A型肉毒毒素对内、外源性P物质引发的大鼠离体幽门平滑肌收缩的作用及其机制
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摘要
目的:观察A型肉毒毒素(botulinum toxin type A,BTX-A)对内源性和外源性P物质(substance P,SP)引发的大鼠离体幽门平滑肌收缩的作用,并探索其作用机理。
方法:①应用电场刺激(electrical ficld stimulation,EFS)诱导幽门平滑肌内源性神经递质释放,引发平滑肌收缩,用阿托品(Atropine,Atr)阻断胆碱能神经后分别观察NK_1受体拮抗剂[D-Arg~1,D-Phe~5,D-Trp~(7,9),Leu~(11)]-substance P(DDDL-SP,1μmol·L~(-1),n=10)和BTX-A(10U·mL~(-1),n=10)对肌条收缩的影响;②每隔30min加入SP(1μmol·L~(-1))诱发孵育在不同剂量的BTX-A(4U·mL~(-1),n=8;10U·mL~(-1),n=8)中的肌条收缩,持续记录4h,分析BTX-A抑制SP引起平滑肌收缩的量效和时效作用。
结果:①EFS增加平滑肌收缩振幅(P＜0.05)、频率和张力(P＜0.01);该作用可被阿托品(1μmol·L~(-1))不完全抑制,尚存的余波可分别被DDDL-SP(1μmol·L~(-1))抑制(振幅P＜0.05,张力和频率P＜0.01),或被BTX-A(10U·mL~(-1))抑制(振幅P＜0.05,张力、频率P＜0.01),BTX-A抑制后的余波不再被DDDL-SP进一步抑制。②分别用低剂量(4U·mL~(-1))和高剂量(10U·mL~(-1))的BTX-A孵育幽门平滑肌条,并每隔30 min加入SP(1μmol·L~(-1))连续观察4h,两组SP诱导的收缩张力均随时间逐渐降低,第4h时,BTX-A低剂量组收缩张力为SP诱导的原发张力的73.36±11.46%(P=0.011＜0.05),而高剂量组为25.09±8.08%(P=0.000＜0.01)。
结论:EFS可诱导离体胃幽门平滑肌释放内源性ACh和SP;BTX-A对EFS诱发的内源性SP引起的幽门平滑肌收缩有抑制作用;BTX-A对外源性SP引起的幽门平滑肌收缩亦有抑制作用,且该作用呈时间、剂量依赖性。
Objective:To investigate the effect and mechanism of botulinum toxin type A (BTX-A)on endo- and exo-genous substance P(SP)-induced contractility in the pyloric muscle strips in rats.
Methods:(1)Electrical field stimulation(EFS)was used to induce contraction of pyloric circular muscle strips incubated in Krebs bicarbonate buffer via enhancing neurotransmitter release.An antagonist of NK1-receptor([D-Arg~1,D-Phe~5,O-Trp~(7,9), Leu~(11)]-substance P,1μmol.L~(-1),DDDL-SP,n=10)or BTX-A(10 U·mL~(-1),n=10)was respectively administrated following atropine(1μmol·L~(-1))treatment for observing these inhibitory effect on endogenous SP-induced contractibility.(2)SP(1μmol·L~(-1)) was added once every 30 min into organ bath in which pyloric circular muscle strips were suspended and contained the different concentration of BTX-A(4 U·mL~(-1),n=8 and 10 U·mL~(-1),n=8)in Krebs bicarbonate buffer for 4 hours in order to estimate the inhibitory effects of BTX-A on exogenous SP-induced contractile response.
Results:(1)Pyloric strips contractility was enhanced including the amplitude(P＜0.05),frequency and tension(P＜0.01)by EFS.The EFS-induced pyloric contractile response was inhibited partly by atropine,an antagonist of cholinergic muscarinic receptor.The residual contractility in pyloric muscle strips was further decreased by subsequent administration of DDDL-SP(1μmol·L~(-1)),an antagonist of NK_1-receptor, or BTX-A(10 U·mL~(-1)).(2)The pyloric muscle strips were incubated in BTX-A with low concentration(4 U·mL~(-1))or higher concentration(10 U·mL~(-1)),and SP(1μmol·L~(-1))was added once every 30 min during 4 hours.SP-induced contractile response was gradually decreased along with time in two groups.In addition,the decrease volumes of SP-induced contractile tension between two groups of BTX-A were significantly different at the 4~(th)hour,the inhibitory ratios were 73.36±11.46%in low dose group(P=0.011＜0.05)and 25.09±8.08%in high dose group(P=0.000＜0.01)respectively compared to SP-induced contractile tension without BTX-A.
Conclusion:EFS-induced contraction in pyloric muscle strips is partly suppressed by atropine,residual contractile waves are similarly inhibited by DDDL-SP or BTX-A.These results suggest that EFS induces ACh and endo-genous SP release and pyloric contraction is the endo-genous SP-induced contractily is inhibited by BTX-A. Exo-genous SP-induced contractility of the pyloric smooth muscle strips is inhibited by BTX-A with a time- and dose-dependent.
方法:①应用电场刺激(electrical ficld stimulation,EFS)诱导幽门平滑肌内源性神经递质释放,引发平滑肌收缩,用阿托品(Atropine,Atr)阻断胆碱能神经后分别观察NK_1受体拮抗剂[D-Arg~1,D-Phe~5,D-Trp~(7,9),Leu~(11)]-substance P(DDDL-SP,1μmol·L~(-1),n=10)和BTX-A(10U·mL~(-1),n=10)对肌条收缩的影响;②每隔30min加入SP(1μmol·L~(-1))诱发孵育在不同剂量的BTX-A(4U·mL~(-1),n=8;10U·mL~(-1),n=8)中的肌条收缩,持续记录4h,分析BTX-A抑制SP引起平滑肌收缩的量效和时效作用。
结果:①EFS增加平滑肌收缩振幅(P＜0.05)、频率和张力(P＜0.01);该作用可被阿托品(1μmol·L~(-1))不完全抑制,尚存的余波可分别被DDDL-SP(1μmol·L~(-1))抑制(振幅P＜0.05,张力和频率P＜0.01),或被BTX-A(10U·mL~(-1))抑制(振幅P＜0.05,张力、频率P＜0.01),BTX-A抑制后的余波不再被DDDL-SP进一步抑制。②分别用低剂量(4U·mL~(-1))和高剂量(10U·mL~(-1))的BTX-A孵育幽门平滑肌条,并每隔30 min加入SP(1μmol·L~(-1))连续观察4h,两组SP诱导的收缩张力均随时间逐渐降低,第4h时,BTX-A低剂量组收缩张力为SP诱导的原发张力的73.36±11.46%(P=0.011＜0.05),而高剂量组为25.09±8.08%(P=0.000＜0.01)。
结论:EFS可诱导离体胃幽门平滑肌释放内源性ACh和SP;BTX-A对EFS诱发的内源性SP引起的幽门平滑肌收缩有抑制作用;BTX-A对外源性SP引起的幽门平滑肌收缩亦有抑制作用,且该作用呈时间、剂量依赖性。
Objective:To investigate the effect and mechanism of botulinum toxin type A (BTX-A)on endo- and exo-genous substance P(SP)-induced contractility in the pyloric muscle strips in rats.
Methods:(1)Electrical field stimulation(EFS)was used to induce contraction of pyloric circular muscle strips incubated in Krebs bicarbonate buffer via enhancing neurotransmitter release.An antagonist of NK1-receptor([D-Arg~1,D-Phe~5,O-Trp~(7,9), Leu~(11)]-substance P,1μmol.L~(-1),DDDL-SP,n=10)or BTX-A(10 U·mL~(-1),n=10)was respectively administrated following atropine(1μmol·L~(-1))treatment for observing these inhibitory effect on endogenous SP-induced contractibility.(2)SP(1μmol·L~(-1)) was added once every 30 min into organ bath in which pyloric circular muscle strips were suspended and contained the different concentration of BTX-A(4 U·mL~(-1),n=8 and 10 U·mL~(-1),n=8)in Krebs bicarbonate buffer for 4 hours in order to estimate the inhibitory effects of BTX-A on exogenous SP-induced contractile response.
Results:(1)Pyloric strips contractility was enhanced including the amplitude(P＜0.05),frequency and tension(P＜0.01)by EFS.The EFS-induced pyloric contractile response was inhibited partly by atropine,an antagonist of cholinergic muscarinic receptor.The residual contractility in pyloric muscle strips was further decreased by subsequent administration of DDDL-SP(1μmol·L~(-1)),an antagonist of NK_1-receptor, or BTX-A(10 U·mL~(-1)).(2)The pyloric muscle strips were incubated in BTX-A with low concentration(4 U·mL~(-1))or higher concentration(10 U·mL~(-1)),and SP(1μmol·L~(-1))was added once every 30 min during 4 hours.SP-induced contractile response was gradually decreased along with time in two groups.In addition,the decrease volumes of SP-induced contractile tension between two groups of BTX-A were significantly different at the 4~(th)hour,the inhibitory ratios were 73.36±11.46%in low dose group(P=0.011＜0.05)and 25.09±8.08%in high dose group(P=0.000＜0.01)respectively compared to SP-induced contractile tension without BTX-A.
Conclusion:EFS-induced contraction in pyloric muscle strips is partly suppressed by atropine,residual contractile waves are similarly inhibited by DDDL-SP or BTX-A.These results suggest that EFS induces ACh and endo-genous SP release and pyloric contraction is the endo-genous SP-induced contractily is inhibited by BTX-A. Exo-genous SP-induced contractility of the pyloric smooth muscle strips is inhibited by BTX-A with a time- and dose-dependent.
引文
1.李俊,杨进.胃肠壁内神经丛的组织学研究进展[J].首都医学院学报.1988,9(1):6.
2.万选才.消化系的神经系统.现代胃肠病学[M].北京:科学出版社.1994:2-18.
3.周吕.肠神经系统脑肠肽[J].中华消化杂志.1996,16(5);287-289.
4.Dogiel,A.S.Ueber den Bau der Ganglien in den Geflechten des Darmes und der Gallenblase des Menschen und der Saugetiere.Arch.Ant Physiol[J].Leipzig 1899,Anat.Abt.Jg.1899:130.
5.Fumess,J.B.Bomstein,J.C.Trussell,D.C.:Shape of nerve cells in the guinea-pig small intestine revealed by the intracellular injection of dye.Cell Tissue Ress[J].1988,254:561-571.
6.Stach,W.:A revised morphological classfication of neurons in the enteric nervous systerm,in:Nerves and the gastrointestinal tract.1989,29,Singer,M.V.,Goebell,H(eds),Lancaster,U.K.:Kluwer Academic Publishers.
7.周吕,柯美云.胃肠动力学.基础与临床[M]一北京:科学出版社.1999:67-68.
8.Hope BT,Michael GJ,Knigge KM,et al.Neuronal NASPH-di2aphorase is a nitric exide synthase[J].Proc 1 Natl Acad Sci,USA,1991,88:2 811.
9.Euler,U.S.V.,Gaddum,J.H.An unidentified depressor substance in tissue extracts.[J].J.Physiol.1931,72:74-87.
10.贲长恩,李叔庚.组织化学[M].北京:人民卫生出版社,2001:615-617.
11.熊观瀛.P物质与肠易激综合征[J].国外医学内科学分册,2003,30(6):245-248.
12.展淑琴.血管活性肠肽和P物质与胃肠运动[J].陕西医学杂志,1998,27(1);33-35.
13.刘秀等.P物质对大鼠胃窦肌条收缩活动的影响及其机制探讨[J].生理学报.1994,46(1);1-7.
14.Shibata C,Sasaki I,Naito H,et al.Effects of substance P on gastric motility differ depending on the sites and vagal innervation in conscious dog[J].TohokuJ Exp Med,1994;174(2):119.
15.Schantz EJ,Johnson E.Properties and use of botulinum toxin and other microbial neurotoxins in medicine[J].Microbiol Rev,1992,56(1):80.
16.Scott AB,Suzuki D.Systemic toxicity of botulinum toxin by intramuscular injection in the monkey[J].Mov Disord,1988,3(4):333.
17.Schiavo G,Matteoli M,Montecucco C.Neurotoxins affecting neuroexocytosis[J].Physiol Rov,2000,80(2):717.
18.Turton K,Chaddock JA,Acharya KR,Botulinum and tetanus neurotoxins:structure,function and therapeutic utility[J].Trends Biochem Sci,2002,27(11):552.
19.Jankovic J.Botulinum toxin in clinical practice[J].J Neurol Neurosurg Psychiatry,2004,75:951-957.
20.Singhi P,RayM.Botulinum toxin in children with cerebral palsy[J].Indian J Pediatr 2004,71:1087-1091.
21.Pasricha PJ,Ravich WJ,Hendrix TR,et al.Intrasphineteric botulinum toxin for the treatment to achalasia[J].N Engl J Med,1995,332(12):774-778.
22.Pasricha PJ,Rai R,Ravich WJ,et al.Botulinum toxin for achlalsia:Long-term follow-up and predictors of outcome[J].Gastroenterology,1996,110(5):1410-1415.
23.Sand J,Nordback I,Arvola P,et al.Effects of botulinum toxin A on the sphineter of Oddis:an in vivo and in vitro study.Gut,1998,42(4):507-510.
24.Gui D,Cassetta E,Anastasio G,et al.Botulinum toxin for chronic anal fissurel Lancet,1994,344:1127.
25.刘文徽,刘庆森,韩辉等.A型肉毒毒素对大鼠胃排空及相关胃肠激素影响的研究[J].胃肠病学和肝病学杂志.2006,15(3):281-284.
26.王斌,张忠兵,顾晓红等.A型肉毒毒素对犬下食管括约肌的作用[J].第二军医大学学报.2003,24(12):1325-1327.
27.Wen WD,Yuan F,Wang JL,Hou YP.B0tulinum toxin therapy in the ovalbumin-sensitized rat[J].Neuroimmunomodulation.2007,14(2):78-83.
28.Hou YP,Zhang YP,Song YF,Zhu CM,Wang YC,Xie GL.Botulinum toxin type A inhibits rat pyloric myoelectrical activity and substance P release in vivo[J].Can J Physiol Pharmacol.2007,85(2):209-214.
29. 张福康,张延武,侯一平等. A型肉毒毒素降低大鼠胃平滑肌收缩及P特质含量[J]. 中国病理生理志. 2005,21(2):314-317.
30. Ulrike Holzer-Petsche, Fred Lembeck, Helmut Seitz. Contractile effects of substance P and neurokinin A on the rat stomach in vivo and in vitro [J]. Br. J. Pharmac. 1987,90:273-279.
31. James AN, Ryan JP, Parkman HP. Inhibitory effects of botulinum toxin on pyloric and antral smooth muscle [J]. Am J Physiol Gastrointest Liver Physiol. 2003,285:G291-G297.
32. George E, Lwein JR. Biomedical. as Pects of botulinmu. Academie Press NIC. Newyokr.1981:36.
33. Dolly JO, Aoki KR. The structure and mode of action of different botulinum toxins [J]. Eur J Neurol. 2006,13(4):1-9.
34. Singhi P, Ray M. Botulinum toxin in children with cerebral palsy [J]. Indian J Pediatr. 2004,71:1087-1091.
35. Morbiato L, Carli L, Johnson EA, Montecucco C, Molgo J, Rossetto O. Neuromuscular paralysis and recovery in mice injected with botulinum neurotoxins A and C [J]. Eur J Neurosci. 2007,25(9):2697-2704.
36. Friedenberg F, Gollmaudi S, Parkman HR. The use of boutlinurn toxin for the treatment of gasrtointestinal motility disorders. Dig Dis Sci.2004,49(2)165-175.
37. Aoki KP. Pharmacology and immunology of botulinum toxin serotypes[J]. J Neurol. 2001,248(suppl1):3-10.
38. Pasricha PJ, Ravich WJ, Kalloo KN. Effects of intrasphincteric botulinum toxin on the lower esophageal sphincter in piglets[J]. Gastroenterology. 1993,105:1045-1049.
39. Shahbazian A, Holzer P. Differences in circular muscle contraction and peristaltic motor inhibition caused by tachykinin NK1 receptor agonists in the guinea-pig small intestine [J]. Neurogastroenterol Motil. 2000,12(2): 197-204.
40. Hall ME, Miley F, Stewart JM. The role of enzymatic processing in the biological actions of substance P [J]. Peptides. 1989,10(4):895-901.
41. Shibata C, Sasaki I, Naito H, Ohtani N, Matsuno S, Mizumoto A, et al. Effects of substance P on gastric motility differ depending on the sites and vagal innervation in conscious dog [J]. Tohoku J Exp Med. 1994,174(2): 119-128.
42. Furness,J.B., Bornstein, J.C., Murphy,R., et al. Roles of Peptides in transmission in the enteric nervous system[J]. Trends in Neurosciences, 1992,15:66-71.
43. Furness JB, Pompolo S, Shuttleworth CWR. Light and electron microscopic immunochemical analysis of nerve fiber types innervating the taenia of the guineapig caecum [J]. Cell Tissue Res. 1992,270(1):125.
44. Puffer EB, Lomneth RB, Sarkar HK, Singh BR. Differential roles of developmentally distinct SNAP-25 isoforms in the neurotransmitter release process [J]. Biochemistry. 2001,40(31):9374-9378.
45. Jurasinski CV, Lieth E, Dang Do AN, Schengrund CL. Correlation of cleavage of SNAP - 25 with muscle function in a rat model of botulinum neurotoxin type A induced paralysis [J]. Toxicon. 2001,39(9):1309-1315.
46. Brin MF. Botulinum toxin : chemistry, pharmacology, toxicity, and immunology [J]. Muscle Nerve.1997,6:146-168.
47. Ji J, Lau H, Sheu L, Diamant NE, Gaisano HY. Distinct regional expression of SNARE proteins in the feline oesophagus [J]. Neurogastroenterol Motil. 2002,14: 383-394.
[1]Pasricha PJ,Ravich WJ,Hendrix TR,et al.Intrasphinctericbotulinum toxin for the treatment to achalasia[J].N Engl J Med,1995,322:774.
[2]Pasricha PJ,Rai R,Ravich WJ,et al.Botulinumtoxin for achlal2sia:Long-termfollow-up and predictors of outcome[J].Gastroen-terology,1996,110.1410.
[3]Pasricha P J,Ravich WJ,Hendrix TR,et al.Treatment to achalasia with intrasphincteric injection of botulinum toxin:Apilottrial[J].Ann Intern Med,1994,121:590.
[4]Jankovic J.Botulinum toxin in clinical practice[J].J NeurolNeurosurg Psychiatry,2004,75:951-957.
[5]Singhi P,RayM.Botulinum toxin in children with cerebral palsy[J].Indian J Pediatr,2004,71:1087-1091.
[6]Jankovic J.Botulinum toxin in clinical practice[J].J Neurol Neurosurg Psychiatry,2004,75:951-957.
[7]Singhi P,Ray M.Botulinum toxin in children with cerebral palsy[J].Indian J Pediatr,2004,71:1087-1091.
[8]Carruthers JD,Lowe NJ,Menter MA,et al.Double-blind,placebo-controlled study of the safety and efficacy of botulinum toxin type A for patients with glabellar lines [J].PlastReconstr Surg,2003,112(4):1089-1098.
[9]Neubrand M,Scheurlen C,Schepke M,et al.Long-term re-suit and prognostic factors in the treatment of achalasia with botulinum toxin[J]Endoscopy,2002,34(7):519-523.
[10]Leyden JE,Moss AC,MacMathuna P.Endoscopic pneumatic dilation versus botulinum toxin injection in the management of primary achalasia[J].Cochrane Database Syst Rev.2006,18(4):CD005046.
[11]Bassotti G,D'Onofrio V,Battaglia E,et al.Treatment with botulinum toxin of octo-nonagerians with oesophageal achalasia:a two-year follow-up study[J].Aliment Pharmacol Ther.2006;23(11):1615-1619.
[12]王旭霞,王景杰,赵曙光等.内镜下注射肉毒毒素治疗贲门失弛缓症的临床研究[J].临床消化病杂志,2006,18(1)56-57.
[13]祝相瑞,王宝生等.A型肉毒毒素食管肌层注射治疗贲门失弛缓症[J].天津药学,2006,18(5)29-30.
[14]Marks JM,Bower AL,Goormastic M,et al.A comparison of common bile duct pressures after botulinum toxin injection into the sphincter of Oddis versus biliary stenting in a canine model[J].Am J Surg,2001,181(1):60-64.
[15]Pasricha P J,Miskovsky EP,Kalloo AN.Intrasphinc.teric in2jection of botulinum toxin for suspected sphincter of Oddis dysfunction[J].Gut,1994,35(9):1319-1321.
[16]Wehrmann T,Seufert H,Seipp M.Endoscopic injection of botuli2num toxin for biliary sphincter of Oddis dysfunction[J].Endoscopy,1998,30(8):702-707.
[17]Maria G,Brisind AG,Bentivoglio AR,et al.Anterior recto2 cele due to obstructed defecation relieved by botulinum toxin[J].Sur2 gery,2001,129(5):524-529.
[18]Ron Y,Avni Y,Lukovetski A,et al.Botulinumtoxin type - A in therapy of patients with anismus[J].Dis Colon Rectum,2001,44(12):1821-1826.
[19]Joo JS,Agachan F,Wolff B,et al.Initial North American experience with botulinum toxin type A for treatment of anismus.Dis[J].Colon Rectum.1996;39(10):1107-1111.
[20]Keshtgar AS,Ward HC,Sanei A,et al.Botulinum toxin,a new treatment modality for chronic idiopathic constipation in children:long-term follow-up of a double-blind randomized trial[J].J Pediatr Surg.2007;42(4):672-680.
[21]杜一华,刘铭,彭强等.BTXA局部注射治疗儿童肛裂[J].四川医学.2002,23(7):681.
[22]Charua Guindic L,Fonseca Munoz E,Guerra Melgar LR,et al.Treatment of chronic anal fissure with botulinic toxin type A[J].Rev Gastroenterol Mex.2007;72(1):22-28.
[23]Massoud BW,Mehrdad V,Baharak T,et al.Botulinum toxin injection versus internal anal sphincterotomy for the treatment of chronic anal fissure[J].Ann Saudi Med.2005;25(2):140-142.
2.万选才.消化系的神经系统.现代胃肠病学[M].北京:科学出版社.1994:2-18.
3.周吕.肠神经系统脑肠肽[J].中华消化杂志.1996,16(5);287-289.
4.Dogiel,A.S.Ueber den Bau der Ganglien in den Geflechten des Darmes und der Gallenblase des Menschen und der Saugetiere.Arch.Ant Physiol[J].Leipzig 1899,Anat.Abt.Jg.1899:130.
5.Fumess,J.B.Bomstein,J.C.Trussell,D.C.:Shape of nerve cells in the guinea-pig small intestine revealed by the intracellular injection of dye.Cell Tissue Ress[J].1988,254:561-571.
6.Stach,W.:A revised morphological classfication of neurons in the enteric nervous systerm,in:Nerves and the gastrointestinal tract.1989,29,Singer,M.V.,Goebell,H(eds),Lancaster,U.K.:Kluwer Academic Publishers.
7.周吕,柯美云.胃肠动力学.基础与临床[M]一北京:科学出版社.1999:67-68.
8.Hope BT,Michael GJ,Knigge KM,et al.Neuronal NASPH-di2aphorase is a nitric exide synthase[J].Proc 1 Natl Acad Sci,USA,1991,88:2 811.
9.Euler,U.S.V.,Gaddum,J.H.An unidentified depressor substance in tissue extracts.[J].J.Physiol.1931,72:74-87.
10.贲长恩,李叔庚.组织化学[M].北京:人民卫生出版社,2001:615-617.
11.熊观瀛.P物质与肠易激综合征[J].国外医学内科学分册,2003,30(6):245-248.
12.展淑琴.血管活性肠肽和P物质与胃肠运动[J].陕西医学杂志,1998,27(1);33-35.
13.刘秀等.P物质对大鼠胃窦肌条收缩活动的影响及其机制探讨[J].生理学报.1994,46(1);1-7.
14.Shibata C,Sasaki I,Naito H,et al.Effects of substance P on gastric motility differ depending on the sites and vagal innervation in conscious dog[J].TohokuJ Exp Med,1994;174(2):119.
15.Schantz EJ,Johnson E.Properties and use of botulinum toxin and other microbial neurotoxins in medicine[J].Microbiol Rev,1992,56(1):80.
16.Scott AB,Suzuki D.Systemic toxicity of botulinum toxin by intramuscular injection in the monkey[J].Mov Disord,1988,3(4):333.
17.Schiavo G,Matteoli M,Montecucco C.Neurotoxins affecting neuroexocytosis[J].Physiol Rov,2000,80(2):717.
18.Turton K,Chaddock JA,Acharya KR,Botulinum and tetanus neurotoxins:structure,function and therapeutic utility[J].Trends Biochem Sci,2002,27(11):552.
19.Jankovic J.Botulinum toxin in clinical practice[J].J Neurol Neurosurg Psychiatry,2004,75:951-957.
20.Singhi P,RayM.Botulinum toxin in children with cerebral palsy[J].Indian J Pediatr 2004,71:1087-1091.
21.Pasricha PJ,Ravich WJ,Hendrix TR,et al.Intrasphineteric botulinum toxin for the treatment to achalasia[J].N Engl J Med,1995,332(12):774-778.
22.Pasricha PJ,Rai R,Ravich WJ,et al.Botulinum toxin for achlalsia:Long-term follow-up and predictors of outcome[J].Gastroenterology,1996,110(5):1410-1415.
23.Sand J,Nordback I,Arvola P,et al.Effects of botulinum toxin A on the sphineter of Oddis:an in vivo and in vitro study.Gut,1998,42(4):507-510.
24.Gui D,Cassetta E,Anastasio G,et al.Botulinum toxin for chronic anal fissurel Lancet,1994,344:1127.
25.刘文徽,刘庆森,韩辉等.A型肉毒毒素对大鼠胃排空及相关胃肠激素影响的研究[J].胃肠病学和肝病学杂志.2006,15(3):281-284.
26.王斌,张忠兵,顾晓红等.A型肉毒毒素对犬下食管括约肌的作用[J].第二军医大学学报.2003,24(12):1325-1327.
27.Wen WD,Yuan F,Wang JL,Hou YP.B0tulinum toxin therapy in the ovalbumin-sensitized rat[J].Neuroimmunomodulation.2007,14(2):78-83.
28.Hou YP,Zhang YP,Song YF,Zhu CM,Wang YC,Xie GL.Botulinum toxin type A inhibits rat pyloric myoelectrical activity and substance P release in vivo[J].Can J Physiol Pharmacol.2007,85(2):209-214.
29. 张福康,张延武,侯一平等. A型肉毒毒素降低大鼠胃平滑肌收缩及P特质含量[J]. 中国病理生理志. 2005,21(2):314-317.
30. Ulrike Holzer-Petsche, Fred Lembeck, Helmut Seitz. Contractile effects of substance P and neurokinin A on the rat stomach in vivo and in vitro [J]. Br. J. Pharmac. 1987,90:273-279.
31. James AN, Ryan JP, Parkman HP. Inhibitory effects of botulinum toxin on pyloric and antral smooth muscle [J]. Am J Physiol Gastrointest Liver Physiol. 2003,285:G291-G297.
32. George E, Lwein JR. Biomedical. as Pects of botulinmu. Academie Press NIC. Newyokr.1981:36.
33. Dolly JO, Aoki KR. The structure and mode of action of different botulinum toxins [J]. Eur J Neurol. 2006,13(4):1-9.
34. Singhi P, Ray M. Botulinum toxin in children with cerebral palsy [J]. Indian J Pediatr. 2004,71:1087-1091.
35. Morbiato L, Carli L, Johnson EA, Montecucco C, Molgo J, Rossetto O. Neuromuscular paralysis and recovery in mice injected with botulinum neurotoxins A and C [J]. Eur J Neurosci. 2007,25(9):2697-2704.
36. Friedenberg F, Gollmaudi S, Parkman HR. The use of boutlinurn toxin for the treatment of gasrtointestinal motility disorders. Dig Dis Sci.2004,49(2)165-175.
37. Aoki KP. Pharmacology and immunology of botulinum toxin serotypes[J]. J Neurol. 2001,248(suppl1):3-10.
38. Pasricha PJ, Ravich WJ, Kalloo KN. Effects of intrasphincteric botulinum toxin on the lower esophageal sphincter in piglets[J]. Gastroenterology. 1993,105:1045-1049.
39. Shahbazian A, Holzer P. Differences in circular muscle contraction and peristaltic motor inhibition caused by tachykinin NK1 receptor agonists in the guinea-pig small intestine [J]. Neurogastroenterol Motil. 2000,12(2): 197-204.
40. Hall ME, Miley F, Stewart JM. The role of enzymatic processing in the biological actions of substance P [J]. Peptides. 1989,10(4):895-901.
41. Shibata C, Sasaki I, Naito H, Ohtani N, Matsuno S, Mizumoto A, et al. Effects of substance P on gastric motility differ depending on the sites and vagal innervation in conscious dog [J]. Tohoku J Exp Med. 1994,174(2): 119-128.
42. Furness,J.B., Bornstein, J.C., Murphy,R., et al. Roles of Peptides in transmission in the enteric nervous system[J]. Trends in Neurosciences, 1992,15:66-71.
43. Furness JB, Pompolo S, Shuttleworth CWR. Light and electron microscopic immunochemical analysis of nerve fiber types innervating the taenia of the guineapig caecum [J]. Cell Tissue Res. 1992,270(1):125.
44. Puffer EB, Lomneth RB, Sarkar HK, Singh BR. Differential roles of developmentally distinct SNAP-25 isoforms in the neurotransmitter release process [J]. Biochemistry. 2001,40(31):9374-9378.
45. Jurasinski CV, Lieth E, Dang Do AN, Schengrund CL. Correlation of cleavage of SNAP - 25 with muscle function in a rat model of botulinum neurotoxin type A induced paralysis [J]. Toxicon. 2001,39(9):1309-1315.
46. Brin MF. Botulinum toxin : chemistry, pharmacology, toxicity, and immunology [J]. Muscle Nerve.1997,6:146-168.
47. Ji J, Lau H, Sheu L, Diamant NE, Gaisano HY. Distinct regional expression of SNARE proteins in the feline oesophagus [J]. Neurogastroenterol Motil. 2002,14: 383-394.
[1]Pasricha PJ,Ravich WJ,Hendrix TR,et al.Intrasphinctericbotulinum toxin for the treatment to achalasia[J].N Engl J Med,1995,322:774.
[2]Pasricha PJ,Rai R,Ravich WJ,et al.Botulinumtoxin for achlal2sia:Long-termfollow-up and predictors of outcome[J].Gastroen-terology,1996,110.1410.
[3]Pasricha P J,Ravich WJ,Hendrix TR,et al.Treatment to achalasia with intrasphincteric injection of botulinum toxin:Apilottrial[J].Ann Intern Med,1994,121:590.
[4]Jankovic J.Botulinum toxin in clinical practice[J].J NeurolNeurosurg Psychiatry,2004,75:951-957.
[5]Singhi P,RayM.Botulinum toxin in children with cerebral palsy[J].Indian J Pediatr,2004,71:1087-1091.
[6]Jankovic J.Botulinum toxin in clinical practice[J].J Neurol Neurosurg Psychiatry,2004,75:951-957.
[7]Singhi P,Ray M.Botulinum toxin in children with cerebral palsy[J].Indian J Pediatr,2004,71:1087-1091.
[8]Carruthers JD,Lowe NJ,Menter MA,et al.Double-blind,placebo-controlled study of the safety and efficacy of botulinum toxin type A for patients with glabellar lines [J].PlastReconstr Surg,2003,112(4):1089-1098.
[9]Neubrand M,Scheurlen C,Schepke M,et al.Long-term re-suit and prognostic factors in the treatment of achalasia with botulinum toxin[J]Endoscopy,2002,34(7):519-523.
[10]Leyden JE,Moss AC,MacMathuna P.Endoscopic pneumatic dilation versus botulinum toxin injection in the management of primary achalasia[J].Cochrane Database Syst Rev.2006,18(4):CD005046.
[11]Bassotti G,D'Onofrio V,Battaglia E,et al.Treatment with botulinum toxin of octo-nonagerians with oesophageal achalasia:a two-year follow-up study[J].Aliment Pharmacol Ther.2006;23(11):1615-1619.
[12]王旭霞,王景杰,赵曙光等.内镜下注射肉毒毒素治疗贲门失弛缓症的临床研究[J].临床消化病杂志,2006,18(1)56-57.
[13]祝相瑞,王宝生等.A型肉毒毒素食管肌层注射治疗贲门失弛缓症[J].天津药学,2006,18(5)29-30.
[14]Marks JM,Bower AL,Goormastic M,et al.A comparison of common bile duct pressures after botulinum toxin injection into the sphincter of Oddis versus biliary stenting in a canine model[J].Am J Surg,2001,181(1):60-64.
[15]Pasricha P J,Miskovsky EP,Kalloo AN.Intrasphinc.teric in2jection of botulinum toxin for suspected sphincter of Oddis dysfunction[J].Gut,1994,35(9):1319-1321.
[16]Wehrmann T,Seufert H,Seipp M.Endoscopic injection of botuli2num toxin for biliary sphincter of Oddis dysfunction[J].Endoscopy,1998,30(8):702-707.
[17]Maria G,Brisind AG,Bentivoglio AR,et al.Anterior recto2 cele due to obstructed defecation relieved by botulinum toxin[J].Sur2 gery,2001,129(5):524-529.
[18]Ron Y,Avni Y,Lukovetski A,et al.Botulinumtoxin type - A in therapy of patients with anismus[J].Dis Colon Rectum,2001,44(12):1821-1826.
[19]Joo JS,Agachan F,Wolff B,et al.Initial North American experience with botulinum toxin type A for treatment of anismus.Dis[J].Colon Rectum.1996;39(10):1107-1111.
[20]Keshtgar AS,Ward HC,Sanei A,et al.Botulinum toxin,a new treatment modality for chronic idiopathic constipation in children:long-term follow-up of a double-blind randomized trial[J].J Pediatr Surg.2007;42(4):672-680.
[21]杜一华,刘铭,彭强等.BTXA局部注射治疗儿童肛裂[J].四川医学.2002,23(7):681.
[22]Charua Guindic L,Fonseca Munoz E,Guerra Melgar LR,et al.Treatment of chronic anal fissure with botulinic toxin type A[J].Rev Gastroenterol Mex.2007;72(1):22-28.
[23]Massoud BW,Mehrdad V,Baharak T,et al.Botulinum toxin injection versus internal anal sphincterotomy for the treatment of chronic anal fissure[J].Ann Saudi Med.2005;25(2):140-142.