缬草提取物对兔心室肌细胞离子通道的影响
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摘要
目的：研究缬草提取物(VE)对兔心室肌细胞跨膜动作电位时程(APD)、钠电流(I_(Na))、L-钙电流(I_(Ca-L))、短暂外向钾电流(I_(to))、延迟整流钾电流(I_K)、内向整流钾电流(I_(Kl))、三磷酸腺苷敏感性钾电流(I_(KATP))的影响，以探讨其抗心律失常作用的细胞电生理机制。
方法：使用酶解法分离单个兔心室肌细胞。采用全细胞膜片钳技术，在电压钳模式下记录不同浓度VE对I_(Na)、I_(Ca-L)、I_(to)、I_K、I_(Kl)、I_(KATP)的影响。在电流钳模式下观察跨膜动作电位的变化。
结果：① 30μg／L、60μg／L缬草提取物(VE)可使动作电位时程(APD)明显缩短，APD_(50)和APD_(90)分别由给药前的(352±27)ms和(416±33)ms缩短至(257±24)ms、(168±20)ms和(316±31)ms、(265±23)ms，分别缩短了27.0％、52.2％和24.0％、35.6％(n=16，p＜0.05)，而动作电位幅值无明显改变；② 30μg／L和60μg／L的VE使兔心室肌细胞I_(Na)峰值(I_(Namax))从(53.47+5.13)pA／pF分别降至(40.25+4.18)pA／pF和(30.89+2.95)pA／pF(n=8，p＜0.05和p＜0.01)，抑制率分别为24.7％和41.9％；VE使I_(Na)的电流-电压曲线上移，但不改变其激活电位、电位峰值和反转电位；VE还减慢钠通道灭活后的恢复过程；③ 30μg／L和60μg／L的缬草提取物(VE)使兔心室肌细胞I_(Ca-L)峰值(I_(Ca-Lmax))由(6.04±0.59)pA／pF分别减至(3.99+0.31)pA／pF和(2.31+0.24)pA／pF，抑制率分别为33.9％和57.1％(n=8，p＜0.01)；VE使I_(Ca-L)的电流-电压曲线上移，但不改变其激活电位、电位峰值和反转电位；VE还使钙电流失活曲线左移；④ 在刺激电压+60mV时，60μg／L和120μg／L的缬草提取物(VE)使瞬时外向钾电流(I_(to))幅值从(4.6±0.42)pA／pF分别降至(2.8±0.23)pA／pF和(1.7±0.14)pA／pF(n=7，p均＜0.01)，抑制率分别为39.1％和63.0％；⑤ 缬草提取物(VE)对延迟整流钾电流(I_K)、内向整流钾电流(I_(Kl))的电流幅值和电流-电压曲线的影响不明显(n=7，p＞0.05)；⑥ 不同浓度VE均不能引出三磷酸腺苷敏感性钾电流(I_(KATP))。
结论：缬草提取物(VE)能明显缩短动作电位时程(APD)；缬草提取物(VE)浓度依赖性抑制I_(Na)、I_(Ca-L)、I_(to)；缬草提取物(VE)对I_K、I_(Kl)、I_(KATP)无明显影响，对I_(KATP)无直接开放作用。VE对抗心律失常作用可能与其对上述离子通道的影响有关。
Objective: To investigate the effects of valerian extract (VE) on action potential duration(APD), sodium current(INa), L-calcium current (Ica-L),transient outward potassium current(Ito), delayed rectifier potrssium current(IK) inward rectifier potassium current(IKl) and adenosine triphosphate-sensitive potassium current (Ikatp) in isolated rabbit ventricular myocytes.
Methods: Single rabbit's ventricular myocytes were isolated with enzyme. The whole-cell patch clamp recording technique was used to observe the changes of action potential duration(APD) , sodium current(INa), L-calcium current (ICa-L),transient outward potassium current(Ito), delayed rectifier potassium current(IK), inward rectifier potassium current(IK1) and adenosine triphosphate-sensitive potassium current (Ikatp) under different concentration of VE.
Results: (1)30 ug/L VE, 60 u g/L VE could shortened APD50 and APD90 from (352 ±27)ms to (257±24) ms, (168±20)ms, and (416±33)ms to (316±31)ms, (265 ± 23)ms(27.0%, 52.2%; 24.0%,35.6%, n=16, p<0.05) respectively, but had no significant effect on action potential amplitude.(2)VE at 30,60 u g/L decreased peak INa (INamax) from (53.47±5.13)pA/pF to(40.25±4.18)pA/pF and (30.89±2.95)pA/pF (24.7%,41.9%, n=8, p<0.05 and p<0.01), respectively.VE upshifted the INa I-V curves of without changes of their active, peak and reverse potentials; VE at 60 u g/L turned the steady-state inactication curve to right.(3)VE at 30,60 u g/L decreased peak ICa-L (Ica-Lmax) from (6.04±0.59)pA/pF to(3.99±0.31)pA/pF and(2.31±0.24)pA/pF (33.9%,57.1%, n=8, p<0.01), respectively.VE upshifted the I-V curves of Ica-L without changes of their active, peak and reverse potentials; (4)At 60mV, VE at 60 u g/L and 120 u g/L decreased Ito current amplitude from( 4.6±0.42) pA/pF to (2.8±0.23) pA/pF and (1.7±0.14) pA/pF(n=7, p<0.01,respectively);(5)VE
did not inhibit Ik, Ik1 with no change on reversal-potential(n=7,p>0.05).(6) VE did not induce Ikatp directly.
Conclusion: VE shortened APD in dose-dependent ;VE blocks INa in a concentration dependent manner and probably inhibits Ina in its inactive state ; VE blocks Ica-L manner and probably inhibits Ica-L in its inactive state ; VE inhibited Ito in a concentration dependent ;these could be the important mechanisms of its antiarrhythmic and its cardioprotective effects.
方法：使用酶解法分离单个兔心室肌细胞。采用全细胞膜片钳技术，在电压钳模式下记录不同浓度VE对I_(Na)、I_(Ca-L)、I_(to)、I_K、I_(Kl)、I_(KATP)的影响。在电流钳模式下观察跨膜动作电位的变化。
结果：① 30μg／L、60μg／L缬草提取物(VE)可使动作电位时程(APD)明显缩短，APD_(50)和APD_(90)分别由给药前的(352±27)ms和(416±33)ms缩短至(257±24)ms、(168±20)ms和(316±31)ms、(265±23)ms，分别缩短了27.0％、52.2％和24.0％、35.6％(n=16，p＜0.05)，而动作电位幅值无明显改变；② 30μg／L和60μg／L的VE使兔心室肌细胞I_(Na)峰值(I_(Namax))从(53.47+5.13)pA／pF分别降至(40.25+4.18)pA／pF和(30.89+2.95)pA／pF(n=8，p＜0.05和p＜0.01)，抑制率分别为24.7％和41.9％；VE使I_(Na)的电流-电压曲线上移，但不改变其激活电位、电位峰值和反转电位；VE还减慢钠通道灭活后的恢复过程；③ 30μg／L和60μg／L的缬草提取物(VE)使兔心室肌细胞I_(Ca-L)峰值(I_(Ca-Lmax))由(6.04±0.59)pA／pF分别减至(3.99+0.31)pA／pF和(2.31+0.24)pA／pF，抑制率分别为33.9％和57.1％(n=8，p＜0.01)；VE使I_(Ca-L)的电流-电压曲线上移，但不改变其激活电位、电位峰值和反转电位；VE还使钙电流失活曲线左移；④ 在刺激电压+60mV时，60μg／L和120μg／L的缬草提取物(VE)使瞬时外向钾电流(I_(to))幅值从(4.6±0.42)pA／pF分别降至(2.8±0.23)pA／pF和(1.7±0.14)pA／pF(n=7，p均＜0.01)，抑制率分别为39.1％和63.0％；⑤ 缬草提取物(VE)对延迟整流钾电流(I_K)、内向整流钾电流(I_(Kl))的电流幅值和电流-电压曲线的影响不明显(n=7，p＞0.05)；⑥ 不同浓度VE均不能引出三磷酸腺苷敏感性钾电流(I_(KATP))。
结论：缬草提取物(VE)能明显缩短动作电位时程(APD)；缬草提取物(VE)浓度依赖性抑制I_(Na)、I_(Ca-L)、I_(to)；缬草提取物(VE)对I_K、I_(Kl)、I_(KATP)无明显影响，对I_(KATP)无直接开放作用。VE对抗心律失常作用可能与其对上述离子通道的影响有关。
Objective: To investigate the effects of valerian extract (VE) on action potential duration(APD), sodium current(INa), L-calcium current (Ica-L),transient outward potassium current(Ito), delayed rectifier potrssium current(IK) inward rectifier potassium current(IKl) and adenosine triphosphate-sensitive potassium current (Ikatp) in isolated rabbit ventricular myocytes.
Methods: Single rabbit's ventricular myocytes were isolated with enzyme. The whole-cell patch clamp recording technique was used to observe the changes of action potential duration(APD) , sodium current(INa), L-calcium current (ICa-L),transient outward potassium current(Ito), delayed rectifier potassium current(IK), inward rectifier potassium current(IK1) and adenosine triphosphate-sensitive potassium current (Ikatp) under different concentration of VE.
Results: (1)30 ug/L VE, 60 u g/L VE could shortened APD50 and APD90 from (352 ±27)ms to (257±24) ms, (168±20)ms, and (416±33)ms to (316±31)ms, (265 ± 23)ms(27.0%, 52.2%; 24.0%,35.6%, n=16, p<0.05) respectively, but had no significant effect on action potential amplitude.(2)VE at 30,60 u g/L decreased peak INa (INamax) from (53.47±5.13)pA/pF to(40.25±4.18)pA/pF and (30.89±2.95)pA/pF (24.7%,41.9%, n=8, p<0.05 and p<0.01), respectively.VE upshifted the INa I-V curves of without changes of their active, peak and reverse potentials; VE at 60 u g/L turned the steady-state inactication curve to right.(3)VE at 30,60 u g/L decreased peak ICa-L (Ica-Lmax) from (6.04±0.59)pA/pF to(3.99±0.31)pA/pF and(2.31±0.24)pA/pF (33.9%,57.1%, n=8, p<0.01), respectively.VE upshifted the I-V curves of Ica-L without changes of their active, peak and reverse potentials; (4)At 60mV, VE at 60 u g/L and 120 u g/L decreased Ito current amplitude from( 4.6±0.42) pA/pF to (2.8±0.23) pA/pF and (1.7±0.14) pA/pF(n=7, p<0.01,respectively);(5)VE
did not inhibit Ik, Ik1 with no change on reversal-potential(n=7,p>0.05).(6) VE did not induce Ikatp directly.
Conclusion: VE shortened APD in dose-dependent ;VE blocks INa in a concentration dependent manner and probably inhibits Ina in its inactive state ; VE blocks Ica-L manner and probably inhibits Ica-L in its inactive state ; VE inhibited Ito in a concentration dependent ;these could be the important mechanisms of its antiarrhythmic and its cardioprotective effects.
引文
1．江苏新医学院编．中药大词典．上册．上海：上海科技出版社，1986．566-567．
2．肖培根，刘昌孝．国外药用植物的研究、生产和需求概况．中草药，1983，14(6)：40-44．
3. Hendriks H, Bos R. Pharmacological screening of valerenal and some other components of essential oil valeriana officinalis. Planta Med, 1981,42(1):62-68.
4. Wagner H, Jurcic K. On the spasmolytic activity of the valeriana extracts. Planta Med, 1979,37(1):84-95.
5．张宝恒，齐治，沈莉纳．几种缬草分离物对小白鼠心肌摄取~(86)Rb的影响．中草药，1983，2：25-27．
6．张宝恒，孟和平，王彤等．缬草乙醇提取物(VES)对心血管的作用．药学学报，1982，17(5)：382-384．
7．薛存宽，蒋彦章，杨晶，等．神农缬草挥发油对动物心血管系统的作用．中西医结合杂志，1988，理论研究特集：8-12．
8．尹虹，薛存宽，叶建明等．缬草提取物抗心肌缺血再灌注损伤的实验研究．微循还学杂志，2000，10(1)：12-14．
9．杨桂兰，王玮．宽叶缬草治疗冠心病的临床研究．中国中西医结合杂志，1994，14(9)：540-542．
10. Cionga E. Colum chromatography of the roots and rhizomes of valerian has fumished crude fractions with interesting pharmacol activities. Pharmazie, 1961,16:43-48.
11．任世兰，余龙顺，裴宁．宽叶缬草对平滑肌和心血管的药理作用．中草药，1982，13(3)：23-25．
12．山西中药研究所资料室．抗心律失常的中草药—缬草(甘松)．新中医，1979，1：46-49．
13．马传庚，项思远，岑德意等．甘松乙醇提出液的抗心律失常的实验研究．安医学报，1980，15(4)：9-12．
14．钟达锦，林斌，陈素娟等．复方甘松汤治疗心律失常55例临床疗效观察与实验研究的初步报告．浙江医学，4(1)：49-51
15．王玉良，徐森根，范世藩．缬草抗心律失常的心肌细胞电生理学观察．中华心血管病杂志，1979，7(4)：275-282．
16．袁韶华，张宝恒，吴凤简．缬草提取物(V_(3d))抗心律失常的实验研究．中药药理与临床，1989，5(6)：15-18．
17．贾健宁，张宝恒．缬草提取物(V_(3d))对心血管系统的作用．广西中医学院学报，1999，16(1)：40-42．
18. Mitra R and Morad M. A uniform enzymatic method for dissociation of myocytes from hearts and stomachs of vertebrates. Am J Physiol,1985,249:H1056-H1060.
19. Tytgat J. How to isolate cardiac myocytes. Cardiovasc Res, 1994,28:280-283.
20. Hamill OP, Marty A, Neher E, et al. Improved patch clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch,1981,391:85-100.
21. Sakakibara Y, Wasserstrom JA, Furukawa T, et al. Characterization of the sodium current in single human atrial myocytes. Circ Res,1992,71: 535-546.
22. The Cardiac Arrhythmia Suppression Trial (CAST) Investigations: Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med, 1989,321: 406-412.
23. Maltsev VA, Sabbah HN, Higgins RSD, et al. Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes. Circulation, 1998, 98:2545-2552.
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2．肖培根，刘昌孝．国外药用植物的研究、生产和需求概况．中草药，1983，14(6)：40-44．
3. Hendriks H, Bos R. Pharmacological screening of valerenal and some other components of essential oil valeriana officinalis. Planta Med, 1981,42(1):62-68.
4. Wagner H, Jurcic K. On the spasmolytic activity of the valeriana extracts. Planta Med, 1979,37(1):84-95.
5．张宝恒，齐治，沈莉纳．几种缬草分离物对小白鼠心肌摄取~(86)Rb的影响．中草药，1983，2：25-27．
6．张宝恒，孟和平，王彤等．缬草乙醇提取物(VES)对心血管的作用．药学学报，1982，17(5)：382-384．
7．薛存宽，蒋彦章，杨晶，等．神农缬草挥发油对动物心血管系统的作用．中西医结合杂志，1988，理论研究特集：8-12．
8．尹虹，薛存宽，叶建明等．缬草提取物抗心肌缺血再灌注损伤的实验研究．微循还学杂志，2000，10(1)：12-14．
9．杨桂兰，王玮．宽叶缬草治疗冠心病的临床研究．中国中西医结合杂志，1994，14(9)：540-542．
10. Cionga E. Colum chromatography of the roots and rhizomes of valerian has fumished crude fractions with interesting pharmacol activities. Pharmazie, 1961,16:43-48.
11．任世兰，余龙顺，裴宁．宽叶缬草对平滑肌和心血管的药理作用．中草药，1982，13(3)：23-25．
12．山西中药研究所资料室．抗心律失常的中草药—缬草(甘松)．新中医，1979，1：46-49．
13．马传庚，项思远，岑德意等．甘松乙醇提出液的抗心律失常的实验研究．安医学报，1980，15(4)：9-12．
14．钟达锦，林斌，陈素娟等．复方甘松汤治疗心律失常55例临床疗效观察与实验研究的初步报告．浙江医学，4(1)：49-51
15．王玉良，徐森根，范世藩．缬草抗心律失常的心肌细胞电生理学观察．中华心血管病杂志，1979，7(4)：275-282．
16．袁韶华，张宝恒，吴凤简．缬草提取物(V_(3d))抗心律失常的实验研究．中药药理与临床，1989，5(6)：15-18．
17．贾健宁，张宝恒．缬草提取物(V_(3d))对心血管系统的作用．广西中医学院学报，1999，16(1)：40-42．
18. Mitra R and Morad M. A uniform enzymatic method for dissociation of myocytes from hearts and stomachs of vertebrates. Am J Physiol,1985,249:H1056-H1060.
19. Tytgat J. How to isolate cardiac myocytes. Cardiovasc Res, 1994,28:280-283.
20. Hamill OP, Marty A, Neher E, et al. Improved patch clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch,1981,391:85-100.
21. Sakakibara Y, Wasserstrom JA, Furukawa T, et al. Characterization of the sodium current in single human atrial myocytes. Circ Res,1992,71: 535-546.
22. The Cardiac Arrhythmia Suppression Trial (CAST) Investigations: Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med, 1989,321: 406-412.
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