乙酰胆碱、P物质对人食管下括约肌细胞的收缩作用
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摘要
目的:医学界对食管下括约肌(lower esophagealsphincter,LES)是否存在及其结构特点的探讨经历了一个很长的发展过程。直到1979年,Liebermann—Meffert等学者通过对32例尸体标本的解剖研究,详细阐明了食管胃连接部(esophagogastricjunction,EGJ)平滑肌束的宏观排列,进一步提出人类LES的肌肉系统由套索纤维(sling fibers)和钩状纤维(clasp fibers)共同构成。套索纤维是一组不完整的U形肌束悬挂于胃食管交界部,食管下端的左侧,His角上方。它的开口侧位于胃小弯,闭口侧位于胃大弯。钩状纤维位于LES右侧,呈半环形。这两束肌肉共同维持LES的关闭状态,并形成了LES高压带(high-pressure zone,HPZ,1 5～30 mmHg)。这一理论为进一步研究LES的生理、病理和药理学特性奠定了基础。随后学者们主要对不同动物LES的生理学特点和功能调节进行了更进一步的探讨,发现LES具有明显不同于其它平滑肌结构的特性。而且更为重要的是,构成LES的钩状纤维和套索纤维在诸多方面也存在着很大的差异性。神经递质Ach是食管下括约肌的最主要的兴奋性神经递质。体外实验证明套索纤维对乙酰胆碱(Ach)的敏感性更高。钩状纤维有更大的自发张力。造成LES套索纤维和钩状纤维结构和功能的不同的机制还未完全阐明。许多实验证明无论是在离体还是活体情况下,Ach引起食管下括约肌环形肌和纵形肌的兴奋。乙酰胆碱能神经元大部分位于食管下括约肌的左侧壁,右侧壁由轴突支配。这可能是食管下括约肌左侧压力较右侧为高的原因。P物质为脑肠肽类神经递质,P物质免疫相关性神经纤维在猫和豚鼠的食管下端中数量很多,在肠肌丛和黏膜下丛分布也较多,在环型肌和纵形肌及黏膜中也有分布。免疫组化证明,P物质存在于迷走神经末梢中。食管末端P物质可能作为对化学伤害感受刺激的神经递质,加强食管平滑肌的收缩反应。本文试图研究在乙酰胆碱和p物质这两种不同的神经递质作用下套索纤维和钩状纤维功能上的差异是否表现在细胞收缩程度上的不同。本实验应用平滑肌细胞分离技术,在倒置显微镜下通过测量平滑肌细胞长度变化来测定乙酰胆碱、P物质分别对人食管下括约肌钩状纤维、套索纤维、食管环形肌和胃底环行肌的作用,并为将来治疗食管功能性疾病奠定基础。
方法:选取2008年12月至2009年12月在河北医科大学第四医院因食管中段癌行食管大部切除术患者30例,其中男性18例,女性12例,平均年龄59.3岁。手术室采集新鲜手术标本,锐性剥去胃贲门部及食管下段的粘膜层及粘膜下层后,制备食管环形肌、胃底环形肌、套索纤维、钩状纤维的肌条,将肌条剪成1 mm3-2mm3的小块,用含胶原酶II的细胞分离液分离出单个平滑肌细胞。确认分离细胞活性在90%以上。然后用37℃Hepes缓冲液悬浮备用。细胞存活率测定:取5滴细胞悬浮液,加1滴0.2%的台盼蓝溶液,混匀3 min内计数,当细胞死亡时将被染成红色,活细胞无色。用以下公式计算细胞存活率:存活率(%)=活性细胞总数/(活性细胞数+死细胞数)×100%。然后在倒置显微镜下分别测定乙酰胆碱、P物质作用于套索纤维和钩状纤维与食管环形肌、胃底环形肌后,这四种肌纤维单细胞分别的收缩情况。每一个反应的细胞悬液被放在载玻片上,加盖玻片后在倒置显微镜下观察,随机检测30个细胞长度。细胞收缩的反应以前后细胞变化的百分数来表示。
结果:在倒置显微镜下,游离的平滑肌细胞形态呈梭形,胞质密度高,表面光滑、透明,中间有一圆形或椭圆形的核。(Fig.1-Fig.4)在HEPEs缓冲液孵育的状态下,钩状纤维平均长度为(97.99±12.15)μm (n=210)、套索纤维平均长度为(99.33±10.98)μm (n =210)、食管环形肌纤维平均长度为(97.86±12.27)μm (n =210)、胃底环形肌纤维平均长度为(99.32±11.50)μm (n =210)。四组纤维细胞长度间无统计学差异。(P=6.57)
乙酰胆碱可以引起食管下括约肌的钩状纤维、套索纤维及食管环形肌、胃底环形肌四种类型的肌纤维收缩,这四种肌细胞的收缩程度不同,收缩百分比分别为(11.94±2.21)%、(22.62±3.22)%、(16.62±9.71)%和(22.82±2.84)%;四组纤维细胞长度间有统计学差异(P=0) (Table 2)。P物质引起食管下括约肌钩状纤维、套索纤维及食管环形肌、胃底环形肌的收缩百分比分别为(22.48±3.36)%、(24.77±9.01)%、(19.01±4.35)%和(19.11±3.21)%;四组纤维细胞长度间有统计学差异(P=0) (Table 3)。
结论:乙酰胆碱可以引起食管下括约肌的套索纤维、钩状纤维、食管环形肌细胞和胃底环形肌细胞产生收缩效应。其中套索纤维产生的收缩效应最大;P物质同样可以引起食管下括约肌的套索纤维、钩状纤维、食管环形肌细胞和胃底环形肌细胞产生收缩效应,其中套索纤维、钩状纤维收缩效应最明显,两者之间无差异。
Objective: :The existence and structural equivalent of the lower esophageal sphincter (LES) in human beings have been a matter of speculation for many years. After studying the anatomy of 32 cadavers, Liebermann-Meffert et al described the arrangement of the smooth muscles at the esophagogastric junction (EGJ) in detail.They demonstrated that the musculature of the human LES consisted of sling fibers and clasp fibers.LES clasp fibers is a semi-circular in the right side,while sling fibers is U-shaped band hoisted in the gastroesophageal junction.Both muscle muscles maintain the closure status of the LES,and form a high-pressure zone (HPZ,15-30mmHg).This theory laid the foundation for further studies on the physiology,pathology and pharmacology of the LES.From then on,some reseachers have investigated the physiology and regulation mechanism of LES from different animals,and found that LES had diffemt property different from other smooth muscle structure.And more importantly, there are also great differences in the sling fibers and clasp fibers.Therefore,the abnormal changes of LES structure and function may be the pathological basis of a variety of esophageal diseases. Acetylcholine (Ach) is the most important excitatory neurotransmitter in the lower esophageal sphincter. Sling fiber is more sensitive to Ach in vitro. Clasp fibers have greater spontaneous tension. The different mechanisms of structure and function of the sling and clasp fibers in LES are not well known yet. Many experiments have proved that Ach could induce contraction of circular muscle and longitudinal muscle of the lower esophageal sphincter either in vitro or in vivo. Acetylcholine neurons mostly in the left of the lower esophageal sphincter, and in the right is the axon. This might be the right reason for the higher pressure on left side of the lower esophageal sphincter. P substance is one of the brain-gut peptide neurotransmitters, and most of its immune nerve fibers distributed in the lower esophageal muscles, intestinal submucosal plexus and plexus, and the ring and longitudinal muscles and mucosa of cats and guinea pigs. Immunohistochemical study demonstrayed that substance P was distributed in nerve endings of the vagus. The substance P might be a chemical neurotransmitters for nociceptive stimulation of the end of esophagous to induce esophageal smooth muscle contraction. In this experiment, we measured the contraction of the clasp fibers, sling fibers, circular muscle of the gastric fundus, circular muscle of the esophagus which was induced by acetylcholine and substance P, for the puepose of understanding and future treatment of esophageal motility disorders.
Methods: Smooth muscles of the sling fibers, clasp fibers, circular muscles of the esophagus and gastric fundus were obtained from 30 patients who underwent subtotal esophagectomy for middle thoracic esophageal carcinoma in the Fourth Hospital,Hebei Medical University from December 2008 to December 2009. There were 18 males and 12 females with a mean age of 59.3 years.Fresh specimens of EGJ was collected from operating room. Sharp dissection of mucosal and submucosal layers were performed.The muscle strips of sling and clasp fibers were seperated and then cut to small pieces of 1mm3 ~2 mm3.Single cells was isolated using cell separation solution containing collagenase II.After more than 90 percent viability of the cells was confirmed,the cells were resuspended in Hepes buffer at 37℃for subsequent use.Five drops of cell suspention and 1 drop of 0.2%the trypan blue was mixed for 3 min for cell viability determination.Dead cells were dyed red,and living cells colorless.The percentage of cell viability was calculated with the following formula:survival percentage=number of viable cells/total number of cells (viable cell+dead cell)×100%.Cells from clasp fiber, sling fiber, circular muscles of the esophagus and gastric fundus were contracted by exposure to acetylcholine, substance P. Then we measured the contraction of the sling fibers, clasp fibers, circular muscles of the esophagus and gastric fundus which induced by acetylcholine and substance P. A drop of the cell-containing medium was placed on a glass slide and covered with a cover slip. The length of 30 consecutive intact cells encountered at random in each slide was measured with a phase-contrast microscope. The average length of 30 cells measured in the absence of agonists was taken as“control”length. In addition, average cell length was measured after addition of test agents.
Results: Under photomicrograph,the smooth muscle cells were spindle and had a high density of nucleus . Its surface was smooth and transparent, and there was a round or oval nucleus in the middle of the cell . In HEPEs buffer incubation, the average length of clasp fibers was 94.09±17.53μm (n = 210) in length, sling fibers was 97.05±11.79μm (n = 210), esophageal circular muscle fibers was 97.21±10.76μm (n = 210), and gastric circular muscle fiber was 97.25±13.719μm (n = 210). There was no significant difference between the length of four groups fiber cells (F=2.67, P=0.07).
Acetylcholine could induce contraction of the clasp fibers, sling fibers, circular muscles of the esophagus and gastric fundus, the percentage of muscle cell contraction was (11.94±2.21)% , (22.62±3.22)%, (16.62±9.71)% and (22.82±2.84)%, respectively. There was statistical significance of the length of four smooth musle cells groups ((F=196.97, P = 0). Substance P could induce contraction of clasp fibers, sling fibers, circular muscles of the esophagus and gastric fundus and the percentage of contraction was (22.48±3.36)%, (24.77±9.01)%, (19.01±4.35 )% and (19.11±3.21)% respectively. There was statistical significance for four groups of fiber cells (F=152.27,P = 0).
Conclusions: Acetylcholine could cause the contraction of sling fibers, clasp fibers, circular muscles of the esophagus and gastric fundus, and the strongest contraction is on the sling fibers. Substance P could also cause contraction of the four kinds of fibers, and sling fibers and clasp fibers contract gtrongest.
方法:选取2008年12月至2009年12月在河北医科大学第四医院因食管中段癌行食管大部切除术患者30例,其中男性18例,女性12例,平均年龄59.3岁。手术室采集新鲜手术标本,锐性剥去胃贲门部及食管下段的粘膜层及粘膜下层后,制备食管环形肌、胃底环形肌、套索纤维、钩状纤维的肌条,将肌条剪成1 mm3-2mm3的小块,用含胶原酶II的细胞分离液分离出单个平滑肌细胞。确认分离细胞活性在90%以上。然后用37℃Hepes缓冲液悬浮备用。细胞存活率测定:取5滴细胞悬浮液,加1滴0.2%的台盼蓝溶液,混匀3 min内计数,当细胞死亡时将被染成红色,活细胞无色。用以下公式计算细胞存活率:存活率(%)=活性细胞总数/(活性细胞数+死细胞数)×100%。然后在倒置显微镜下分别测定乙酰胆碱、P物质作用于套索纤维和钩状纤维与食管环形肌、胃底环形肌后,这四种肌纤维单细胞分别的收缩情况。每一个反应的细胞悬液被放在载玻片上,加盖玻片后在倒置显微镜下观察,随机检测30个细胞长度。细胞收缩的反应以前后细胞变化的百分数来表示。
结果:在倒置显微镜下,游离的平滑肌细胞形态呈梭形,胞质密度高,表面光滑、透明,中间有一圆形或椭圆形的核。(Fig.1-Fig.4)在HEPEs缓冲液孵育的状态下,钩状纤维平均长度为(97.99±12.15)μm (n=210)、套索纤维平均长度为(99.33±10.98)μm (n =210)、食管环形肌纤维平均长度为(97.86±12.27)μm (n =210)、胃底环形肌纤维平均长度为(99.32±11.50)μm (n =210)。四组纤维细胞长度间无统计学差异。(P=6.57)
乙酰胆碱可以引起食管下括约肌的钩状纤维、套索纤维及食管环形肌、胃底环形肌四种类型的肌纤维收缩,这四种肌细胞的收缩程度不同,收缩百分比分别为(11.94±2.21)%、(22.62±3.22)%、(16.62±9.71)%和(22.82±2.84)%;四组纤维细胞长度间有统计学差异(P=0) (Table 2)。P物质引起食管下括约肌钩状纤维、套索纤维及食管环形肌、胃底环形肌的收缩百分比分别为(22.48±3.36)%、(24.77±9.01)%、(19.01±4.35)%和(19.11±3.21)%;四组纤维细胞长度间有统计学差异(P=0) (Table 3)。
结论:乙酰胆碱可以引起食管下括约肌的套索纤维、钩状纤维、食管环形肌细胞和胃底环形肌细胞产生收缩效应。其中套索纤维产生的收缩效应最大;P物质同样可以引起食管下括约肌的套索纤维、钩状纤维、食管环形肌细胞和胃底环形肌细胞产生收缩效应,其中套索纤维、钩状纤维收缩效应最明显,两者之间无差异。
Objective: :The existence and structural equivalent of the lower esophageal sphincter (LES) in human beings have been a matter of speculation for many years. After studying the anatomy of 32 cadavers, Liebermann-Meffert et al described the arrangement of the smooth muscles at the esophagogastric junction (EGJ) in detail.They demonstrated that the musculature of the human LES consisted of sling fibers and clasp fibers.LES clasp fibers is a semi-circular in the right side,while sling fibers is U-shaped band hoisted in the gastroesophageal junction.Both muscle muscles maintain the closure status of the LES,and form a high-pressure zone (HPZ,15-30mmHg).This theory laid the foundation for further studies on the physiology,pathology and pharmacology of the LES.From then on,some reseachers have investigated the physiology and regulation mechanism of LES from different animals,and found that LES had diffemt property different from other smooth muscle structure.And more importantly, there are also great differences in the sling fibers and clasp fibers.Therefore,the abnormal changes of LES structure and function may be the pathological basis of a variety of esophageal diseases. Acetylcholine (Ach) is the most important excitatory neurotransmitter in the lower esophageal sphincter. Sling fiber is more sensitive to Ach in vitro. Clasp fibers have greater spontaneous tension. The different mechanisms of structure and function of the sling and clasp fibers in LES are not well known yet. Many experiments have proved that Ach could induce contraction of circular muscle and longitudinal muscle of the lower esophageal sphincter either in vitro or in vivo. Acetylcholine neurons mostly in the left of the lower esophageal sphincter, and in the right is the axon. This might be the right reason for the higher pressure on left side of the lower esophageal sphincter. P substance is one of the brain-gut peptide neurotransmitters, and most of its immune nerve fibers distributed in the lower esophageal muscles, intestinal submucosal plexus and plexus, and the ring and longitudinal muscles and mucosa of cats and guinea pigs. Immunohistochemical study demonstrayed that substance P was distributed in nerve endings of the vagus. The substance P might be a chemical neurotransmitters for nociceptive stimulation of the end of esophagous to induce esophageal smooth muscle contraction. In this experiment, we measured the contraction of the clasp fibers, sling fibers, circular muscle of the gastric fundus, circular muscle of the esophagus which was induced by acetylcholine and substance P, for the puepose of understanding and future treatment of esophageal motility disorders.
Methods: Smooth muscles of the sling fibers, clasp fibers, circular muscles of the esophagus and gastric fundus were obtained from 30 patients who underwent subtotal esophagectomy for middle thoracic esophageal carcinoma in the Fourth Hospital,Hebei Medical University from December 2008 to December 2009. There were 18 males and 12 females with a mean age of 59.3 years.Fresh specimens of EGJ was collected from operating room. Sharp dissection of mucosal and submucosal layers were performed.The muscle strips of sling and clasp fibers were seperated and then cut to small pieces of 1mm3 ~2 mm3.Single cells was isolated using cell separation solution containing collagenase II.After more than 90 percent viability of the cells was confirmed,the cells were resuspended in Hepes buffer at 37℃for subsequent use.Five drops of cell suspention and 1 drop of 0.2%the trypan blue was mixed for 3 min for cell viability determination.Dead cells were dyed red,and living cells colorless.The percentage of cell viability was calculated with the following formula:survival percentage=number of viable cells/total number of cells (viable cell+dead cell)×100%.Cells from clasp fiber, sling fiber, circular muscles of the esophagus and gastric fundus were contracted by exposure to acetylcholine, substance P. Then we measured the contraction of the sling fibers, clasp fibers, circular muscles of the esophagus and gastric fundus which induced by acetylcholine and substance P. A drop of the cell-containing medium was placed on a glass slide and covered with a cover slip. The length of 30 consecutive intact cells encountered at random in each slide was measured with a phase-contrast microscope. The average length of 30 cells measured in the absence of agonists was taken as“control”length. In addition, average cell length was measured after addition of test agents.
Results: Under photomicrograph,the smooth muscle cells were spindle and had a high density of nucleus . Its surface was smooth and transparent, and there was a round or oval nucleus in the middle of the cell . In HEPEs buffer incubation, the average length of clasp fibers was 94.09±17.53μm (n = 210) in length, sling fibers was 97.05±11.79μm (n = 210), esophageal circular muscle fibers was 97.21±10.76μm (n = 210), and gastric circular muscle fiber was 97.25±13.719μm (n = 210). There was no significant difference between the length of four groups fiber cells (F=2.67, P=0.07).
Acetylcholine could induce contraction of the clasp fibers, sling fibers, circular muscles of the esophagus and gastric fundus, the percentage of muscle cell contraction was (11.94±2.21)% , (22.62±3.22)%, (16.62±9.71)% and (22.82±2.84)%, respectively. There was statistical significance of the length of four smooth musle cells groups ((F=196.97, P = 0). Substance P could induce contraction of clasp fibers, sling fibers, circular muscles of the esophagus and gastric fundus and the percentage of contraction was (22.48±3.36)%, (24.77±9.01)%, (19.01±4.35 )% and (19.11±3.21)% respectively. There was statistical significance for four groups of fiber cells (F=152.27,P = 0).
Conclusions: Acetylcholine could cause the contraction of sling fibers, clasp fibers, circular muscles of the esophagus and gastric fundus, and the strongest contraction is on the sling fibers. Substance P could also cause contraction of the four kinds of fibers, and sling fibers and clasp fibers contract gtrongest.
引文
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25 Bonner TI, Young AC, Brann MR, et al. Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes. Neuron, 1988, 1(5):403-410
26周吕,王新.胃动素对大鼠胃平滑肌细胞收缩活动的作用.生理学报,1996,48-65
27 Bonner TI, Buckley NJ, Young AC, et al. Identification of a family of muscarinic acetylcholine receptor genes. Science, 1987, 237(4814): 527-532
28 Sharma VK, Colecraft HM, Rubin LE. Does mammalian heart contain only the M2 muscarinic receptor subtype. Life Sci, 1997, 60(12): 1023-1029
29 Sohn UD, Harnett KM, Cao W, et al. Acute experimental esophagitis activates a second signal transduction pathway in cat smooth muscle from the lower esophageal sphincter. J Pharmacol Exp Ther, 1997, 283(3): 1293-1304
30 Fox JET and Daniel EE. Role of Ca2+ in genesis of lower esophageal sphincter tone and other active contractions. Am J Physiol Endocrinol Metab Gastrointest Physiol 237: E163-E171, 1979
31温士旺,刘俊峰,高立平,等.毒蕈碱受体亚型对人食管下括约肌的调节作用.中国药理学通报,2008,24:889-893
32高立平,刘俊峰,温士旺,等.胆囊收缩素受体对人食管下括约肌套索纤维和钩状纤维的调节机制.中华实验外科杂志,2006,23(4):581-582
33 Biancani P, Hillemeier C, Bitar KN, and Makhlouf GM. Contraction mediated by Ca2+ influx in esophageal muscle and by Ca2+ release in the LES. Am J Physiol Gastrointest Liver Physiol 253: G760-G766, 1987
34 Allescher HD, Berezin I, Jury J, and Daniel EE. Characteristics of canine lower esophageal sphincter: a new electrophysiological tool. Am J PhysiolGastrointest Liver Physiol 255: G441-G453, 1988
35 Salapatek AMF, Lam A, and Daniel EE. Calcium source diversity in canine lower esophageal sphincter muscle. J Pharmacol Exp Ther 287: 98-106, 1998
36 Tottrup A, Forman A, Uldbjerg N, Funch-Jensen P, and Andersson KE. Mechanical properties of isolated human esophageal smooth muscle. Am J Physiol Gastrointest Liver Physiol 258: G338-G343, 1990
37 Sohn UD, Chiu TT, Bitar KN, et al. Calcium requirements for acetylcholine-induced contraction of cat esophageal circular musclecells. Am J Physiol Gastrointest Liver Physiol 1994; 266: 330-338
38 Cao WB, Sohn UD, Bitar KN, et al. MAPK mediates PKC-dependent contraction of cat esophageal and lower esophageal sphincter circular smooth muscle. Am J Physiol Gastrointest Liver Physiol 2003; 285:86-95
39 Biancani P, Harnett KM, Sohn UD, et al. Differential signal transduction pathways in cat LES tone and response to ACh. Am J Physiol 1994; 266: 767-774
40高立平,刘俊峰,温士旺,等.胃泌素和胃动素对人离体食管下括约肌张力的调节机制.基础医学与临床,2006,26 (3):257-260
41温士旺,刘俊峰,高立平,等.一氧化氮介导人食管下括约肌舒张的作用机制.中华医学杂志,2006,86(1):31-34
42 Biancani P, Hillemeier C, Bitar KN, et al. Contraction mediated by Ca2+ influx in esophageal muscle and by Ca2+ release in the LES.Am J Physiol 1987; 253: 760-766
43 orsapati H, Babaei A, Bhargava V, et al. Cholinergic stimulation induces asynchrony between the circular and longitudinal muscle contraction during esophageal peristalsis. Am J Physiol Gastrointest Liver Physiol, 2008, 294: 694-698
44 Tian ZQ, Liu JF, Wang GY, et al. Responses of human clasp and sling fibers to neuromimetics. J Gastroenterol Hepatol, 2004, 19: 440-447
45 Muinuddin A, Naqvi K, Sheu L, et al. Regional differences in cholinergic regulation of potassium current in feline esophageal circular smoothmuscle. Am J Physiol Gastrointest Liver Physiol, 2005, 288: 1233-1240
46 James AN, Ryan JP, Crowell MD, et al. Regional gastric contractility alterations in a diabetic gastroparesis mouse model: effects of cholinergic and serotoninergic stimulation. Am J Physiol Gastrointest Liver Physiol, 2004, 287: 612-619
47 Preiksaitis HG, Krysiak PS, Chrones T, et al. Pharmacological and molecular characterization of muscarinic receptor subtypes in human esophageal smooth muscle. J Pharmacol Exp Ther, 2000, 295: 879-888
48 Kang HY, Lee TS, Lee YP, et al. Interaction of calmodulin- and PKC- dependent contractile pathways in cat lower esophageal sphincter (LES). Arch Pharm Res 2001; 24: 546-551
49 Preiksaitis HG, Diamant NE. Regional differences in cholinergic activity of muscle fibers from the human gastroesophageal junction. Am J Physiol, 1997, 272(6 Pt 1): G1321-1327
50 Keef KD, Ward SM, Stevens RJ, et al. Electrical and mechanical effects of acetylcholine and substance P in subregions of canine colon. Am J Physiol, 1992, 262(2 Pt 1): G298-G307
51郑礼,崔艳英。大鼠胃平滑肌细胞收缩模型及其药物研究。中国药理学通报。2003,Jun;19(6):675-8
52 Itoh Z, Aizawa I, Honda R, et al. Control of lower-esophageal-sphincter contractile activity by motilin in conscious dogs. Am J Dig Dis, 1978, 23: 341-345
53 Wess J,Bonner TI,Dorje F,et a1.Delineation of muscarinic receptor domains conferring selectivity of coupling to guanine nucleotide-binding proteins and second messengers.Mol Pharmacol,1 990,3 8(4):5l7-523
54 Peralta EG,Ashkenazi A,Wins.10w JW,et a1.Differential regulation of PI hydrolysis and adenylyl cyclase by muscarinic receptor subtypes. Nature, 1 988, 334(6 1 8 1): 434-437
55 Lai J,Waite SL,Bloom JW,et a1.The m2 muscarinic lacetylcholine receptors are coupled to multiple signalingpathways via pertussis toxin-sensitive guanine nucleotideregulatory proteins.J Pharmacol ExpTher,1991,258(3):938-944
56韩勇,赵正源,王云杰兔食管下括约肌与体部形态及乙酰胆碱对其功能影响的比较.世界华人消杂,2005,13(1):434-43
57 Pachori AS, Smith A, McDonald P, Zhang L, Dzau VJ, Melo LG. Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway. J Mol Cell Cardiol 2007; 43: 580-592
58 McKee KK, Tan CP, Palyha OC, et al. Cloning and characterization of two human G protein-couples receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotension receptors. Genomics, 1997, 46(3): 426-434
59 Stein HJ, Korn O, Liebermann-Meffert D, et al. Manometric vector volume of analysis to lower esophageal sphincter function. Ann Chir Gynaec, 1995, 84(2): 151-158
60 Mosley RG, Reichelderfer M,Sengupta A, Singaram C. Innervation of an esophageal ectatic submucosal blood vessel in achalasia and a comparison with normals. Am J Gastroenterol 1994; 89: 1874-1879
61 Ziegler K, Sanft C, Friedrich M, et al. Endosonographic appearance of the esophagus in achalasia. Endoscopy, 1990, 22(1):1-4
62 Purkiss J,Welch M,Doward S,et a1.Capsaicin-stimulated related of substance P from cultured dorsal root ganglin neuros:involvement of two distinct mechanisms[J] . Biochem Pharmacol , 2000 , 59(Suppl) :1403-1406.
63 FarréR, Sifrim D. Regulation of basal tone, relaxation and contraction of the lower esophageal sphincter. Relevance to drug discovery for esophageal disorders. Br J Pharmacol 2008; 153: 858-869
64 M,Radespiel-Tr?ger M.Anterograde tracing and immunohistochemical characterization of potentially mechanosensitive vagal afferents in the esophagus. J Comp Neurol 1999; 412: 161-172
65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物质含量.中国病理生理杂志,2005 21(2):314-317
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3 Kahrilas PJ. Review article: is stringent control of gastric pH useful and practical in GERD? Aliment Pharmacol Ther, 2004, 20: 89-94
4 Sarkar S, Thompson DG, Woolf CJ, et al. Patients with chest pain and occult gastroesophageal reflux demonstrate visceral pain hypersensitivity which may be partially responsive to acid suppression. Am J Gastroenterol, 2004, 99: 1998-2006
5 Green BT, O’Connor JB.Most GERD symptoms are not due to acid reflux in patients with Very low 24-hour acid contact times. Dig Dis Sci, 2004, 49: 1084-1087
6 He HZ, Song ZM, Wang K, et al. A1terations in expression, proteolysis and intracellular localizations of clusterin in esophageal squamous cell carcinoma. World J Gastroenterol, 2004, 10: 1387-1391
7 Lerche W. The esophagus and pharynx in action. A study of structure in relation to function. Oxford: Charles Thomas, 1950, 1-70
8 Fyke FE. The gastroesophageal sphincter in healthy human beings. Gastroenterology, 1956, 86(3): 135-150
9 Liebermann-Meffert D, Allgower M, Schmid P, et al. Muscular equivalent of the lower esophageal sphincter. Gastroenterology, 1979, 76(1): 31-38
10周吕王立东:胃肠道平滑肌的结构和功能胃肠生理学(周吕主编.)北京:科学出版社,1991,6-21
11 Stein HJ, Korn O, Liebermann-Meffert D. Manometric vector v olume analysis to assess lower esophageal sphincter function. Ann Chir Gynaec, 1995, 84(2): 151-158
12 Stein HJ, Liebermann-Meffert D, DeMeester TR, et al. Three-dimensionalpressure image and muscular structure of the human lower esophageal sphincter. Surgery, 1995, 117(6): 692-698
13 reiksaitis HG, Diamant NE. Regional differences in cholinergic activity of muscle fibers from the human gastroesophageal junction. Am J Physiol Gastrointest Liver Physiol, 1997, 272(6 Pt 1): G1321-1327
14 Sngawara K, et al. Eeffet of seeertin and eholeeysrokinin on gastric motility. Am J Physiol, 1969, 217: 1633
15 Goard PA,Libby GW,Farthing MJG. 5-hydroxytryptamine and human small intestinal motiliyt: eeffet of inhibiting 5-hydroxytryptamine reuptake. Gut, 1994, 35: 496-500
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17 Cholecystokinin and panic disorder-three unsettled questions. Regul Pept, 2000, 93(1/3): 79-83
18 Moran TH. Cholecystokinin and satiety: current perspectives. Nutrition, 2000, 16(10): 858~865Rehfeld JF
19 Obal F Jr, Kapas L, Krueger JM. Albumin enhances sleep in the youn rat. Physiol Behav, 1998, 64(3): 261-266
20 Nomoto S, Miyake M, Ohta M, et al. Impaired learning and memory in OLETF rats without cholecystokinin (CCK)-A receptor. Physiol Behav, 1999, 66(5): 869-872
21 Clerc P, Wang TC, Dockray GT, et al. Expression of CCK2 receptors in the murine pancreas: proliferation, transdifferentiation of acinar cells, and neoplasia. Gastroenterology, 2002, 122(2): 428-437
22唐承薇,韩军.胆囊收缩素对胰腺生理及病理生理的调节作用.中华消化杂志, 2001, 21(1): 43-45
23 Sutherland EW, Rall TW, Menon T. Adenylyl cyclase.1. Distribution,PreParation,and properties. J Biol Chem, 1962,237: 1220-1243
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25 Rodrigo J, Uttenthal LO, Peinado MA, Esteban FJ, Fernández AP, Serrano J, Martínez de Velasco J, Santacana M, Bentura ML, Martínez- Murillo R, Pedrosa JA. Distribution of nitric oxide synthase in the esophagus of the cat and monkey.J Auton Nerv Syst 1998; 70: 164-179
26 Goyal RK, Padmanabhan R, Sang Q. Neural circuits in swallowing and abdominal vagal afferent~mediated lower esophageal sphincter relaxation.Am J Med, 2001, 111(3); Suppl 8A: 95S-105
27 Preiksaitis HG, Diamant NE. Regional differences in cholinergic activity of muscle fibers from the human gastroesophageal junction. Am J Physiol Gastrointest Liver Physiol, 1997, G1321-1327
28 Kang HY, Lee TS, Lee YP, Lee DW, La HO, Song HJ, Sohn UD. Interaction of calmodulin- and PKC-dependent contractile pathways in cat lower esophageal sphincter (LES). Arch Pharm Res 2001; 24: 546-551
29 Biancani HG, Krysiak PS, Chrones T, Rajgopal V, Laurier LG. Pharmacological and molecular characterization of muscarinic receptor subtypes in human esophageal smooth muscle. J Pharmacol Exp Ther 2000; 295: 879-888
30 Pachori AS, Smith A, McDonald P, Zhang L, Dzau VJ, Melo LG. Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway. J Mol Cell Cardiol 2007; 43: 580-592
31 Imaeda K, Cunnane TC. Electrophysiological properties of inhibitory junction potential in murine lower oesophagealsphincter. J Smooth Muscle Res 2003; 39: 119-133
32 Sidhu AS, Triadafilopoulos G. Neuro-regulation of lower esophageal sphincter function as treatment for gastroesophageal reflux disease. World J Gastroenterol 2008; 14: 985-99
33 Tsumori T, Ando A, Domoto T, Oki M, Nakamura T. Coexistence of vasoactive intestinal polypeptide and neuropeptide Y immunoreactivity within axon terminals in the canine and human lower esophageal sphincter:electron microscopy by a double immunogold labeling procedure. Acta Anat (Basel) 1994; 149: 272-278
34 Mosley RG, Reichelderfer M, Sengupta A, Singaram C. Innervation of an esophageal ectatic submucosal blood vessel in achalasia and a comparison with normals. Am J Gastroenterol 1994; 89: 1874-1879
35 Kressel M, Radespiel-Tr?ger M. Anterograde tracing and immu- nohistochemical characterization of potentially mechanosensitive vagal afferents in the esophagus. J Comp Neurol 1999; 412: 161-172
36 Newton M, Kamm MA, Soediono PO, Milner P, Burnham WR, Burnstock G. Oesophageal epithelial innervation in health and reflux oesophagitis. Gut 1999; 44: 317-322
37 Gonzalez BJ, Basille M, Vaudry D, Fournier A, Vaudry H. [Pituitary adenylate cyclase-activating polypeptide] Ann Endocrinol (Paris) 1998; 59: 364-405
38 Makovec F, Revel L, Letari O, et al. Characterization of antisecretory and antiulcer activity of CR 2945, a new potent and selective gastrin/CCK(B) receptor antagonist. Eur J Pharmacol, 1999, 369(1): 81-90
39 Straathof JW, Tieleman S, Lamers CB, Masclee AA. Effect of somatostatin on lower esophageal sphincter characteristics in man. Scand J Gastroenterol 2000; 35: 910-915
40 Fan YP, Chakder S, Gao F, Rattan S. Inducible and neuronal nitric oxide synthase involvement in lipopolysaccharide-induced sphincteric dysfunction. Am J Physiol Gastrointest Liver Physiol 2001; 280: G35-G40
41 Bitar KN, Makhlouf GM.Reee Ptosr on smoothmuse cells:eharacterization by contraction and specific antgaonists.Am J Physiol 1996,242:G405-407
42 Bitar KN and Malouf GM. Measuer ment of funtion in islated smooth muscle cells .Am J Physiol 1997,250:G357-360
2 Liu JF, Zhang J, Tian ZQ, et al. Long-term outcome of esophageal myotomy for achalasia.World J Gastroenterol, 2004, 10: 287-291
3 Kahrilas PJ. Review article: is stringent control of gastric pH useful and practical in GERD? Aliment Pharmacol Ther, 2004, 20: 89-94
4 Sarkar S, Thompson DG, Woolf CJ, et al. Patients with chest pain and occult gastroesophageal reflux demonstrate visceral pain hypersensitivity which may be partially responsive to acid suppression. Am J Gastroenterol, 2004, 99: 1998-2006
5 Green BT, O’Connor JB.Most GERD symptoms are not due to acid reflux in patients with Very low 24-hour acid contact times. Dig Dis Sci, 2004, 49: 1084-1087
6 Lerche W. The esophagus and pharynx in action. A study of structure in relation to function. Oxford: Charles Thomas, 1950, 1-70
7 Fyke FE. The gastroesophageal sphincter in healthy human beings. Gastroenterology, 1956, 86(3): 135-150
8 Liebermann-Meffert D, Allgower M, Schmid P, et al. Muscular equivalent of the lower esophageal sphincter. Gastroenterology, 1979, 76(1): 31-38
9 lower esophageal sphincter relaxation.Gastroenterology,1995,109(2):601-610
10 Stein HJ,Kom O,Liebermann-Meffert D.Manometric vector volume analysis to assess lower esophageal sphincter function.Ann Chir Gynaec,1995,84(2):151-158
11 Stein HJ,Liebermann-Meffert D De Meester TR,et a1.Three-dimensional pressure image and muscular structure of the human lower esophageal sphincter.Surgery,1995,117(6):692-98
12 Sohn UD,Chiu TT,Bitar KN,et al. Calcium requirements foracetylcholine-induced contraction of cat esophageal circular musclecells. Am J Physiol Gastrointest Liver Physiol 1994; 266: 330-338
13 Cao WB, Sohn UD, Bitar KN, et al. MAPK mediates PKC-dependent contraction of cat esophageal and lower esophageal sphincter circular smooth muscle. Am J Physiol Gastrointest Liver Physiol 2003; 285:86-95
14 Biancani P, Harnett KM, Sohn UD, et al. Differential signal transduction pathways in cat LES tone and response to ACh. Am J Physiol 1994; 266: 767-774
15 Biancani P, Hillemeier C, Bitar KN, et al. Contraction mediated by Ca2+ influx in esophageal muscle and by Ca2+ release in the LES.Am J Physiol 1987; 253: 760-766
16 Iegler K, Sanft C, Friedrich M, et al. Endosonographic appearance of the esophagus in achalasia. Endoscopy, 1990, 22(1):1-4
17 Richardson BJ, Welch RW. Differential effect of atropine on rightward and leftward lower esophageal sphincter pressure. Gastroenterology, 1981, 81(1):85-89
18 Preiksaitis HG, Diamant NE. Regional differences in cholinergic activity of muscle fibers from the human gastroesophageal junction. Am J Physiol, 1997, G1272-G1327
19 Gahagn T. The function of the musculature of the esophagus and stomach in the esophagogastric sphincter mechanism. Surg Gynecol Obstet, 1962, 114:293-303
20 Friedland GW, Kohatsu S, Lewin K. Comparative anatomy of feline and canine gastric sling fibers. Analogy to human anatomy. Am J Dig Dis, 1971, 16(6):493-507
21 Furness JB. Types of neurons in the enteric nervous system. J Auton Nerv Syst, 2000, 81(1-3):87-96
22 Goyal RK, Hirano I. The enteric nervous system. N Engl J Med, 1996, 334(17):1106-1115
23 Dorje F, Wess J, Lambrecht G, et al. Antagonist binding profiles of five cloned human muscarinic receptor subtypes. J Pharmacol Exp Ther, 1991,256(2):727-733
24 Peralta EG, Ashkenazi A, Winslow JW, et al. Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. EMBO J, 1987, 6(13):3923-3929
25 Bonner TI, Young AC, Brann MR, et al. Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes. Neuron, 1988, 1(5):403-410
26周吕,王新.胃动素对大鼠胃平滑肌细胞收缩活动的作用.生理学报,1996,48-65
27 Bonner TI, Buckley NJ, Young AC, et al. Identification of a family of muscarinic acetylcholine receptor genes. Science, 1987, 237(4814): 527-532
28 Sharma VK, Colecraft HM, Rubin LE. Does mammalian heart contain only the M2 muscarinic receptor subtype. Life Sci, 1997, 60(12): 1023-1029
29 Sohn UD, Harnett KM, Cao W, et al. Acute experimental esophagitis activates a second signal transduction pathway in cat smooth muscle from the lower esophageal sphincter. J Pharmacol Exp Ther, 1997, 283(3): 1293-1304
30 Fox JET and Daniel EE. Role of Ca2+ in genesis of lower esophageal sphincter tone and other active contractions. Am J Physiol Endocrinol Metab Gastrointest Physiol 237: E163-E171, 1979
31温士旺,刘俊峰,高立平,等.毒蕈碱受体亚型对人食管下括约肌的调节作用.中国药理学通报,2008,24:889-893
32高立平,刘俊峰,温士旺,等.胆囊收缩素受体对人食管下括约肌套索纤维和钩状纤维的调节机制.中华实验外科杂志,2006,23(4):581-582
33 Biancani P, Hillemeier C, Bitar KN, and Makhlouf GM. Contraction mediated by Ca2+ influx in esophageal muscle and by Ca2+ release in the LES. Am J Physiol Gastrointest Liver Physiol 253: G760-G766, 1987
34 Allescher HD, Berezin I, Jury J, and Daniel EE. Characteristics of canine lower esophageal sphincter: a new electrophysiological tool. Am J PhysiolGastrointest Liver Physiol 255: G441-G453, 1988
35 Salapatek AMF, Lam A, and Daniel EE. Calcium source diversity in canine lower esophageal sphincter muscle. J Pharmacol Exp Ther 287: 98-106, 1998
36 Tottrup A, Forman A, Uldbjerg N, Funch-Jensen P, and Andersson KE. Mechanical properties of isolated human esophageal smooth muscle. Am J Physiol Gastrointest Liver Physiol 258: G338-G343, 1990
37 Sohn UD, Chiu TT, Bitar KN, et al. Calcium requirements for acetylcholine-induced contraction of cat esophageal circular musclecells. Am J Physiol Gastrointest Liver Physiol 1994; 266: 330-338
38 Cao WB, Sohn UD, Bitar KN, et al. MAPK mediates PKC-dependent contraction of cat esophageal and lower esophageal sphincter circular smooth muscle. Am J Physiol Gastrointest Liver Physiol 2003; 285:86-95
39 Biancani P, Harnett KM, Sohn UD, et al. Differential signal transduction pathways in cat LES tone and response to ACh. Am J Physiol 1994; 266: 767-774
40高立平,刘俊峰,温士旺,等.胃泌素和胃动素对人离体食管下括约肌张力的调节机制.基础医学与临床,2006,26 (3):257-260
41温士旺,刘俊峰,高立平,等.一氧化氮介导人食管下括约肌舒张的作用机制.中华医学杂志,2006,86(1):31-34
42 Biancani P, Hillemeier C, Bitar KN, et al. Contraction mediated by Ca2+ influx in esophageal muscle and by Ca2+ release in the LES.Am J Physiol 1987; 253: 760-766
43 orsapati H, Babaei A, Bhargava V, et al. Cholinergic stimulation induces asynchrony between the circular and longitudinal muscle contraction during esophageal peristalsis. Am J Physiol Gastrointest Liver Physiol, 2008, 294: 694-698
44 Tian ZQ, Liu JF, Wang GY, et al. Responses of human clasp and sling fibers to neuromimetics. J Gastroenterol Hepatol, 2004, 19: 440-447
45 Muinuddin A, Naqvi K, Sheu L, et al. Regional differences in cholinergic regulation of potassium current in feline esophageal circular smoothmuscle. Am J Physiol Gastrointest Liver Physiol, 2005, 288: 1233-1240
46 James AN, Ryan JP, Crowell MD, et al. Regional gastric contractility alterations in a diabetic gastroparesis mouse model: effects of cholinergic and serotoninergic stimulation. Am J Physiol Gastrointest Liver Physiol, 2004, 287: 612-619
47 Preiksaitis HG, Krysiak PS, Chrones T, et al. Pharmacological and molecular characterization of muscarinic receptor subtypes in human esophageal smooth muscle. J Pharmacol Exp Ther, 2000, 295: 879-888
48 Kang HY, Lee TS, Lee YP, et al. Interaction of calmodulin- and PKC- dependent contractile pathways in cat lower esophageal sphincter (LES). Arch Pharm Res 2001; 24: 546-551
49 Preiksaitis HG, Diamant NE. Regional differences in cholinergic activity of muscle fibers from the human gastroesophageal junction. Am J Physiol, 1997, 272(6 Pt 1): G1321-1327
50 Keef KD, Ward SM, Stevens RJ, et al. Electrical and mechanical effects of acetylcholine and substance P in subregions of canine colon. Am J Physiol, 1992, 262(2 Pt 1): G298-G307
51郑礼,崔艳英。大鼠胃平滑肌细胞收缩模型及其药物研究。中国药理学通报。2003,Jun;19(6):675-8
52 Itoh Z, Aizawa I, Honda R, et al. Control of lower-esophageal-sphincter contractile activity by motilin in conscious dogs. Am J Dig Dis, 1978, 23: 341-345
53 Wess J,Bonner TI,Dorje F,et a1.Delineation of muscarinic receptor domains conferring selectivity of coupling to guanine nucleotide-binding proteins and second messengers.Mol Pharmacol,1 990,3 8(4):5l7-523
54 Peralta EG,Ashkenazi A,Wins.10w JW,et a1.Differential regulation of PI hydrolysis and adenylyl cyclase by muscarinic receptor subtypes. Nature, 1 988, 334(6 1 8 1): 434-437
55 Lai J,Waite SL,Bloom JW,et a1.The m2 muscarinic lacetylcholine receptors are coupled to multiple signalingpathways via pertussis toxin-sensitive guanine nucleotideregulatory proteins.J Pharmacol ExpTher,1991,258(3):938-944
56韩勇,赵正源,王云杰兔食管下括约肌与体部形态及乙酰胆碱对其功能影响的比较.世界华人消杂,2005,13(1):434-43
57 Pachori AS, Smith A, McDonald P, Zhang L, Dzau VJ, Melo LG. Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway. J Mol Cell Cardiol 2007; 43: 580-592
58 McKee KK, Tan CP, Palyha OC, et al. Cloning and characterization of two human G protein-couples receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotension receptors. Genomics, 1997, 46(3): 426-434
59 Stein HJ, Korn O, Liebermann-Meffert D, et al. Manometric vector volume of analysis to lower esophageal sphincter function. Ann Chir Gynaec, 1995, 84(2): 151-158
60 Mosley RG, Reichelderfer M,Sengupta A, Singaram C. Innervation of an esophageal ectatic submucosal blood vessel in achalasia and a comparison with normals. Am J Gastroenterol 1994; 89: 1874-1879
61 Ziegler K, Sanft C, Friedrich M, et al. Endosonographic appearance of the esophagus in achalasia. Endoscopy, 1990, 22(1):1-4
62 Purkiss J,Welch M,Doward S,et a1.Capsaicin-stimulated related of substance P from cultured dorsal root ganglin neuros:involvement of two distinct mechanisms[J] . Biochem Pharmacol , 2000 , 59(Suppl) :1403-1406.
63 FarréR, Sifrim D. Regulation of basal tone, relaxation and contraction of the lower esophageal sphincter. Relevance to drug discovery for esophageal disorders. Br J Pharmacol 2008; 153: 858-869
64 M,Radespiel-Tr?ger M.Anterograde tracing and immunohistochemical characterization of potentially mechanosensitive vagal afferents in the esophagus. J Comp Neurol 1999; 412: 161-172
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