银杏叶提取物对胃肠运动的影响及其机制研究
摘要
本研究通过在体小肠推进实验、离体器官灌流技术、游离结肠平滑肌细胞测量技术和建立冷束缚应激引起的胃肠动力紊乱模型，并运用放射免疫分析方法以及比色法，以胃内色素残留率、小肠推进率、离体肠段肌张力变化、单个结肠平滑肌细胞长度变化以及SP、VIP、NO含量的变化等为观察指标，从在体、离体器官、细胞分子等不同水平观察银杏叶提取物(EGb)对肠平滑肌动力的影响并分析其机制，为探索因肠平滑肌运动机能障碍和胃肠动力紊乱所致疾病的发病机制提供基础依据，亦为充分利用银杏叶这一天然药物资源、开发研制一类用于调节、改善胃肠动力，防治因胃肠动力紊乱所致疾病(如肠易激综合症等)的药物提供科学的理论依据。
1 EGb对豚鼠单个结肠平滑肌细胞的影响
1．1不同浓度的EGb对结肠平滑肌细胞的影响用不同浓度的EGb(0.11～3.5g·L~(-1))孵育细胞，可使单个结肠平滑肌细胞舒张，呈一定剂量-效应关系，最大反应浓度为1.75 g·L~(-1)。
1．2 EGb对ACh引起结肠平滑肌细胞收缩效应的影响 ACh(10~(-6)mol·L~(-1))明显增强结肠平滑肌细胞的收缩，与对照组相比增强49.1％。用EGb预先孵育3 mjn，可明显抑制ACh收缩效应的44.1％。
1．3 Forskolin对EGb效应的影响腺苷酸环化酶激动剂Forskolin(10~(-2)mol·L~(-1))可增强EGb的舒张效应，与单独应用EGb组相比较平滑肌细胞舒张百分数增加8.9％(P＜0.05)。观察了单独应用EGb组和Forskolin+EGb组，平滑肌细胞舒张百
安徽医科大学硕士学位论文
分数分别是12.8%(P<0.05)和22.7%(P<0.01)。
2 EGb对豚鼠结肠平滑肌运动的影响及其机制的初步探讨
2.1不同浓度的EGb对豚鼠离体结肠运动的影响EGb(0.5一50.Omg·L一‘)，可使
豚鼠离体结肠平滑肌运动出现抑制和兴奋两种不同反应，其中以抑制作用为主，
浓度为10.Omg·IJ一’时作用最强。
2.2不同浓度的银杏黄酮对豚鼠离体结肠运动的影响银杏黄酮(Flavon山〔15)
(0.01一0.巧mg·L一，)可使豚鼠离体结肠运动受到抑制，当银杏黄酮为0.10 mg·L一，
时，其运动的幅度和张力受抑制的程度最为明显，分别为一21.8士5.6、一14.7士6.3。
EGb对ACh、5一HT引起的结肠平滑肌强直性收缩的抑制作用
ACh(10一6
·L一‘)和5一Hr(10一魂mol·L一，)0.
ml可引起离体结肠强直性收缩，其收缩幅
Odl万1
O
9︺m
度和张力较给药前明显增强，于3 min后再加入EGb(10.Omg·
部分拮抗ACh、5一HT增强肠平滑肌收缩的效应。
L一‘)0 .lml
2.4 EGb对V工P、GABA、阿托品、肾上腺素引起的结肠运动抑制效应的影响
，则可
在平
滑肌浴槽内分别加入血管活性肠肤(vIP)(10一魂mol·L一，)、Y一氨基丁酸(GABA)(10一‘
mol
、阿托品(Atropine)(10一6 mol·L一，)、’肾上腺素(Adr)(10一5 mol·L一，
离体结肠运动受到抑制，再加入EGb(10mg·L一，)0.lml后，vIP组收
一，
rLI止
.用
缩幅度和张力进一步降低，其幅度和张力分别由一10.9士8.3、一10.7士5.3下降到
一18.6士7.3、一25.1士8.7(P<0.05);而Atropine、GABA、Adr组与未加E〔;b组
比较变化无显著性。
2.5钙对EGb作用的影响用无钙Krebs液替代普通KrebS液灌流结肠标本，待
肠管运动稳定后，加入EGb(10 mg·L一‘)0.lml，发现EGb可进一步抑制结肠运动，
其运动幅度和张力分别由一23.5士12.6、一21.7士12.3下降到一52.2士6.8(P<
O.GI)、一38.7士16.4(P<0.05)，与用普通KrebS液灌流相比有显著性差异(P>
安徽医科大学硕士学位论文
0 .05)。
3 EGb对BALB/c小鼠小肠推进速度的影响
E(3b(2 .0 mg·L一，)0.lml/109可使BALB/c小鼠小肠推进率明显降低，与对照
组相比具有显著性差异(P<0.01)。
4肠功能紊乱模型的建立
4.1 EGb对胃肠动力的影响EGb(2 .Omg·L一，)10ml/kg体重可明显抑制大鼠的
小肠推进率(P<0.05)，对胃排空速度无显著性影响(P>.05)。
4.2 EGb对冷束缚应激引起的大鼠胃肠动力改变的影响冷束缚应激可明显增加
大鼠胃排空速度〔P<0.05)，并显著抑制大鼠小肠推进率(P<0.01)。EGb干预可
明显拮抗应激引起的胃排空增快和小肠推进率降低(P<0.05)。
4.3 EGb对大鼠结肠组织、血浆中SP、VIP和N0含量的影响EGb组中远端结肠
组织和血浆中SP含量均显著高于对照组(P<0.05或P<0.01)，且血浆中SP含
量增高幅度(148.9%)较结肠组织中(25.sryo)更为显著;EGb组远端结肠组织中
VIP的含量明显增加(P<0.05)，但血浆中VIP、NO含量及远端结肠组织中的N0
含量一没有显著变化(p>0.05)。
4.4冷束缚应激对大鼠结肠组织、血浆SP、VIP和N0含量的影响冷束缚应激组
中，远端结肠中SP、VIP含量显著下降(P<0.05)，血浆中SP、N0含量显著增
加(P<0.05或P<0.01)，血浆中VIP含量、远端结肠中NO含量无显著性下降
(P>.05)。应用EGb千预的应激组中，血浆中SP含量进一步升高，远端结肠
组织中SP、VIP含量进一步下降，血浆中N0含量显著下降，其值接近于正常对照
组值，而血浆中VIP，结肠中NO含量无显著性变化。
结论
1.EGb对豚鼠游离结肠平滑肌细胞具有舒张作用，这种作用可能与cAMP信号转导
安徽医科大学硕士学位论文
通路相关。
2.D北对豚鼠离体结肠运
Objective: To investigate the effects of ginkgo biloba extract (EGb) on gastrointestinal motility from integrate-organ-cell-molecule levels and reveal the mechanisms of EGb how to regulate colon functions and explore the potential role of gut peptide in stress-inducing colonic motor disorder.
Methods: 1.Using blue dextran 2000 (DB 2000) as a marker, we observed the effects of EGb and stress on gastric emptying and motor activity of small intestine. 2. The effects of EGb and Flavonoids on isolated colon motility were separately observed. 3. Smooth muscle cells were isolated from the colon of the guinea pig and the response to EGb
was observed. 4. The contents of VIP, SP, NO in plasma and colonic muscle layer were
measured by radiommunoassay (RIA) and chemical method.
Results: 1. Motor activity of small intestine in BALB/c mice was inhibited by EGb at
dosage of 2.0 mg/L.
2. EGb can induce colon biphasic actions: inhibition and excitation, the first is primary. EGb could antagonize the effect stimulated by ACh and 5-HT. And it could increase the inhibitory effect of VIP and perfusion by free Ca2+ Krebs solution. But EGb have no
effect on Adr, GABA and Atropine. Flavonoids could inhibite significantly the spontaneous contraction of colon dose-dependently.
3. Isolated smooth muscle cells were obstaind. When incubated with 0.11, 0.22 , 0.44,
0.88, 1.75 and 3.5 g-L-1 of EGb , the most relaxatant response of smooth muscle cells that is in 1.75 g-L-1 is 12.8% (P < 0.05). EGb (1.75 g-L-1) significantly inhibited 44.1%
of contraction response of colonic smooth muscle cells caused by ACh (P < 0.01).
Forskolin increased relaxatant effect of EGb on colonic smooth muscle cells in guinea pig to 8.9% compared with effect of only EGb.
4. Cold-restraint stress can enhance significantly gastric emptying and inhibite motor activity of small intestine in rats. EGb can inhibit the sooner gastric emptying and enhance the slower motor activity of small intestine induced by cold stress.
5. SP levels in blood and SP, VIP in colon of EGb group were higher than the control groups (P < 0.05 or P < 0.01), while VIP levels in blood and NO levels in colon and blood were no change obviously (P > 0.05). SP and NO levels in blood of cold stress were significantly higher (P < 0.01) ; SP , VIP levels in colonic layers and VIP levels in blood of cold-restraint stress were significantly lower than the control group (P < 0.05 or P < 0.01), while NO levels in colonic layers of cold stress didn't change. In the stress
groups after being treated with EGb , SP in blood improved apparently , while SP , VIP
in colon and NO in blood decreased. Conclusion:
1. EGb has a direct relaxatant effect on the colonic smooth muscle cells of guinea pig,
and this effect of EGb may mediate partly by cAMP messenger pathway . SP , VIP and
NO levels in colon and blood of cold stress may be related to the gastrointestinal motility disorders presented in cold stress rats;
2. EGb may regulate the motility of colon of Guinea pig through 5-HT ACh, VIP,
Ca 2+ , M-receptor and direct effect on the intestinal muscle. Flavonoids has restraining
effect on isolated colon movement, may be one of valid elements of EGb which inhibits colonic contraction;
3. EGb can inhibit motor activity of small intestine in BALB/c mice and Wistar rats;
4. EGb can change the levels of SP, VIP , NO in colon and blood of normal and stress
rats, to presume that SP, VIP,.NO are related with the effect of EGb to normal and stress rats .
1 EGb对豚鼠单个结肠平滑肌细胞的影响
1．1不同浓度的EGb对结肠平滑肌细胞的影响用不同浓度的EGb(0.11～3.5g·L~(-1))孵育细胞，可使单个结肠平滑肌细胞舒张，呈一定剂量-效应关系，最大反应浓度为1.75 g·L~(-1)。
1．2 EGb对ACh引起结肠平滑肌细胞收缩效应的影响 ACh(10~(-6)mol·L~(-1))明显增强结肠平滑肌细胞的收缩，与对照组相比增强49.1％。用EGb预先孵育3 mjn，可明显抑制ACh收缩效应的44.1％。
1．3 Forskolin对EGb效应的影响腺苷酸环化酶激动剂Forskolin(10~(-2)mol·L~(-1))可增强EGb的舒张效应，与单独应用EGb组相比较平滑肌细胞舒张百分数增加8.9％(P＜0.05)。观察了单独应用EGb组和Forskolin+EGb组，平滑肌细胞舒张百
安徽医科大学硕士学位论文
分数分别是12.8%(P<0.05)和22.7%(P<0.01)。
2 EGb对豚鼠结肠平滑肌运动的影响及其机制的初步探讨
2.1不同浓度的EGb对豚鼠离体结肠运动的影响EGb(0.5一50.Omg·L一‘)，可使
豚鼠离体结肠平滑肌运动出现抑制和兴奋两种不同反应，其中以抑制作用为主，
浓度为10.Omg·IJ一’时作用最强。
2.2不同浓度的银杏黄酮对豚鼠离体结肠运动的影响银杏黄酮(Flavon山〔15)
(0.01一0.巧mg·L一，)可使豚鼠离体结肠运动受到抑制，当银杏黄酮为0.10 mg·L一，
时，其运动的幅度和张力受抑制的程度最为明显，分别为一21.8士5.6、一14.7士6.3。
EGb对ACh、5一HT引起的结肠平滑肌强直性收缩的抑制作用
ACh(10一6
·L一‘)和5一Hr(10一魂mol·L一，)0.
ml可引起离体结肠强直性收缩，其收缩幅
Odl万1
O
9︺m
度和张力较给药前明显增强，于3 min后再加入EGb(10.Omg·
部分拮抗ACh、5一HT增强肠平滑肌收缩的效应。
L一‘)0 .lml
2.4 EGb对V工P、GABA、阿托品、肾上腺素引起的结肠运动抑制效应的影响
，则可
在平
滑肌浴槽内分别加入血管活性肠肤(vIP)(10一魂mol·L一，)、Y一氨基丁酸(GABA)(10一‘
mol
、阿托品(Atropine)(10一6 mol·L一，)、’肾上腺素(Adr)(10一5 mol·L一，
离体结肠运动受到抑制，再加入EGb(10mg·L一，)0.lml后，vIP组收
一，
rLI止
.用
缩幅度和张力进一步降低，其幅度和张力分别由一10.9士8.3、一10.7士5.3下降到
一18.6士7.3、一25.1士8.7(P<0.05);而Atropine、GABA、Adr组与未加E〔;b组
比较变化无显著性。
2.5钙对EGb作用的影响用无钙Krebs液替代普通KrebS液灌流结肠标本，待
肠管运动稳定后，加入EGb(10 mg·L一‘)0.lml，发现EGb可进一步抑制结肠运动，
其运动幅度和张力分别由一23.5士12.6、一21.7士12.3下降到一52.2士6.8(P<
O.GI)、一38.7士16.4(P<0.05)，与用普通KrebS液灌流相比有显著性差异(P>
安徽医科大学硕士学位论文
0 .05)。
3 EGb对BALB/c小鼠小肠推进速度的影响
E(3b(2 .0 mg·L一，)0.lml/109可使BALB/c小鼠小肠推进率明显降低，与对照
组相比具有显著性差异(P<0.01)。
4肠功能紊乱模型的建立
4.1 EGb对胃肠动力的影响EGb(2 .Omg·L一，)10ml/kg体重可明显抑制大鼠的
小肠推进率(P<0.05)，对胃排空速度无显著性影响(P>.05)。
4.2 EGb对冷束缚应激引起的大鼠胃肠动力改变的影响冷束缚应激可明显增加
大鼠胃排空速度〔P<0.05)，并显著抑制大鼠小肠推进率(P<0.01)。EGb干预可
明显拮抗应激引起的胃排空增快和小肠推进率降低(P<0.05)。
4.3 EGb对大鼠结肠组织、血浆中SP、VIP和N0含量的影响EGb组中远端结肠
组织和血浆中SP含量均显著高于对照组(P<0.05或P<0.01)，且血浆中SP含
量增高幅度(148.9%)较结肠组织中(25.sryo)更为显著;EGb组远端结肠组织中
VIP的含量明显增加(P<0.05)，但血浆中VIP、NO含量及远端结肠组织中的N0
含量一没有显著变化(p>0.05)。
4.4冷束缚应激对大鼠结肠组织、血浆SP、VIP和N0含量的影响冷束缚应激组
中，远端结肠中SP、VIP含量显著下降(P<0.05)，血浆中SP、N0含量显著增
加(P<0.05或P<0.01)，血浆中VIP含量、远端结肠中NO含量无显著性下降
(P>.05)。应用EGb千预的应激组中，血浆中SP含量进一步升高，远端结肠
组织中SP、VIP含量进一步下降，血浆中N0含量显著下降，其值接近于正常对照
组值，而血浆中VIP，结肠中NO含量无显著性变化。
结论
1.EGb对豚鼠游离结肠平滑肌细胞具有舒张作用，这种作用可能与cAMP信号转导
安徽医科大学硕士学位论文
通路相关。
2.D北对豚鼠离体结肠运
Objective: To investigate the effects of ginkgo biloba extract (EGb) on gastrointestinal motility from integrate-organ-cell-molecule levels and reveal the mechanisms of EGb how to regulate colon functions and explore the potential role of gut peptide in stress-inducing colonic motor disorder.
Methods: 1.Using blue dextran 2000 (DB 2000) as a marker, we observed the effects of EGb and stress on gastric emptying and motor activity of small intestine. 2. The effects of EGb and Flavonoids on isolated colon motility were separately observed. 3. Smooth muscle cells were isolated from the colon of the guinea pig and the response to EGb
was observed. 4. The contents of VIP, SP, NO in plasma and colonic muscle layer were
measured by radiommunoassay (RIA) and chemical method.
Results: 1. Motor activity of small intestine in BALB/c mice was inhibited by EGb at
dosage of 2.0 mg/L.
2. EGb can induce colon biphasic actions: inhibition and excitation, the first is primary. EGb could antagonize the effect stimulated by ACh and 5-HT. And it could increase the inhibitory effect of VIP and perfusion by free Ca2+ Krebs solution. But EGb have no
effect on Adr, GABA and Atropine. Flavonoids could inhibite significantly the spontaneous contraction of colon dose-dependently.
3. Isolated smooth muscle cells were obstaind. When incubated with 0.11, 0.22 , 0.44,
0.88, 1.75 and 3.5 g-L-1 of EGb , the most relaxatant response of smooth muscle cells that is in 1.75 g-L-1 is 12.8% (P < 0.05). EGb (1.75 g-L-1) significantly inhibited 44.1%
of contraction response of colonic smooth muscle cells caused by ACh (P < 0.01).
Forskolin increased relaxatant effect of EGb on colonic smooth muscle cells in guinea pig to 8.9% compared with effect of only EGb.
4. Cold-restraint stress can enhance significantly gastric emptying and inhibite motor activity of small intestine in rats. EGb can inhibit the sooner gastric emptying and enhance the slower motor activity of small intestine induced by cold stress.
5. SP levels in blood and SP, VIP in colon of EGb group were higher than the control groups (P < 0.05 or P < 0.01), while VIP levels in blood and NO levels in colon and blood were no change obviously (P > 0.05). SP and NO levels in blood of cold stress were significantly higher (P < 0.01) ; SP , VIP levels in colonic layers and VIP levels in blood of cold-restraint stress were significantly lower than the control group (P < 0.05 or P < 0.01), while NO levels in colonic layers of cold stress didn't change. In the stress
groups after being treated with EGb , SP in blood improved apparently , while SP , VIP
in colon and NO in blood decreased. Conclusion:
1. EGb has a direct relaxatant effect on the colonic smooth muscle cells of guinea pig,
and this effect of EGb may mediate partly by cAMP messenger pathway . SP , VIP and
NO levels in colon and blood of cold stress may be related to the gastrointestinal motility disorders presented in cold stress rats;
2. EGb may regulate the motility of colon of Guinea pig through 5-HT ACh, VIP,
Ca 2+ , M-receptor and direct effect on the intestinal muscle. Flavonoids has restraining
effect on isolated colon movement, may be one of valid elements of EGb which inhibits colonic contraction;
3. EGb can inhibit motor activity of small intestine in BALB/c mice and Wistar rats;
4. EGb can change the levels of SP, VIP , NO in colon and blood of normal and stress
rats, to presume that SP, VIP,.NO are related with the effect of EGb to normal and stress rats .
引文
1．韦素玲，杨盛昌．银杏叶提取物(EGb)对生理机能的影响，广西民族学院学报(自然科学版)，2000；6(3)：187～189
2. (?). (?)olak, A. zahin,(?). Alatas et al. The effect of Ginkgo biloba on the activity of catalase and lipid peroxidation in experimental strangulation ileus. International Journal of Clinical & Laboratory Research. 1998: 28(1):69～71
3．王刚，黄振信，祝延．肠系膜下神经节—远端结肠的形态、功能学研究进展．华北煤炭医学院学报，2002；4(2)：165～167
4．张玲，胡金兰，孔德虎等．银杏叶提取物对豚鼠腹腔神经节细胞生物电的影响．安徽医科大学学报，2002；37(2)：99～102．
5．操寄望，罗和声．单个结肠平滑肌细胞的制备，武汉大学学报(医学版)，2001；22(3)：281～282
6. Lan Mei, Wang Xin, Liu Na, et al. Contraction effect of senna extract on colon smooth muscle cells in guinea pig. J Fourth Mil Med Univ, 2002; 23(4): 289～291
7．王玲，周吕．胃动素和胃泌素引起大鼠胃窦平滑肌细胞收缩的信号转导通路．生理学报，2000，52(4)：272～276
8．周吕，柯美云．胃肠动力学基础与临床，科学出版社，1999；293～301
9．姚泰，罗自强．生理学．北京：人民卫生出版社，2001；490～491
10．钱大青，张根葆，刘德蔚。银杏叶提取物对豚鼠小肠平滑肌活动的影响．咸阳医学院学报，2000；14(2)：91～93
11．周吕．胃肠动力学基础与临床．北京：科学出版社，1999；62
12. Kleijnen J, Knipschild R Ginkgo biloba. Lancet, 1992; 340:1136～1139
13. Landes P. Market report: whole foods managazine's 2nd annual gerb market survey for US. Health food stores. Herbal Gram, 1997; 40: 52
14．周吕．胃肠动力与相关受体．基础医学与临床，2001；21(supple)：13～15．
15. Birmbaumer L.Codina J, Mattera R, et al.Regulation of hormone receptors and adenolate cyclases by guanine nucleotide binding N profeins. Rec.Prog. Hom, 1985;41:53～58
16. Tomlinson S, MacNeil S, Brown B L. Calcium cyclic AMP and hormone action. Clin Endocrinol, 1985;23: 595～602
17. Macovschi O, Prigent AF, Nemoz G, et al. Effects of an extract of Ginkgo biloba on the 3'-5'-cyclic AMP phosphodiesterase activity of the brain of normal and triethytin-intoxicated rats. J Neurochem, 1987; 49 (1) : 107～114
18. Bitar K N, Burgess G M, Putney J W, et al. Source of activator calcium in isolated guinea pig and human gastric muscle cells. Am J Physiol, 1986; 250 (3pt1):G280～286
19. Bitar KN, Bradford PG, Putney JW, et al. Stoichiometry of contraction and Ca~(2+) mobilization by inositol 1,4,5-triphosphate in isolated gastric smooth muscle. J Biol Chem, 1986; 261 (35): 16591～16596
20. Reynolds JC. Chanenges in the treatment of colonic motility disorders.Am J Health. Sys Pharm, 1996; 53:S17～26
21．徐虹，李兆申．许国铭．应激状态下胃肠动力的研究．华人消化杂志，1998；6(4)： 345～346
22．陈代陆，夏正武，王振华，等．长期饥饿应激对大鼠肠神经系统神经递质的影响． 临床消化杂志，2001；13(5)：195～196
23．桂先勇，潘国泉，柯美云，等．胃肠肽在应激所致结肠动力紊乱中的作用．中华医学杂志，1997；77，(1)：31～34
24．曲瑞瑶，刘素梅，王伟，等．实验性脾虚证大鼠胃肠动力学与胃肠肽关系的研究．中国中西医结合杂志，1998；18(supl)：237～240
25. Cayabyab F S. Jimenez M, Vergera P, et al. Influence of nitric oxide and vasoactive intestinal peptide on the spontaneous and triggered electrial and mechanical activities of the canine ileum. Can J Physiol Pharmacol, 1997; 75(5):383～387
26．严茂祥，占宏伟，陈芝芸，等．游泳致疲劳对大鼠血和结肠组织中胃肠激素的影响．浙江中医学院学报，2000；24(4)：44～45
27. Maake C, Kloas W, Szendefi M, et al. Neurohormonal peptides, serotonin and nitric oxide synthase in the enteric nervous system and endocrine cells of the gastrointestinal tract of neotenic and thyroid hormone-treated axolotls. Cell Tissue Res, 1999; 297(1): 91～101
28. Lordal M, Theodorsson E, Hellstrom P M. Tachykinms influence interdigestive rhythm and contracrive strength of human small intestine. Dig Dis Sci, 1997; 42(9): 1940～1949
29. Wheatley I M, Hutson J M, Chow C W, et al. Slow-transit constipation in childhood. J Pediatr Surg, 1999; 34(5): 829～833
30. Lijffler S, Holzer P, Maggi CA, et al. Inhibition of NKI receptors of the electrically evoked release of acetylcholine from guinea pig myenteric neurons. Naunyn Schmiedeberg's Arch Pharmacol, 1994; 349 ( Suppl ): R881
31. Barone F C, Deegan J F, Price W J, et al. Cold-restraint stress increase rat fecal pellet output and colonic transit. Am J Physiol, 1990; 258(21): G329～G337
32. Hockerfelt U, Franzen L, Norrgard O, et al. Early increase and later decrease in VIP and substance P nerve fiber densities following abdominal radiotherapy: a study on the human colon. Int J Radiat Biol, 2002; 78 (11): 1045～1053
33. Ergun Y, Ogulener N, Dikmen A. Involvement of nitric oxide in non-adrenergic non-cholinergic relaxation and action of vasoactive intestinal polypeptide in circular
muscle strips of the rat gastric fundus. Pharmacol Res, 2001; 44 (3): 221～228
34. Xu CT, Pan BR, Wang YM,et al. Substance P was active intestinal peptide and leuaenkephalin in plasma and gastric juice of patients with precancerous lesions and gastric cancer. China Natl J New Gastroenterol, 1995; 1: 27～29
35. Brenneman DE, Hauser J, Phillips TM, et al. Vasoactive intestinal peptide.Link between electrical activity and gila-mediated neurotrophism. Ann N Y Acad Sci, 1999; 897:17～26
36. Schulzke JD, Riecken EO, Fromm M. Distension-induced electrogenic cl—secrection is mediated via VIP-ergic neurons in rat rectal colon, Am J Physiol, 1995; 268 (5ptl): G725～G731.
37. Evangelista S. Involvenment of tachykinin in intestinal inflammation. Curr Pharm Des, 2001; 7(1): 19～30
38. McCabe RD, Dharmsathaphorn K. Mechanism of VIP-stimulated chloride secretion by intestinal epithelial cells.Ann N Y Acad Sci, 1988; 527:326～345
39. Stark ME, Szurszewski JH. Role of nitric oxide in gastrointestinal and hepatic function and disease. Gastroententerology, 1992; 103 (6): 1928～1935
40. Yamashiro S, Kuniyoshi Y, Arakaki K, et al. The effect of insufficiency of tetrahydrobiopterin on endothelial function and vasoactivity. Jpn J Thorac Cardiovasc Surg, 2002; 50(11): 472～477
41. Landmesser U, Spiekermann S, Dikalov S, et al. Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation, 2002; 106(24): 3073～3078
42. Shaul PW, Afshar S, Gibson LL, et al. Developmental changes in nitric oxide synthase isoform expression and nitric oxide production in fetal baboon lung. Am J Physiol Lung Cell Mol Physiol, 2002; 283(6).. L1192～1199
43. Rabiller A, Nunes H, Lebrec D, et al. Prevention of gram-negative translocation reduces the severity of hepatopulmonary syndrome. Am J Respir Crit Care Med, 2002: 166(4): 514～517
44. Lerouet D, Beray-Berthat V, Palmier B, et al. Changes in oxidative stress, iNOS activity and neutrophil infiltration in severe transient focal cerebral ischemia in rats. Brain Res, 2002; 958(1): 166～175
45. Golikov PP, Nikolaeva NI, Gavrilenko IA, et al. Nitric oxide and lipid peroxidation as factors in endogenous intoxication in emergency states. Patol Fiziol Eksp Ter, 2000; (2): 6～9
46. Hogman M, Holmkvist T, Walinder R, et al. Increased nitric oxide elimination from the airways after smoking cessation. Clin Sci (Lond), 2002; 103(1): 15～19
47. Dai ZK, Tan MS, Chai CY, et al. Effects of increased pulmonary flow on the expression of endothelial nitric oxide synthase and endothelin-1 in the rat. Clin Sci (Lond), 2002; 103(Supp148): 289S～293S
48. Furness JB, Li ZS, Young HM, et al. Nitric oxide synthase in the enteric nervous system of the guinea-pig: a quantitative description. Cell tissue Res, 1994; 277(1): 139～149
49. Liu TH, Robinson EK, Helmer KS, et al. Does upregulation of inducible nitric oxide synthase play a role in hepatic injury? Shock, 2002; 18(6): 549～554
50. Malmstrom RE, Bjorne H, Oldner A, et al. Intestinal nitric oxide in the normal and endotoxemicpig. Shock, 2002; 18(5): 456～460
51. Bartho L, Benko R, Lazar Z, et al. Nitric oxide is involved in the relaxant effect of capsaicin in the human sigmoid colon circular muscle. Naunyn Schrniedebergs Arch Pharmacol, 2002; 366(5): 496～500
52. Kong XY, Liao LM, Lei DL, et al. Influence of leadon activity of nitric oxide synthase in neurons and vessel smooth muscle of small intestine in rats. Hunan Yike
Daxue Xue bao, 2000; 25(2):135～37
53. Grisham MB, Pavlick KP, Laroux FS, et al. Nitric oxide and chronic gut inflammation: controversies in inflammatory bowel disease. J Investig Med, 2002; 50(4):272～283
54. Tomita R, Fujisaki S, Ikeda T, et al. Role of nitric oxide in the colon of patients with slow-transit constipation. Dis Colon Rectum, 2002;45(5): 593～600
55．周吕，柯美云，李在硫．胃肠动力学-基础与临床．第1版．科学出版社，1999：3-13：227～245
56. Keef KD, Shuttleworth CW, Xue C, et al. Relationship between nitric oxide and vasoactive intestinal polypeptide in enteric inhibitory neurotransmission. Neuropharmacology, 1994; 33(11): 1303～1314
57. Lefebvre RA, Smits G J, Timmermans JE Study of NO and VIP as non-adrenergic non-cholinergic neurotransmitters in the pig gastric fundus. Br J Pharmacol, 1995; 116(3):2017～2026
58．陈芝芸，严茂祥，项柏康，等．慢性应激大鼠血和结肠粘膜胃肠激素的变化．世界华人消化杂志，2001：9(1)：59～61
2. (?). (?)olak, A. zahin,(?). Alatas et al. The effect of Ginkgo biloba on the activity of catalase and lipid peroxidation in experimental strangulation ileus. International Journal of Clinical & Laboratory Research. 1998: 28(1):69～71
3．王刚，黄振信，祝延．肠系膜下神经节—远端结肠的形态、功能学研究进展．华北煤炭医学院学报，2002；4(2)：165～167
4．张玲，胡金兰，孔德虎等．银杏叶提取物对豚鼠腹腔神经节细胞生物电的影响．安徽医科大学学报，2002；37(2)：99～102．
5．操寄望，罗和声．单个结肠平滑肌细胞的制备，武汉大学学报(医学版)，2001；22(3)：281～282
6. Lan Mei, Wang Xin, Liu Na, et al. Contraction effect of senna extract on colon smooth muscle cells in guinea pig. J Fourth Mil Med Univ, 2002; 23(4): 289～291
7．王玲，周吕．胃动素和胃泌素引起大鼠胃窦平滑肌细胞收缩的信号转导通路．生理学报，2000，52(4)：272～276
8．周吕，柯美云．胃肠动力学基础与临床，科学出版社，1999；293～301
9．姚泰，罗自强．生理学．北京：人民卫生出版社，2001；490～491
10．钱大青，张根葆，刘德蔚。银杏叶提取物对豚鼠小肠平滑肌活动的影响．咸阳医学院学报，2000；14(2)：91～93
11．周吕．胃肠动力学基础与临床．北京：科学出版社，1999；62
12. Kleijnen J, Knipschild R Ginkgo biloba. Lancet, 1992; 340:1136～1139
13. Landes P. Market report: whole foods managazine's 2nd annual gerb market survey for US. Health food stores. Herbal Gram, 1997; 40: 52
14．周吕．胃肠动力与相关受体．基础医学与临床，2001；21(supple)：13～15．
15. Birmbaumer L.Codina J, Mattera R, et al.Regulation of hormone receptors and adenolate cyclases by guanine nucleotide binding N profeins. Rec.Prog. Hom, 1985;41:53～58
16. Tomlinson S, MacNeil S, Brown B L. Calcium cyclic AMP and hormone action. Clin Endocrinol, 1985;23: 595～602
17. Macovschi O, Prigent AF, Nemoz G, et al. Effects of an extract of Ginkgo biloba on the 3'-5'-cyclic AMP phosphodiesterase activity of the brain of normal and triethytin-intoxicated rats. J Neurochem, 1987; 49 (1) : 107～114
18. Bitar K N, Burgess G M, Putney J W, et al. Source of activator calcium in isolated guinea pig and human gastric muscle cells. Am J Physiol, 1986; 250 (3pt1):G280～286
19. Bitar KN, Bradford PG, Putney JW, et al. Stoichiometry of contraction and Ca~(2+) mobilization by inositol 1,4,5-triphosphate in isolated gastric smooth muscle. J Biol Chem, 1986; 261 (35): 16591～16596
20. Reynolds JC. Chanenges in the treatment of colonic motility disorders.Am J Health. Sys Pharm, 1996; 53:S17～26
21．徐虹，李兆申．许国铭．应激状态下胃肠动力的研究．华人消化杂志，1998；6(4)： 345～346
22．陈代陆，夏正武，王振华，等．长期饥饿应激对大鼠肠神经系统神经递质的影响． 临床消化杂志，2001；13(5)：195～196
23．桂先勇，潘国泉，柯美云，等．胃肠肽在应激所致结肠动力紊乱中的作用．中华医学杂志，1997；77，(1)：31～34
24．曲瑞瑶，刘素梅，王伟，等．实验性脾虚证大鼠胃肠动力学与胃肠肽关系的研究．中国中西医结合杂志，1998；18(supl)：237～240
25. Cayabyab F S. Jimenez M, Vergera P, et al. Influence of nitric oxide and vasoactive intestinal peptide on the spontaneous and triggered electrial and mechanical activities of the canine ileum. Can J Physiol Pharmacol, 1997; 75(5):383～387
26．严茂祥，占宏伟，陈芝芸，等．游泳致疲劳对大鼠血和结肠组织中胃肠激素的影响．浙江中医学院学报，2000；24(4)：44～45
27. Maake C, Kloas W, Szendefi M, et al. Neurohormonal peptides, serotonin and nitric oxide synthase in the enteric nervous system and endocrine cells of the gastrointestinal tract of neotenic and thyroid hormone-treated axolotls. Cell Tissue Res, 1999; 297(1): 91～101
28. Lordal M, Theodorsson E, Hellstrom P M. Tachykinms influence interdigestive rhythm and contracrive strength of human small intestine. Dig Dis Sci, 1997; 42(9): 1940～1949
29. Wheatley I M, Hutson J M, Chow C W, et al. Slow-transit constipation in childhood. J Pediatr Surg, 1999; 34(5): 829～833
30. Lijffler S, Holzer P, Maggi CA, et al. Inhibition of NKI receptors of the electrically evoked release of acetylcholine from guinea pig myenteric neurons. Naunyn Schmiedeberg's Arch Pharmacol, 1994; 349 ( Suppl ): R881
31. Barone F C, Deegan J F, Price W J, et al. Cold-restraint stress increase rat fecal pellet output and colonic transit. Am J Physiol, 1990; 258(21): G329～G337
32. Hockerfelt U, Franzen L, Norrgard O, et al. Early increase and later decrease in VIP and substance P nerve fiber densities following abdominal radiotherapy: a study on the human colon. Int J Radiat Biol, 2002; 78 (11): 1045～1053
33. Ergun Y, Ogulener N, Dikmen A. Involvement of nitric oxide in non-adrenergic non-cholinergic relaxation and action of vasoactive intestinal polypeptide in circular
muscle strips of the rat gastric fundus. Pharmacol Res, 2001; 44 (3): 221～228
34. Xu CT, Pan BR, Wang YM,et al. Substance P was active intestinal peptide and leuaenkephalin in plasma and gastric juice of patients with precancerous lesions and gastric cancer. China Natl J New Gastroenterol, 1995; 1: 27～29
35. Brenneman DE, Hauser J, Phillips TM, et al. Vasoactive intestinal peptide.Link between electrical activity and gila-mediated neurotrophism. Ann N Y Acad Sci, 1999; 897:17～26
36. Schulzke JD, Riecken EO, Fromm M. Distension-induced electrogenic cl—secrection is mediated via VIP-ergic neurons in rat rectal colon, Am J Physiol, 1995; 268 (5ptl): G725～G731.
37. Evangelista S. Involvenment of tachykinin in intestinal inflammation. Curr Pharm Des, 2001; 7(1): 19～30
38. McCabe RD, Dharmsathaphorn K. Mechanism of VIP-stimulated chloride secretion by intestinal epithelial cells.Ann N Y Acad Sci, 1988; 527:326～345
39. Stark ME, Szurszewski JH. Role of nitric oxide in gastrointestinal and hepatic function and disease. Gastroententerology, 1992; 103 (6): 1928～1935
40. Yamashiro S, Kuniyoshi Y, Arakaki K, et al. The effect of insufficiency of tetrahydrobiopterin on endothelial function and vasoactivity. Jpn J Thorac Cardiovasc Surg, 2002; 50(11): 472～477
41. Landmesser U, Spiekermann S, Dikalov S, et al. Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation, 2002; 106(24): 3073～3078
42. Shaul PW, Afshar S, Gibson LL, et al. Developmental changes in nitric oxide synthase isoform expression and nitric oxide production in fetal baboon lung. Am J Physiol Lung Cell Mol Physiol, 2002; 283(6).. L1192～1199
43. Rabiller A, Nunes H, Lebrec D, et al. Prevention of gram-negative translocation reduces the severity of hepatopulmonary syndrome. Am J Respir Crit Care Med, 2002: 166(4): 514～517
44. Lerouet D, Beray-Berthat V, Palmier B, et al. Changes in oxidative stress, iNOS activity and neutrophil infiltration in severe transient focal cerebral ischemia in rats. Brain Res, 2002; 958(1): 166～175
45. Golikov PP, Nikolaeva NI, Gavrilenko IA, et al. Nitric oxide and lipid peroxidation as factors in endogenous intoxication in emergency states. Patol Fiziol Eksp Ter, 2000; (2): 6～9
46. Hogman M, Holmkvist T, Walinder R, et al. Increased nitric oxide elimination from the airways after smoking cessation. Clin Sci (Lond), 2002; 103(1): 15～19
47. Dai ZK, Tan MS, Chai CY, et al. Effects of increased pulmonary flow on the expression of endothelial nitric oxide synthase and endothelin-1 in the rat. Clin Sci (Lond), 2002; 103(Supp148): 289S～293S
48. Furness JB, Li ZS, Young HM, et al. Nitric oxide synthase in the enteric nervous system of the guinea-pig: a quantitative description. Cell tissue Res, 1994; 277(1): 139～149
49. Liu TH, Robinson EK, Helmer KS, et al. Does upregulation of inducible nitric oxide synthase play a role in hepatic injury? Shock, 2002; 18(6): 549～554
50. Malmstrom RE, Bjorne H, Oldner A, et al. Intestinal nitric oxide in the normal and endotoxemicpig. Shock, 2002; 18(5): 456～460
51. Bartho L, Benko R, Lazar Z, et al. Nitric oxide is involved in the relaxant effect of capsaicin in the human sigmoid colon circular muscle. Naunyn Schrniedebergs Arch Pharmacol, 2002; 366(5): 496～500
52. Kong XY, Liao LM, Lei DL, et al. Influence of leadon activity of nitric oxide synthase in neurons and vessel smooth muscle of small intestine in rats. Hunan Yike
Daxue Xue bao, 2000; 25(2):135～37
53. Grisham MB, Pavlick KP, Laroux FS, et al. Nitric oxide and chronic gut inflammation: controversies in inflammatory bowel disease. J Investig Med, 2002; 50(4):272～283
54. Tomita R, Fujisaki S, Ikeda T, et al. Role of nitric oxide in the colon of patients with slow-transit constipation. Dis Colon Rectum, 2002;45(5): 593～600
55．周吕，柯美云，李在硫．胃肠动力学-基础与临床．第1版．科学出版社，1999：3-13：227～245
56. Keef KD, Shuttleworth CW, Xue C, et al. Relationship between nitric oxide and vasoactive intestinal polypeptide in enteric inhibitory neurotransmission. Neuropharmacology, 1994; 33(11): 1303～1314
57. Lefebvre RA, Smits G J, Timmermans JE Study of NO and VIP as non-adrenergic non-cholinergic neurotransmitters in the pig gastric fundus. Br J Pharmacol, 1995; 116(3):2017～2026
58．陈芝芸，严茂祥，项柏康，等．慢性应激大鼠血和结肠粘膜胃肠激素的变化．世界华人消化杂志，2001：9(1)：59～61