逼尿肌兴奋性与逼尿肌不稳定的关系研究
摘要
逼尿肌不稳定是泌尿外科最常见的一种膀胱功能障碍性疾病，发生率极高，主要表现为储尿期膀胱逼尿肌出现无抑制收缩而引起尿频、尿急、尿失禁等症状。绝大多数原因不明，针对病因治疗显得极为困难。
逼尿肌不稳定主要表现为逼尿肌的无抑制收缩，肌肉的收缩是通过兴奋-收缩耦连机制来实现的，逼尿肌自身兴奋性在逼尿肌不稳定的发生中起着重要作用。细胞膜上K+电流参与膜电位的形成及动作电位末期复极，对细胞兴奋性的产生起着决定性的作用。Ca2+作为细胞内最普遍和最重要的信号转导成分，介导兴奋收缩耦联、信号转导、神经递质的释放等各种细胞功能，对增加和维持平滑肌细胞兴奋性和收缩力起重要作用。本研究通过对逼尿肌兴奋性的特性进行观察，了解逼尿肌兴奋性与逼尿肌不稳定之间的关系，并对逼尿肌不稳定时逼尿肌中钙通道和钾通道与逼尿肌兴奋性之间的关系进行了初步探讨。主要实验结果及结论如下：
1. 我们同时制作了最常见的特发性逼尿肌不稳定、BOO和骶髓上脊髓损害三种模型，对逼尿肌不稳定时逼尿肌组织功能与结构变化的共性进行初步探讨。逼尿肌组织在一定张力下都可引起收缩，表明逼尿肌组织是一种在特定前负荷下具有自发兴奋并引起收缩的组织。逼尿肌不稳定各组肌条在较小的张力下即出现自发性收缩；在相同前负荷下，不稳定组肌条自发性收缩频率较正常组增高。提示逼尿肌不稳定时逼尿肌自发兴奋能力增高。细胞间出现大量锯齿状的胞突连接以及较多的桥粒与缝隙连接。这种细胞间连接变化引起的兴奋性传导易化是逼尿肌不稳定发生、发展的结构基础。
2. 逼尿肌自身“肌源性”改变在逼尿肌不稳定的发生中起着重要作用，发生逼尿肌不稳定时存在一些共同的病理生理改变：1.功能基础：逼尿肌在特定条件下都具有自发性收缩的能力，DI逼尿肌在较小的前负荷下即可出现自发性兴奋和收缩；在同等的前负荷下DI逼尿肌的自发收缩频率更高；2. 结构基础：逼尿肌不稳定时细胞间出现的大量锯齿状的胞突连接以及较多桥粒与缝隙连接形成了逼尿肌不稳定的结构基础。兴奋性是肌源性因素中的一个重要组成部分。逼尿肌自身兴奋性的变化在逼尿肌不稳定的发生中起着重要作用。
3. 膜片钳技术能够精确直观地对细胞膜离子通道活动进行分析，直接得到有关细胞跨膜电位及电流变化信息。我们采用组织切片膜片钳全细胞记录技术，盲法获得逼尿肌平滑肌细胞，对逼尿肌不稳定时逼尿肌细胞兴奋性变化进行观察。发现BOO和
SCT组中逼尿肌细胞兴奋性的升高与细胞静息电位升高（绝对值减小）有关。IDI组上述变化不明显，说明对于不同类型的逼尿肌不稳定，其兴奋性改变原因不尽相同。BOO、SCT和IDI组逼尿肌细胞在阈强度刺激下即可诱发动作电位产生，而正常对照组则需将刺激强度增加至120%阈强度方可诱发出动作电位。这说明逼尿肌不稳定时细胞细胞兴奋性上升，对刺激的反应性增强。
4. 在细胞浴液中分别加入TEA（钙激活钾通道阻滞剂）和4-AP（延迟整流钾通道阻滞剂）可使逼尿肌细胞钾电流明显减弱，但是在细胞浴液中同时加入TEA和4-AP不能完全抑制逼尿肌钾电流的产生，说明逼尿肌细胞钾电流由多种电流成分组成，以钙离子依赖钾电流(KCa)和内向整流钾电流(KDR)为主，但尚有其他钾电流成分的存在。
5. 膀胱流出道梗阻组和脊髓横断组中逼尿肌细胞钾通道平均外向电流较正常对照组明显下降。说明逼尿肌细胞钾电流降低是产生逼尿肌不稳定的重要原因。4-AP对BOO和SCT组中逼尿肌细胞钾电流的抑制作用较Stable组明显。加入TEA后各组间钾电流变化相差不明显。说明延迟整流钾电流在逼尿肌不稳定的产生中具有重要作用，钙激活钾电流作用不明显。
6. Kv2.1在BOO和SCT组逼尿肌中的表达低于正常对照组，提示Kv家族钾通道在逼尿肌不稳定的产生中占有重要地位。BKCa、SKCa在大鼠膀胱逼尿肌中均有表达，但各组间二者表达无明显差异。KCa通道在逼尿肌不稳定发生中的具体作用仍需进行深入研究。KATP在BOO组和SCT组中的表达较正常组明显升高，而无明显病因的不稳定组中，KATP变化则不明显。这可能与BOO和SCT导致局部逼尿肌组织发生较明显的病理生理与结构变化有关。
7. 根据L型和T型钙通道的电压依赖失活及激活特性，可以使用不同钳制电压加以区分。IDI组、BOO组和SCT组中逼尿肌细胞钙通道峰电流强度较正常对照组均有明显提高。L和T型电流均有明显增加，T型钙电流成分较正常组明显增加。提示在逼尿肌不稳定时钙电流的升高起着重要作用，其中T型电流在其中起主要作用。
8. 正常组中L型钙通道含量明显多于T型钙通道，BOO组、SCI组和不稳定组中L和T型均有不同程度增加，T型钙通道增加更明显。提示在正常生理条件下，平滑肌中钙通道以L型钙通道为主。钙通道的变化在逼尿肌不稳定的产生中起着重要作用，其中T型钙通道的作用更加明显。
9. 不稳定组、BOO组和SCT组平滑肌细胞内游离 Ca2+含量在静息状态下较正常对照组明显增高。这是由于逼尿肌不稳定时于钙通道的表达和功能增强，钙离子内流增多所致。
Background: Detrusor instability (DI) is one of the most common micturation dysfunction diseases in clinic, mainly appears to be urinary frequency, urinary urgency and stress incontinence et al. The pathogenesis causing DI is still unclear, while somebody thinks the pathological change of nervous system is the main cause of detrusor instability, but the antagonist and agonist of different nerves in the treatment of detrusor instability are not satisfactory. Detrusor is a kind of excitable tissue, so the excitability of detrusor must play a key role in the occurring of detrusor instability, but there were few reports about the excitability of detrusor. The objective of this study is to investigate the mechanism of detrusor instability, especially the relationship between the excitability and detrusor instability, and the effects of potassium and calcium on detrusor excitability.
Materials and Methods: Idiopathic (IDI), bladder outlet obstruction (BOO) and spinal cord transection (SCT) caused detrusor instability model were established in female Wistar rats by operation and urodynamics. Pathological changes in detrusor were studied by light and electronic microscope. The spontanouse contraction frequency and strength of detrusor strip were measured: ①The minimums tension while spontaneous contraction occurred was recorded; ②The contraction frequency of strip at fixed tension (1.0g) was recorded; ③The effect of carbachol (muscarinic receptor agonist) and atropine (muscarinic receptor antagonist) on the contraction frequency of strip at fixed tension (1.0g) were recorded. The blind whole cell patch clamp recording technique for detrusor bladder smooth muscle cell (DSMC) in bladder muscle slice was performed. The resting membrane potential (RMP), input resistance (IR) and action potential (AP) were recorded and compared. The potassium currents of DSMC were recorded and the components were analyzed. The changes of the currents in DI groups were evaluated. The expressions of all the kinds of potassium channels were detected by RT-PCR technique. The changes of the potassium channels' expression in DI groups were evaluated. The concentration of free Ca2+ in DSMC was measured by laser scanning confocal microscope (LSCM). The calcium currents of DSMC were recorded and the components were analyzed. The changes of calcium currents in DI were evaluated. Expressions of L and T type of calcium channels were detected by RT-PCR. The changes of the calcium channels' expression in DI groups were evaluated.
Results and discussion: The detrusor smooth muscle cells appeared hypertrophy, more gap junctions and protrusion junctions were found. Detrusor of all groups contracted at definite tension. DI strips contracted in lower tension and had the higher contraction frequency than that of stable. There were no obviously changes while the detrusor strips mustarded by muscarinic receptor antagonist and agonist, which means the excitability of detrusor is determined mainly by myogenic factors instead of muscarinic receptor. DSMCs with detrusor instability groups had the higher RMP and IR. AP of DSMC with detrusor instability groups could be evoked with lower depolarized stimulation compared with control. The duration of AP was prolonged in DI groups. The potassium current of DSMC was composed by many kinds of currents. Delayed rectifying potassium current and Ca2+ activated potassium current were the main parts. Delayed rectifying potassium current in DSMC with DI was higher than that of control. There were many kinds of potassium channels expressed in Wistar rat detrusor, such as Kv 1.2, 1.3, 1.4, 1.5, 2.1, 3.2, and 4.2, BKCa, SKCa and KATP. The expression of Kv2.1 in BOO and SCI were much lower than that of control, and the expression of KATP in BOO and SCI were much higher than that of control. Potassium channels can affect the excitability of cells, so changes of function and expression of potassium channel may be one of the cause in the occurring of DI. The calcium current of DSMC was composed of many kinds of currents, t
逼尿肌不稳定主要表现为逼尿肌的无抑制收缩，肌肉的收缩是通过兴奋-收缩耦连机制来实现的，逼尿肌自身兴奋性在逼尿肌不稳定的发生中起着重要作用。细胞膜上K+电流参与膜电位的形成及动作电位末期复极，对细胞兴奋性的产生起着决定性的作用。Ca2+作为细胞内最普遍和最重要的信号转导成分，介导兴奋收缩耦联、信号转导、神经递质的释放等各种细胞功能，对增加和维持平滑肌细胞兴奋性和收缩力起重要作用。本研究通过对逼尿肌兴奋性的特性进行观察，了解逼尿肌兴奋性与逼尿肌不稳定之间的关系，并对逼尿肌不稳定时逼尿肌中钙通道和钾通道与逼尿肌兴奋性之间的关系进行了初步探讨。主要实验结果及结论如下：
1. 我们同时制作了最常见的特发性逼尿肌不稳定、BOO和骶髓上脊髓损害三种模型，对逼尿肌不稳定时逼尿肌组织功能与结构变化的共性进行初步探讨。逼尿肌组织在一定张力下都可引起收缩，表明逼尿肌组织是一种在特定前负荷下具有自发兴奋并引起收缩的组织。逼尿肌不稳定各组肌条在较小的张力下即出现自发性收缩；在相同前负荷下，不稳定组肌条自发性收缩频率较正常组增高。提示逼尿肌不稳定时逼尿肌自发兴奋能力增高。细胞间出现大量锯齿状的胞突连接以及较多的桥粒与缝隙连接。这种细胞间连接变化引起的兴奋性传导易化是逼尿肌不稳定发生、发展的结构基础。
2. 逼尿肌自身“肌源性”改变在逼尿肌不稳定的发生中起着重要作用，发生逼尿肌不稳定时存在一些共同的病理生理改变：1.功能基础：逼尿肌在特定条件下都具有自发性收缩的能力，DI逼尿肌在较小的前负荷下即可出现自发性兴奋和收缩；在同等的前负荷下DI逼尿肌的自发收缩频率更高；2. 结构基础：逼尿肌不稳定时细胞间出现的大量锯齿状的胞突连接以及较多桥粒与缝隙连接形成了逼尿肌不稳定的结构基础。兴奋性是肌源性因素中的一个重要组成部分。逼尿肌自身兴奋性的变化在逼尿肌不稳定的发生中起着重要作用。
3. 膜片钳技术能够精确直观地对细胞膜离子通道活动进行分析，直接得到有关细胞跨膜电位及电流变化信息。我们采用组织切片膜片钳全细胞记录技术，盲法获得逼尿肌平滑肌细胞，对逼尿肌不稳定时逼尿肌细胞兴奋性变化进行观察。发现BOO和
SCT组中逼尿肌细胞兴奋性的升高与细胞静息电位升高（绝对值减小）有关。IDI组上述变化不明显，说明对于不同类型的逼尿肌不稳定，其兴奋性改变原因不尽相同。BOO、SCT和IDI组逼尿肌细胞在阈强度刺激下即可诱发动作电位产生，而正常对照组则需将刺激强度增加至120%阈强度方可诱发出动作电位。这说明逼尿肌不稳定时细胞细胞兴奋性上升，对刺激的反应性增强。
4. 在细胞浴液中分别加入TEA（钙激活钾通道阻滞剂）和4-AP（延迟整流钾通道阻滞剂）可使逼尿肌细胞钾电流明显减弱，但是在细胞浴液中同时加入TEA和4-AP不能完全抑制逼尿肌钾电流的产生，说明逼尿肌细胞钾电流由多种电流成分组成，以钙离子依赖钾电流(KCa)和内向整流钾电流(KDR)为主，但尚有其他钾电流成分的存在。
5. 膀胱流出道梗阻组和脊髓横断组中逼尿肌细胞钾通道平均外向电流较正常对照组明显下降。说明逼尿肌细胞钾电流降低是产生逼尿肌不稳定的重要原因。4-AP对BOO和SCT组中逼尿肌细胞钾电流的抑制作用较Stable组明显。加入TEA后各组间钾电流变化相差不明显。说明延迟整流钾电流在逼尿肌不稳定的产生中具有重要作用，钙激活钾电流作用不明显。
6. Kv2.1在BOO和SCT组逼尿肌中的表达低于正常对照组，提示Kv家族钾通道在逼尿肌不稳定的产生中占有重要地位。BKCa、SKCa在大鼠膀胱逼尿肌中均有表达，但各组间二者表达无明显差异。KCa通道在逼尿肌不稳定发生中的具体作用仍需进行深入研究。KATP在BOO组和SCT组中的表达较正常组明显升高，而无明显病因的不稳定组中，KATP变化则不明显。这可能与BOO和SCT导致局部逼尿肌组织发生较明显的病理生理与结构变化有关。
7. 根据L型和T型钙通道的电压依赖失活及激活特性，可以使用不同钳制电压加以区分。IDI组、BOO组和SCT组中逼尿肌细胞钙通道峰电流强度较正常对照组均有明显提高。L和T型电流均有明显增加，T型钙电流成分较正常组明显增加。提示在逼尿肌不稳定时钙电流的升高起着重要作用，其中T型电流在其中起主要作用。
8. 正常组中L型钙通道含量明显多于T型钙通道，BOO组、SCI组和不稳定组中L和T型均有不同程度增加，T型钙通道增加更明显。提示在正常生理条件下，平滑肌中钙通道以L型钙通道为主。钙通道的变化在逼尿肌不稳定的产生中起着重要作用，其中T型钙通道的作用更加明显。
9. 不稳定组、BOO组和SCT组平滑肌细胞内游离 Ca2+含量在静息状态下较正常对照组明显增高。这是由于逼尿肌不稳定时于钙通道的表达和功能增强，钙离子内流增多所致。
Background: Detrusor instability (DI) is one of the most common micturation dysfunction diseases in clinic, mainly appears to be urinary frequency, urinary urgency and stress incontinence et al. The pathogenesis causing DI is still unclear, while somebody thinks the pathological change of nervous system is the main cause of detrusor instability, but the antagonist and agonist of different nerves in the treatment of detrusor instability are not satisfactory. Detrusor is a kind of excitable tissue, so the excitability of detrusor must play a key role in the occurring of detrusor instability, but there were few reports about the excitability of detrusor. The objective of this study is to investigate the mechanism of detrusor instability, especially the relationship between the excitability and detrusor instability, and the effects of potassium and calcium on detrusor excitability.
Materials and Methods: Idiopathic (IDI), bladder outlet obstruction (BOO) and spinal cord transection (SCT) caused detrusor instability model were established in female Wistar rats by operation and urodynamics. Pathological changes in detrusor were studied by light and electronic microscope. The spontanouse contraction frequency and strength of detrusor strip were measured: ①The minimums tension while spontaneous contraction occurred was recorded; ②The contraction frequency of strip at fixed tension (1.0g) was recorded; ③The effect of carbachol (muscarinic receptor agonist) and atropine (muscarinic receptor antagonist) on the contraction frequency of strip at fixed tension (1.0g) were recorded. The blind whole cell patch clamp recording technique for detrusor bladder smooth muscle cell (DSMC) in bladder muscle slice was performed. The resting membrane potential (RMP), input resistance (IR) and action potential (AP) were recorded and compared. The potassium currents of DSMC were recorded and the components were analyzed. The changes of the currents in DI groups were evaluated. The expressions of all the kinds of potassium channels were detected by RT-PCR technique. The changes of the potassium channels' expression in DI groups were evaluated. The concentration of free Ca2+ in DSMC was measured by laser scanning confocal microscope (LSCM). The calcium currents of DSMC were recorded and the components were analyzed. The changes of calcium currents in DI were evaluated. Expressions of L and T type of calcium channels were detected by RT-PCR. The changes of the calcium channels' expression in DI groups were evaluated.
Results and discussion: The detrusor smooth muscle cells appeared hypertrophy, more gap junctions and protrusion junctions were found. Detrusor of all groups contracted at definite tension. DI strips contracted in lower tension and had the higher contraction frequency than that of stable. There were no obviously changes while the detrusor strips mustarded by muscarinic receptor antagonist and agonist, which means the excitability of detrusor is determined mainly by myogenic factors instead of muscarinic receptor. DSMCs with detrusor instability groups had the higher RMP and IR. AP of DSMC with detrusor instability groups could be evoked with lower depolarized stimulation compared with control. The duration of AP was prolonged in DI groups. The potassium current of DSMC was composed by many kinds of currents. Delayed rectifying potassium current and Ca2+ activated potassium current were the main parts. Delayed rectifying potassium current in DSMC with DI was higher than that of control. There were many kinds of potassium channels expressed in Wistar rat detrusor, such as Kv 1.2, 1.3, 1.4, 1.5, 2.1, 3.2, and 4.2, BKCa, SKCa and KATP. The expression of Kv2.1 in BOO and SCI were much lower than that of control, and the expression of KATP in BOO and SCI were much higher than that of control. Potassium channels can affect the excitability of cells, so changes of function and expression of potassium channel may be one of the cause in the occurring of DI. The calcium current of DSMC was composed of many kinds of currents, t
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