芍药甙调节兔Oddi括约肌运动机制的研究及其对Oddi括约肌功能障碍的影响
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摘要
背景：Oddi括约肌(sphincter of Oddi, SO)是位于十二指肠降段(第二段)内侧偏下部位肠壁内向肠腔突出的含有纵行、斜行及环形的平滑肌。由三个部分组成：单纯包绕胆管的部分称之为胆管括约肌,胰管部分为胰管括约肌,胆胰管合并后共同部为乳头括约肌。Oddi括约肌有规律的收缩和舒张是保证胆囊充盈和排出,维持胆道压力的重要条件。Oddi括约肌功能障碍或紊乱是胆道系统及其它疾病发生的重要动力学诱因之一。目前公认,Oddi括约肌功能紊乱实质是痉挛状态。魏经国等已经证实高胆固醇血症可使SO动力发生异常改变；高胆固醇血症可引起兔Oddi括约肌功能紊乱,导致兔SO舒缩功能受损。其中,高胆固醇对胆道系统动力学影响已经有文献报道。
国内外有关胃肠道运动的作用机制研究文献较多,而关于Oddi括约肌运动机制的研究还比较少。国内已研究证实中药芍药有效成分芍药甙可以通过多种途径舒张胃肠道平滑肌,而芍药甙是否对Oddi括约肌有同样舒张作用及相同信号传导机制,目前未见相关报道。基于以上认识,本实验采用制作兔Oddi括约肌肌环、高胆固醇血症兔动物模型、恒温平滑肌槽及生物机能实验系统设备,观察不同类型的钾通道阻断剂及三磷酸肌醇受体阻断剂对兔SO肌环的舒缩作用,以及芍药甙对其影响；观察芍药甙对高胆固醇血症兔SO肌环收缩作用的影响,探讨芍药甙调节兔Oddi括约肌的运动机制及其对高胆固醇血症兔Oddi括约肌的影响。
目的：
1.探讨电压依赖性钾通道(Kv)、大电导钙激活钾通道(BKCa)对家兔离体Oddi括约肌(sphincter of Oddi, SO)肌环张力的作用；研究中药芍药的有效成分芍药甙对其调控作用。
2.观察三磷酸肌醇(Triphosphate inositol, IP3)受体阻断剂对家兔离体Oddi括约肌肌环张力的作用及芍药甙的调控作用。
3.观察芍药甙对高胆固醇血症(hypercholesterolemia, HC)家兔离体Oddi括约肌肌环收缩活动的影响。
方法：
1.制备离体兔Oddi括约肌肌环标本,放置于平滑肌恒温灌流浴槽中,观察Kv通道阻断剂4-aminopyridine (4-AP)、BKCa通道阻断剂Iberiotoxin (IBTX)对家兔离体SO肌环的收缩作用；观察芍药甙对4-AP和BKca收缩作用的影响。
2.制备离体兔Oddi括约肌肌环标本,放置于平滑肌恒温灌流浴槽中,观察累积浓度芍药甙对乙酰胆碱(Ach)预收缩(乙酰胆碱组)的SO肌环的作用和芍药甙对经无钙液(无钙液组)、无钙液加肝素(肝素组)预处理后的SO肌环的作用。
3.纯种新西兰大耳白家兔16只随机分成两组：对照组(control, CON)和高胆固醇血症(hypercholesterolemia, HC)模型组各8只,CON组饲以标准饲料,HC组饲以标准饲料+胆固醇(cholesterol, Ch),共饲8周。分别取两组SO制备成离体肌环,放置于平滑肌恒温灌流浴槽中,观察累积浓度芍药甙对SO肌环的舒张反应。
结果：
1.①Kv通道阻断剂4-AP可以引起SO肌环收缩；随4-AP浓度增加,收缩程度增强；BKca通道阻断剂IBTX也可引起SO肌环收缩；随BKca浓度增加,收缩程度也在增强。②4-AP和BKca对SO肌环的收缩作用可以被芍药甙抑制。
2.当芍药甙浓度累积达(12.5、25、50、100)μmol/L时,对Ach(10-6mol/L)预收缩的SO肌环产生剂量依赖性舒张作用(P<0.05)。经无钙液预处理后,芍药甙(100μmmol/L)对SO肌环的舒张作用未被阻断；但经无钙液加肝素预处理后,该作用被显著抑制(P<0.01)。
3.当芍药甙浓度累积达(100nmol/L、1μmol/L、10μmol/L、100μmol/L)时,对HC组的SO肌环产生剂量依赖性舒张作用(P<0.01)。
结论：
本实验首次在离体条件下观察了不同类型的钾通道阻断剂对兔SO肌环的舒缩作用,以及芍药甙对其影响；并进一步观察了芍药甙对HC兔SO肌环收缩作用的影响,结果发现：
1.在离体条件下：①Kv通道和BKCa通道在维持Oddi括约肌细胞的静息膜电位起主要作用。②芍药甙可能通过对Kv通道和BKCa通道的调控,实现了对Oddi括约肌细胞的舒张反应。
2.芍药甙对家兔离体Oddi括约肌肌环具有舒张作用,初步确定其机制可能与阻断平滑肌细胞内质网上的三磷酸肌醇(IP3)敏感的钙离子通道,抑制内钙的释放有关。
3.在离体条件下,观察到芍药甙对高胆固醇血症兔Oddi括约肌肌环具有舒张作用,其具体作用机制有待进一步研究。
Background:The sphincter of Oddi is located in the duodenum descending segment (paragraph) under the inside part of the intestinal wall within the lumen side containing prominent vertical lines, oblique lines, and circular smooth muscle. Consists of three parts:a simple part of the surrounding bile ducts called biliary sphincter, pancreatic duct sphincter partially, after the merger of common bile duct sphincter of the Department for the nipple. The sphincter of Oddi regular contraction and relaxation is to ensure that the gallbladder filling and discharge, an important condition for the maintenance of bile duct pressure. The sphincter of Oddi dysfunction or disorder is the biliary system and other diseases, one of the important dynamic incentives. Currently recognized, the sphincter of Oddi dysfunction is essentially spasticity. Wei has been confirmed by the United States and high cholesterol abnormal changes can occur SO motivation; high cholesterol can cause sphincter of Oddi dysfunction in rabbits, resulting in impaired systolic and diastolic function in rabbit SO. Among them, high cholesterol effects on the biliary system dynamics have been reported in the literature.
At home and abroad about the roles of the movement mechanism of gastrointestinal research literature more, but on the sphincter of Oddi mechanism study also relatively small. China has studied the Chinese peony active ingredients proven through a variety of ways paeoniflorin gastrointestinal smooth muscle relaxation, while paeoniflorin whether the same relaxing effect the sphincter of Oddi and the same signal transduction mechanism, currently no relevant reports. Based on the above understanding, the present study, production of rabbit sphincter of Oddi muscle rings, hypercholesterolemia rabbit animal model, temperature and biological function of smooth muscle tank experimental system equipment, observation of different types of potassium channel blockers on rabbit vasomotor role of the SO muscle rings, as well as their impact Paeoniflorin; observed Paeoniflorin on rabbits with hypercholesterolemia the role of SO muscle rings explore the effect of Paeoniflorin regulate the movement mechanism of rabbit sphincter of Oddi and its impact on sphincter of Oddi in rabbits with hypercholesterolemia impact.
Objective:
1. To investingate the regulating role of voltage-gated potassium channels (Kv), large-conductance calcium-activated potassium channel (BKCa) on sphincter of Oddi (sphincter of Oddi, SO) from rabbits muscle tension rings; study of the active ingredients of traditional Chinese medicine peony Paeoniflorin its control effect.
2. Observation of triphosphate inositol (IP3) receptor antagonist on isolated rabbit sphincter of Oddi muscle tension rings effect and Paeoniflorin in vitro.
3. Observed Paeoniflorin right hypercholesterolemia (hypercholestero-lemia, HC) isolated rabbits sphincter of Oddi muscle rings the impact of activities.
Methods:
1. Preparation of isolated rabbit sphincter of Oddi muscle rings specimens, placed on the smooth muscle perfusion bath temperature to observe the Kv channel blocker 4-aminopyridine (4-AP), BKCa channel blocker Iberiotoxin (IBTX) on isolated rabbit SO muscle rings contraction effect; observed Paeoniflorin pairs of 4-AP and BKCa contraction effects.
2. The organ-bath was used to observe the contractile activity of isolated smooth muscle from rabbit sphincter of Oddi muscle rings after cumulatively administrated different concentration of Paeoniflorin (PA), the effect of accumulated PA on SO muscle rings in pre-constricted with acetylcholine (Ach) was observed. And to explore the mechanism, the SO muscle rings were incubated with Ca2+-free medium alone, or Ca2+-free medium plus heparin before pre-contraction with Ach.
3. New Zealand white rabbits with big ears, pure 16 were randomly divided into two groups:control group (CON), and hypercholesterolemia model group (HC) of 8, CON group were fed with standard fodder, HC group were fed with hypercholesterol diet, were fed for 8 weeks. SO groups were prepared to take away from the body into muscle rings, placed on the smooth muscle perfusion bath temperature to observe the cumulative concentration of Paeoniflorin on the SO muscle rings of reaction.
Results:
1.①Kv channel blocker 4-AP can cause SO muscle rings; with the 4-AP concentrations increase in degree of contraction increased; BKca channel blocker IBTX can also be caused by SO muscle rings; with the BKCa increasing concentration, contraction was also enhanced degree of.②4-AP and the BKca right SO muscle ring contraction can be inhibited Paeoniflorin.
2. When the concentration of PA was cumulated to (12.5、25、50、100)μmol/L, it caused concentration-dependent relaxation while SO muscle rings were pre-constricted with Ach (10-6mol/L). This effect was not inhibited by Ca2+-free medium. However, the effect was attenuated by the co-incubation with heparin and Ca2+-free medium [without heparin: (74.56±1.47)% vs (92.31±0.84)%, with heparin:(95.98±0.52)%vs (95.03±0.43)%].
3. When the concentration of Paeoniflorin was accumulated to (100nmol/L, 1μmol/L, 10μmol/L, 100μmol/L), the right HC group SO muscle rings was caused concentration-dependent relaxation (P<0.01).
Conclusion:
In this study, the first time, observed under in vitro conditions, the different types of potassium channel blockers on rabbit SO muscle rings relaxation effects and their impact Paeoniflorin; and further observed Paeoniflorin on HC rabbits the role of SO muscle rings the impact of the results found that:
1. In vitro conditions:①Kv channel and BKca channel in the maintenance of sphincter of Oddi resting membrane potential of cells, play a major role.②Paeoniflorin of Kv channels and possibly through the regulation of BKCa channels to achieve sphincter of Oddi relaxation cells.
2. The results indicate that Paeoniflorin can relax the rabbit SO muscle rings in vitro. The mechanism may include the inhibition of intracellular calcium ions release by the 1,4,5-triposphate inositol-receptor-dependent pathway in SO muscle cells.
3. In vitro conditions, the observed Paeoniflorin right hypercholestero-lemia rabbits sphincter of Oddi muscle rings have a relaxing effect, what the specific mechanism remains to be further studied.
国内外有关胃肠道运动的作用机制研究文献较多,而关于Oddi括约肌运动机制的研究还比较少。国内已研究证实中药芍药有效成分芍药甙可以通过多种途径舒张胃肠道平滑肌,而芍药甙是否对Oddi括约肌有同样舒张作用及相同信号传导机制,目前未见相关报道。基于以上认识,本实验采用制作兔Oddi括约肌肌环、高胆固醇血症兔动物模型、恒温平滑肌槽及生物机能实验系统设备,观察不同类型的钾通道阻断剂及三磷酸肌醇受体阻断剂对兔SO肌环的舒缩作用,以及芍药甙对其影响；观察芍药甙对高胆固醇血症兔SO肌环收缩作用的影响,探讨芍药甙调节兔Oddi括约肌的运动机制及其对高胆固醇血症兔Oddi括约肌的影响。
目的：
1.探讨电压依赖性钾通道(Kv)、大电导钙激活钾通道(BKCa)对家兔离体Oddi括约肌(sphincter of Oddi, SO)肌环张力的作用；研究中药芍药的有效成分芍药甙对其调控作用。
2.观察三磷酸肌醇(Triphosphate inositol, IP3)受体阻断剂对家兔离体Oddi括约肌肌环张力的作用及芍药甙的调控作用。
3.观察芍药甙对高胆固醇血症(hypercholesterolemia, HC)家兔离体Oddi括约肌肌环收缩活动的影响。
方法：
1.制备离体兔Oddi括约肌肌环标本,放置于平滑肌恒温灌流浴槽中,观察Kv通道阻断剂4-aminopyridine (4-AP)、BKCa通道阻断剂Iberiotoxin (IBTX)对家兔离体SO肌环的收缩作用；观察芍药甙对4-AP和BKca收缩作用的影响。
2.制备离体兔Oddi括约肌肌环标本,放置于平滑肌恒温灌流浴槽中,观察累积浓度芍药甙对乙酰胆碱(Ach)预收缩(乙酰胆碱组)的SO肌环的作用和芍药甙对经无钙液(无钙液组)、无钙液加肝素(肝素组)预处理后的SO肌环的作用。
3.纯种新西兰大耳白家兔16只随机分成两组：对照组(control, CON)和高胆固醇血症(hypercholesterolemia, HC)模型组各8只,CON组饲以标准饲料,HC组饲以标准饲料+胆固醇(cholesterol, Ch),共饲8周。分别取两组SO制备成离体肌环,放置于平滑肌恒温灌流浴槽中,观察累积浓度芍药甙对SO肌环的舒张反应。
结果：
1.①Kv通道阻断剂4-AP可以引起SO肌环收缩；随4-AP浓度增加,收缩程度增强；BKca通道阻断剂IBTX也可引起SO肌环收缩；随BKca浓度增加,收缩程度也在增强。②4-AP和BKca对SO肌环的收缩作用可以被芍药甙抑制。
2.当芍药甙浓度累积达(12.5、25、50、100)μmol/L时,对Ach(10-6mol/L)预收缩的SO肌环产生剂量依赖性舒张作用(P<0.05)。经无钙液预处理后,芍药甙(100μmmol/L)对SO肌环的舒张作用未被阻断；但经无钙液加肝素预处理后,该作用被显著抑制(P<0.01)。
3.当芍药甙浓度累积达(100nmol/L、1μmol/L、10μmol/L、100μmol/L)时,对HC组的SO肌环产生剂量依赖性舒张作用(P<0.01)。
结论：
本实验首次在离体条件下观察了不同类型的钾通道阻断剂对兔SO肌环的舒缩作用,以及芍药甙对其影响；并进一步观察了芍药甙对HC兔SO肌环收缩作用的影响,结果发现：
1.在离体条件下：①Kv通道和BKCa通道在维持Oddi括约肌细胞的静息膜电位起主要作用。②芍药甙可能通过对Kv通道和BKCa通道的调控,实现了对Oddi括约肌细胞的舒张反应。
2.芍药甙对家兔离体Oddi括约肌肌环具有舒张作用,初步确定其机制可能与阻断平滑肌细胞内质网上的三磷酸肌醇(IP3)敏感的钙离子通道,抑制内钙的释放有关。
3.在离体条件下,观察到芍药甙对高胆固醇血症兔Oddi括约肌肌环具有舒张作用,其具体作用机制有待进一步研究。
Background:The sphincter of Oddi is located in the duodenum descending segment (paragraph) under the inside part of the intestinal wall within the lumen side containing prominent vertical lines, oblique lines, and circular smooth muscle. Consists of three parts:a simple part of the surrounding bile ducts called biliary sphincter, pancreatic duct sphincter partially, after the merger of common bile duct sphincter of the Department for the nipple. The sphincter of Oddi regular contraction and relaxation is to ensure that the gallbladder filling and discharge, an important condition for the maintenance of bile duct pressure. The sphincter of Oddi dysfunction or disorder is the biliary system and other diseases, one of the important dynamic incentives. Currently recognized, the sphincter of Oddi dysfunction is essentially spasticity. Wei has been confirmed by the United States and high cholesterol abnormal changes can occur SO motivation; high cholesterol can cause sphincter of Oddi dysfunction in rabbits, resulting in impaired systolic and diastolic function in rabbit SO. Among them, high cholesterol effects on the biliary system dynamics have been reported in the literature.
At home and abroad about the roles of the movement mechanism of gastrointestinal research literature more, but on the sphincter of Oddi mechanism study also relatively small. China has studied the Chinese peony active ingredients proven through a variety of ways paeoniflorin gastrointestinal smooth muscle relaxation, while paeoniflorin whether the same relaxing effect the sphincter of Oddi and the same signal transduction mechanism, currently no relevant reports. Based on the above understanding, the present study, production of rabbit sphincter of Oddi muscle rings, hypercholesterolemia rabbit animal model, temperature and biological function of smooth muscle tank experimental system equipment, observation of different types of potassium channel blockers on rabbit vasomotor role of the SO muscle rings, as well as their impact Paeoniflorin; observed Paeoniflorin on rabbits with hypercholesterolemia the role of SO muscle rings explore the effect of Paeoniflorin regulate the movement mechanism of rabbit sphincter of Oddi and its impact on sphincter of Oddi in rabbits with hypercholesterolemia impact.
Objective:
1. To investingate the regulating role of voltage-gated potassium channels (Kv), large-conductance calcium-activated potassium channel (BKCa) on sphincter of Oddi (sphincter of Oddi, SO) from rabbits muscle tension rings; study of the active ingredients of traditional Chinese medicine peony Paeoniflorin its control effect.
2. Observation of triphosphate inositol (IP3) receptor antagonist on isolated rabbit sphincter of Oddi muscle tension rings effect and Paeoniflorin in vitro.
3. Observed Paeoniflorin right hypercholesterolemia (hypercholestero-lemia, HC) isolated rabbits sphincter of Oddi muscle rings the impact of activities.
Methods:
1. Preparation of isolated rabbit sphincter of Oddi muscle rings specimens, placed on the smooth muscle perfusion bath temperature to observe the Kv channel blocker 4-aminopyridine (4-AP), BKCa channel blocker Iberiotoxin (IBTX) on isolated rabbit SO muscle rings contraction effect; observed Paeoniflorin pairs of 4-AP and BKCa contraction effects.
2. The organ-bath was used to observe the contractile activity of isolated smooth muscle from rabbit sphincter of Oddi muscle rings after cumulatively administrated different concentration of Paeoniflorin (PA), the effect of accumulated PA on SO muscle rings in pre-constricted with acetylcholine (Ach) was observed. And to explore the mechanism, the SO muscle rings were incubated with Ca2+-free medium alone, or Ca2+-free medium plus heparin before pre-contraction with Ach.
3. New Zealand white rabbits with big ears, pure 16 were randomly divided into two groups:control group (CON), and hypercholesterolemia model group (HC) of 8, CON group were fed with standard fodder, HC group were fed with hypercholesterol diet, were fed for 8 weeks. SO groups were prepared to take away from the body into muscle rings, placed on the smooth muscle perfusion bath temperature to observe the cumulative concentration of Paeoniflorin on the SO muscle rings of reaction.
Results:
1.①Kv channel blocker 4-AP can cause SO muscle rings; with the 4-AP concentrations increase in degree of contraction increased; BKca channel blocker IBTX can also be caused by SO muscle rings; with the BKCa increasing concentration, contraction was also enhanced degree of.②4-AP and the BKca right SO muscle ring contraction can be inhibited Paeoniflorin.
2. When the concentration of PA was cumulated to (12.5、25、50、100)μmol/L, it caused concentration-dependent relaxation while SO muscle rings were pre-constricted with Ach (10-6mol/L). This effect was not inhibited by Ca2+-free medium. However, the effect was attenuated by the co-incubation with heparin and Ca2+-free medium [without heparin: (74.56±1.47)% vs (92.31±0.84)%, with heparin:(95.98±0.52)%vs (95.03±0.43)%].
3. When the concentration of Paeoniflorin was accumulated to (100nmol/L, 1μmol/L, 10μmol/L, 100μmol/L), the right HC group SO muscle rings was caused concentration-dependent relaxation (P<0.01).
Conclusion:
In this study, the first time, observed under in vitro conditions, the different types of potassium channel blockers on rabbit SO muscle rings relaxation effects and their impact Paeoniflorin; and further observed Paeoniflorin on HC rabbits the role of SO muscle rings the impact of the results found that:
1. In vitro conditions:①Kv channel and BKca channel in the maintenance of sphincter of Oddi resting membrane potential of cells, play a major role.②Paeoniflorin of Kv channels and possibly through the regulation of BKCa channels to achieve sphincter of Oddi relaxation cells.
2. The results indicate that Paeoniflorin can relax the rabbit SO muscle rings in vitro. The mechanism may include the inhibition of intracellular calcium ions release by the 1,4,5-triposphate inositol-receptor-dependent pathway in SO muscle cells.
3. In vitro conditions, the observed Paeoniflorin right hypercholestero-lemia rabbits sphincter of Oddi muscle rings have a relaxing effect, what the specific mechanism remains to be further studied.
引文
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