima T, Sue-A-Quan A. Current techniques in cell and molecular biology.J Crit Care. 1995 Sep;10(3):136-149.
15.Jennings GL, Chin-Dusting JP, Kingwell BA, Dart AM, Cameron J, Esler M, Lewis TV.Modulation of vascular function by diet and exercise.Clin Exp Hypertens. 1997 Jul-Aug;19(5-6):727-737.
16.Marks GS, Brien JF, Nakatsu K, McLaughlin BE.Does carbon monoxide have a physiological function?Trends Pharmacol Sci.1991 May;12(5):185-188.
17.李岩,赵雁,黄启福,王永炎,中医络病的现代认识,北京中医药大学学报,2002(03),P5-9。
1.Faraci FM, Brian JE. Nitric oxide and the cerebral circulation. Stroke. 1994 Mar;25(3):692-703.
2.Dalkara T, Moskowitz MA. The complex role of nitric oxide in the pathophysiology of focal cerebral ischemia.Brain Pathol. 1994 Jan;4(1):49-57.
3.Moro MA, Cardenas A, Hurtado O, Leza JC, Lizasoain I. Role of nitric oxide after brain ischaemia. Cell Calcium. 2004 Sep-Oct;36(3-4):265-275.
4.Jiang MH, Kaku T, Hada J, Hayashi Y. Different effects of eNOS and nNOS inhibition on transient forebrain ischemia. Brain Res. 2002 Aug 9;946(1):139-147.
5.Chen SH, Cheung RT. Neuropeptide Y and its receptor analogs differentially modulate the immunoreactivity for neuronal or endothelial nitric oxide synthase in the rat brain following focal ischemia with reperfusion. J Biomed Sci. 2005;12(2):267-278.
6.Huang Z, Huang PL, Ma J, Meng W, Ayata C, Fishman MC, Moskowitz MA.Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine.J Cereb Blood Flow Metab. 1996 Sep;16(5):981-987.
7.GUO Xinfeng,LAI Shilong, Meta - analysis of Qingkailing Injection for Treating Acute Stroke,Journal of Guangzhou University of Traditional Chinese Medicine,2000Mar;17(01):9-14.
8.Zhu XL, Zhang N, Li PT, Jiang YF, Xu Y. Protective effect of jasminoidin on cascade of damage of cerebral ischemia in rats. Zhongguo Zhong Yao Za Zhi. 2004 Nov;29(11):1065-1068.
9.E.Z. Longa, P.R.Weinstein,S.Carlson,R Cummins.Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 20 (1989) 84-91.
10.Iadecola C, Pelligrino DA, Moskowitz MA, Lassen NA. Nitric oxide synthase inhibition and cerebrovascular regulation.J Cereb Blood Flow Metab. 1994 Mar;14(2):175-192.
11.Leker RR, Teichner A, Ovadia H, Keshet E, Reinherz E, Ben-Hur T. Expression of endothelial nitric oxide synthase in the ischemic penumbra: relationship to expression of neuronal nitric oxide synthase and vascular endothelial growth factor. Brain Res. 2001 Aug 3;909(1-2):1-7.
12.Babaei S, Teichert-Kuliszewska K, Zhang Q, Jones N, Dumont DJ, Stewart DJ.Angiogenicactions of angiopoietin-1 require endothelium-derived nitric oxide.Am J Pathol.2003 Jun;162(6):1927-1936.
13.Zhang R, Wang L, Zhang L, Chen J, Zhu Z, Zhang Z, Chopp M. Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat. Circ Res. 2003 Feb 21;92(3):308-313.
14.Chen J, Zacharek A, Zhang C, Jiang H, Li Y, Roberts C, Lu M, Kapke A, Chopp M. Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. J Neurosci. 2005 Mar 2;25(9):2366-2375.
15.Rikitake Y, Kim HH, Huang Z, Seto M, Yano K, Asano T, Moskowitz MA, Liao JK. Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection.Stroke. 2005 Oct;36(10):2251-7. Epub 2005 Sep 1.
16.Osuka K, Watanabe Y, Usuda N, Nakazawa A, Tokuda M, Yoshida J.Modification of endothelial NO synthase through protein phosphorylation after forebrain cerebral ischemia/reperfusion. Stroke. 2004 Nov;35(11):2582-2586. Epub 2004 Sep 16.
17.Zhang ZG, Chopp M, Zaloga C, Pollock JS, Foerstermann U. Cerebral endothelial nitric oxide synthase expression after focal cerebral ischemia in rats. Stroke. 1993;24:2016-2022.
18.Zhang ZG, Chopp M, Bailey F, Malinski T. Nitric oxide changes in the rat brain after transient middle cerebral artery occlusion. J Neurol Sci.1995;128:22-27.
19.Gajkowska B, Mossakowski MJ. Endothelial nitric oxide synthase in vascular endothelium of rat hippocampus after ischemia: evidence and significance. Folia Neuropathol. 1997;35:171-180.
20.Beasley TC, Bari F, Thore C, Thrikawala N, Louis TM, Busija DW.Cerebral ischemia/reperfusion increases endothelial nitric oxide synthase levels by an indomethacin sensitive mechanism. J Cereb Blood Flow Metab. 1998;18:88-96.
21.Veltkamp R, Rajapakse N, Robins G, Puskar M, Shimizu K, Busija D. Transient focal ischemia increases endothelial nitric oxide synthase in cerebral blood vessels. Stroke. 2002 Nov;33(11):2704-2710.
22.Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage.Sironi L, Cimino M, Guerrini U, Calvio AM, Lodetti B, Asdente M, Balduini W, Paoletti R, Tremoli E. Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):322-327.
23.Tomimoto H, Nishimura M, Suenega T, Nakamura S, Akiguchi I, Wakita H, Kimura J, Mayer B. Distribution of nitric oxide synthase in the human cerebral blood vessels and brain tissues. J Cereb Blood Flow Metab.1994;14:930-938.
24.Hashiguchi A, Yano S, Morioka M, Hamada J, Ushio Y, Takeuchi Y, Fukunaga K. Up-regulation of endothelial nitric oxide synthase via phosphatidylinositol 3-kinase pathway contributes to ischemic tolerance in the CA1 subfield of gerbil hippocampus.J Cereb Blood Flow Metab. 2004 Mar;24(3):271-279.
25.Lo EH, Hara H, Rogowska J, Trocha M, Pierce AR, Huang PL, Fishman MC, Wolf GL,Moskowitz MA.Temporal correlation mapping analysis of the hemodynamic penumbra in mutant mice deficient in endothelial nitric oxide synthase gene expression. Stroke. 1996 Aug;27(8):1381-1385.
1.Bederson JB, Pitts LH, Tsuji M,et al. Rat middle cerebral artry occlusion: evaluation of the model and development of neurologic examination [J]. Stroke, 1986,17:472-476.
2.Eller T, Brauer P, Alber J, Significance and guantitatine analysis of von willebrand factor in human platelets. Thromb Res,1992,65(4-5):631-640.
3.张九莲,罗琳,缺血性脑血管疾病患者 10 项分子标志物测定的意义。齐齐哈尔医学院学报,2000,21(5):503-504。
4.Chambless LE, Shahar E, Sharett AR, Association of transient ischemia attack/stroke symptoms assessed by standardized questionaire and algorithm with cerebral vascular risk factors and carotid artery wall thickness[J].Am J Pidemiol, 1996, 144(9):857-866.
5.Botker HE,Ingerslev J.Plasma concentrations of von Willebrand factor in patients with anginapectoris secondary to coronary.atherosclerosis or cardiac syndrome.ThrombRes, 2000, 97(6):519-523.
6.Kumari M,Marmot M,Brunner E.Social determinants of von willebrand factor:the Whitehall II study. Arterioscler Thromb Vasc Biol,2000;20(7):1842-1847.
7.Verlmuyten K.Detection of neuron specific enolase concentration in cerebrospinal fluid from patients with neurological disorders by means of a sensitive enzyme immunoassay.Clin Chim Acta,1990,187:69-78.
8.Barone FC,Clark RK,Price WJ,Neuron-specific enolase increases in cerebral and systemic circulation following focal ischemia. Brain Res,1993,623(1):77-82.
9.Hatfield RH,Mckeman RM .CSF neuron-specific enolase as a quantitative marker of neuronal damage in rat stroke model [J]. Brain Res,1992;577:249-252.
10.张忱,李刚,徐亚萍,等。大鼠局灶性脑缺血再灌注模型的再灌注时间窗。中日友好医院学报,2000,14(5):255-259。
1.Endres M, Laufs U, Liao JK, Moskowitz MA. Targeting eNOS for stroke protection. Trends Neurosci. 2004 May;27(5):283-289.
2.Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK.Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase.Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8880-8885.
3.Cimino M, Balduini W, Carloni S, Gelosa P, Guerrini U, Tremoli E, Sironi L.Neuroprotective Effect of Simvastatin in Stroke: A Comparison Between Adult andNeonatal Rat Models of Cerebral Ischemia. Neurotoxicology. 2005 May 26; [Epub ahead of print]
4.Asahi M, Huang Z, Thomas S, Yoshimura S, Sumii T, Mori T, Qiu J, Amin-Hanjani S, Huang PL, Liao JK, Lo EH, Moskowitz MA. Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. J Cereb Blood Flow Metab. 2005 Jun;25(6):722-729.
5.Limbourg FP, Huang Z, Plumier JC. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J Clin Invest. 2002 Dec;110(11):1729-1738.
6.Prorock AJ, Hafezi-Moghadam A, Laubach VE, Liao JK, Ley K. Vascular protection by estrogen in ischemia-reperfusion injury requires endothelial nitric oxide synthase. Am J Physiol Heart Circ Physiol. 2003 Jan;284(1):H133-40. Epub 2002 Sep 05.
7.Sasaki Y, Noguchi T, Yamamoto E, Giddings JC, Ikeda K, Yamori Y, Yamamoto J. Effects of Ginkgo biloba extract (EGb 761) on cerebral thrombosis and blood pressure in stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol.2002 Nov;29(11):963-967.
8.Zhu XL, Zhang N, Li PT, Jiang YF, Xu Y. Protective effect of jasminoidin on cascade of damage of cerebral ischemia in rats. Zhongguo Zhong Yao Za Zhi. 2004 Nov;29(11):1065-1068.
9.Gajkowska B, Mossakowski MJ. Endothelial nitric oxide synthase in vascular endothelium of rat hippocampus after ischemia: evidence and significance. Folia Neuropathol. 1997;35:171-180.
10.Beasley TC, Bari F, Thore C, Thrikawala N, Louis TM, Busija DW.Cerebral ischemia/reperfusion increases endothelial nitric oxide synthase levels by an indomethacin sensitive mechanism. J Cereb Blood Flow Metab. 1998;18:88-96.
11.Bredt DS.Endogenous nitric oxide synthesis: biological functions and pathophysiology.Free Radic Res.1999 Dec;31(6):577-596.
12.Moro MA, Cardenas A, Hurtado O, Leza JC, Lizasoain I. Role of nitric oxide after brain ischaemia. Cell Calcium. 2004 Sep-Oct;36(3-4):265-275.
13.Jiang MH, Kaku T, Hada J, Hayashi Y. Different effects of eNOS and nNOS inhibition on transient forebrain ischemia. Brain Res. 2002 Aug 9;946(1):139-147.
14.Zhang ZG, Chopp M, Zaloga C, Pollock JS, Foerstermann U. Cerebral endothelial nitric oxide synthase expression after focal cerebral ischemia in rats. Stroke. 1993;24:2016-2022.
15.Sironi L, Cimino M, Guerrini U, Calvio AM, Lodetti B, Asdente M, Balduini W, Paoletti R, Tremoli E.Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage. Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):322-327.
16.Leker RR, Teichner A, Ovadia H, Keshet E, Reinherz E, Ben-Hur T. Expression of endothelial nitric oxide synthase in the ischemic penumbra: relationship to expression ofneuronal nitric oxide synthase and vascular endothelial growth factor. Brain Res. 2001 Aug 3;909(1-2):1-7.
17.Veltkamp R, Rajapakse N, Robins G, Puskar M, Shimizu K, Busija D. Transient focal ischemia increases endothelial nitric oxide synthase in cerebral blood vessels. Stroke. 2002 Nov;33(11):2704-2710.
18.Qizilbash N, Duffy S, Prentice CR, Boothby M, Warlow C. Von Willebrand factor and risk of ischemic stroke. Neurology. 1997 Dec;49(6):1552-1556.
19.Kumari M, Marmot M, Brunner E. Social determinants of von willebrand factor: the Whitehall II study. Arterioscler Thromb Vasc Biol. 2000 Jul;20(7):1842-1847.
1.Maisonpierre PC, Suri C, Jones PF.Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997 Jul 4;277(5322):55-60.
2.Yancopoulos GD, Klagsbrun M, Folkman J. Vasculogenesis, angiogenesis, and growth factors: ephrins enter the fray at the border. Cell. 1998 May 29;93(5):661-664.
3.Valable S, Bellail A, Lesne S. Angiopoietin-1-induced PI3-kinase activation prevents neuronal apoptosis. FASEB J. 2003 Mar;17(3):443-445. Epub 2003 Jan 02.
4.Yancopoulos GD, Davis S, Gale NW.Vascular-specific growth factors and blood vessel formation. Nature. 2000 Sep 14;407(6801):242-248.
5.Suri C, McClain J, Thurston G. Increased vascularization in mice overexpressing angiopoietin-1. Science. 1998 Oct 16;282(5388):468-471.
6.Jones N, Dumont DJ.The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R. Oncogene. 1998 Sep 3;17(9):1097-1108.
7.Korpelainen EI, Karkkainen M, Gunji Y. Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response. Oncogene. 1999 Jan 7;18(1):1-8.
8.Pettersson A, Nagy JA, Brown LF. Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Lab Invest. 2000 Jan;80(1):99-115.
9.Zhang ZG, Zhang L, Tsang W. Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia. J Cereb Blood Flow Metab. 2002 Apr;22(4):379-392.
10.Lin TN, Wang CK, Cheung WM. Induction of angiopoietin and Tie receptor mRNA expression after cerebral ischemia-reperfusion. J Cereb Blood Flow Metab. 2000 Feb;20(2):387-395.
11.Beck H, Acker T, Wiessner C. Expression of angiopoietin-1, angiopoietin-2, and tie receptors after middle cerebral artery occlusion in the rat. Am J Pathol. 2000 Nov;157(5):1473-1483.
12.Zhang ZG, Zhang L, Croll SD. Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice. Neuroscience. 2002;113(3):683-687.
13.Chen JX, Lawrence ML, Cunningham G, Christman BW, Meyrick B.HSP90 and Akt modulate Ang-1-induced angiogenesis via NO in coronary artery endothelium.J Appl Physiol. 2004 Feb;96(2):612-620. Epub 2003 Oct 10.
1.Jiang X,Namura S,Nagata I.Matrix metalloproteinase inhibitor KB7785 attenuate brain damage resulting from permanent focal cerebral ischemia in mice.Neurosci Lett,2001,305(1):41-44.
2.Heo JH, Lucero J, Abumiya T,et al.Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab,1999 ,19(6):624-33.
3.Schobitz B,De Kloet ER,Holsboer F,Gene expression and function of interleukin 1,interleukin 6 and tumor necrosis factor in the brain.Prog Neurobiol,1994,44(4):397-432.
4.Fajardo LE,Kwan hh,Kowalski J,et al..Dual role of tumor necrosis factor-alpha in angiogenesis.Am J Pathol,1992,140(3):539-544.
5.Liu T,Clark RK,McDonnell PC.Tumor necrosis factor-alpha expression in ischemic neurons. Stroke,1994,25(7):1481-1488.
6.Gong C,Qin Z,Betz AL,Cellular localization of tumor necrosis factor alpha following focal cerebral ischemia in mice. Brain Res,1998,801(1-2):1-8.
7.Gregersen R,Lambertsen K,Finsen B,Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab,2000,20(1):53-65.
8.Zhang Z,Chopp M,Goussev A,Cerebral vessels express interleukin -1beta after focal cerebral ischemia. Brain Res,1998,784(1-2):210-217.
9.Davies CA,Loddick SA,Toulmond S,The progression and topographic distribution of interleukin-1beta expression after permanent middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab,1999,19(1):87-98.
10.Legos JJ,Whitmore RG,Erhardt JA,Quantitative changes in interleukin proteins following focal stroke in the rat. Neurosci Lett,2000,282(3):189-192.
11.Stroemer RP,Rothwell NJ,Exacerbation of ischemic brain damage by localized striatal injection of interleukin-1beta in the rat. J Cereb Blood Flow Metab,1998 Aug;18(8):833-839.
12.Saliba E,Henrot A,Inflammatory mediators and neonatal brain damage. Biol Neonate,2001,79(3-4):224-227.
13.Rosenberg GA,Estrada EY,Dencoff JE.Matrix metalloproteinase and TIMPs are associated with blood brain barrier opening after reperfusion in rat brain.Stroke,1998,29(10):2189-2195.
14.Rosenberg GA, Cunningham LA, Wallace J, Alexander S, Estrada EY, Grossetete M, Razhagi A, Miller K, Gearing A.Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures[J].Brain Res.2001 Mar 2;893(1-2):104-112.
15.Gasche Y, Fujimura M, Morita-Fujimura Y,et al.Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood-brainbarrier dysfunction. J Cereb Blood Flow Metab,1999,19(9):1020-1028.
16.Fujimura M, Gasche Y, Morita-Fujimura Y,et al.Early appearance of activated matrix metalloproteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion.Brain Res,1999,842(1):92-100.
17.Asahi M,Wang X,Mori T,et al.Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci,2001,21(19):7724-7732.
[1]《中医执业助理医师考试指导及习题集》编委,华夏出版社出版,2004年4月第一版,标准书号:ISBN 7-5080-2955-03.
[2]《络病学基础与临床研究》常务编委,中国科学技术出版社出版,2005年10月第一版,标准书号:ISBN 7-5046-4951-4/R.1131.