牛磺酸镁抗哇巴因诱发心肌细胞心律失常的电生理学研究
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摘要
目的：研究牛磺酸镁配合物(taurine magnesium coordination compound, TMCC)对正常心室肌细胞及哇巴因所致大鼠心室细胞心律失常模型的钠电流(INa)和钙电流(ICa,L)的影响,探讨其抗心律失常的作用机制。
方法：酶解法急性分离大鼠单个心室肌细胞,以5μmol·L-1哇巴因诱发细胞水平心律失常,采用全细胞膜片钳技术,在电压钳模式下记录不同浓度的牛磺酸镁、胺碘酮对正常心室肌细胞及哇巴因所致大鼠心室细胞心律失常模型的INa和Ica,L的影响。
结果：
1、TMCC (100,200,400μmol·L-1)使大鼠心室肌细胞INa电流密度由给药前的(45.56±1.96)pA/pF分别减少到(42.42±4.75) pA/pF,(39.71±1.63)pA/pF, (37.59±4.75) pA/pF (n=5,p<0.01),抑制呈浓度依赖性。24.24μmol·L-1胺碘酮则使电流密度减小到(34.23±1.33) pA/pF (n=5, P<0.01)。TMCC和胺碘酮均使INa的电流-电压曲线上移,但不改变其激活电位、峰值电位和反转电位。TMCC和胺碘酮均使INa激活曲线右移,使激活减慢。TMCC及胺碘酮对INa失活曲线的影响是使之右移,失活减慢。
2、5μmol·L-1哇巴因使大鼠心室肌细胞钠电流密度从(45.56±1.96)pA/pF下降至(34.74±1.61)pA/pF(n=5,P<0.01),使INa的电流-电压曲线上移。TMCC (100, 200,400μmol·L-1)作用后使电流密度分别恢复为(39.57.42±1.96) pA/pF, (36.61±2.47) pA/pF, (32.95±1.18) pA/pF(n=5,P<0.01)。24.24μmol·L-1胺碘酮则使其变为(28.47±1.65) pA/pF (n=5,P<0.01)。TMCC (100,200μmol·L-1)可对抗哇巴因引起的INa的电流-电压曲线上移,TMCC (400μmol·L-1)和胺碘酮作用后均使上移的电流-电压曲线进一步上移。5μmol·L-1哇巴因使钠通道激活曲线失活曲线都右移,激活减慢快,失活也减慢。TMCC及胺碘酮作用后则使其右移。
3、TMCC (100,200,400μmol·L-1)使大鼠心室肌细胞ICa，L电流密度由给药前的(4.31±1.62) pA/pF改变为(4.02±0.75) pA/pF、(4.59±0.30) pA/pF、(5.17±0.20) pA/pF,其中400μmol·L-1显著升高钙电流(n=5,<0.01)。胺碘酮作用后的电流密度减小为(2.84±0.19)pA/pF(n=5,P<0.01).400μmol·L-1 TMCC使ICa,L的I-V曲线下移,100,200μmol·L-1 TMCC对I-V曲线影响不明显,胺碘酮则使I-V曲线上移。TMCC使钙通道激活曲线左移,激活加快；胺碘酮使曲线右移,激活减慢。TMCC使钙通道失活曲线右移,失活减慢；胺碘酮使曲线左移,失活加快。
4、哇巴因大鼠心室肌细胞钙电流密度从(4.31±1.62) pA/pF下降到(2.89±0.52) pA/pF (n=5, P<0.01),使ICa,L的电流-电压曲线上移。TMCC (100, 200,400μmol·L-1)作用后使电流密度分别恢复为(2.86±0.65)pA/pF, (3.87±0.57) pA/pF, (4.48±0.91)pA/pF。24.24μmol·L-1胺碘酮则使其变为(2.55±0.49) pA/pF (n=5,P<0.01)。TMCC使电流-电压曲线下移,胺碘酮使电流-电压曲线上移。5μmol·L-1哇巴因使激活曲线右移,失活曲线左移。TMCC和胺碘酮使激活、失活曲线恢复正常。
结论：
1、100,200,400μmol·L-1TMCC呈浓度依赖性抑制大鼠正常心肌细胞INa,在-45 mV除极电压时,与正常INa相比分别下降6.89%,12.84%(n=5,p<0.01),17.49%(n=5,p<0.01),使钠通道的激活延迟,使钠通道失活提前；可增强哇巴因引起的INa抑制作用,但影响较小。
2、TMCC对大鼠正常心肌细胞ICa,L呈双向作用,100μmol·L-1TMCC可抑制ICa,L, 400μmol·L-1TMCC可增强ICa,L; 100μmol·L-1TMCC可增强哇巴因引起的浓度抑制(1.03%,p>0.05),200,400μmol·L-1TMCC可对抗哇巴因引起ICa,L抑制,使其电流峰值分别增加33.91%和55.17%(p均小于0.01),浓度依赖性使钙通道激活提前,失活延迟。
3、TMCC通过对INa和Ica,L的作用而发挥抗心律失常作用。
4、与胺碘酮相比,TMCC对大鼠正常心肌细胞的IN。的抑制作用较温和,而且不会在钠通道处于抑制状态时加重这些通道的抑制；TMCC对钙的作用则表现为双向作用,TMCC可能是一种致心律失常作用弱于胺碘酮的化合物。
Objectives:To investigate the antiarrhythmic mechanism of TMCC,we observed the effect of TMCC on sodium current (INa) and L-type calcium current (ICa,L) in rat ventricular cardiomyocytes of arrhythmia induced by oubaine.
Methods:Enzymatic dissociation was used to get single rat ventricular myocytes and whole-cell patch clamp was used to record INa and ICa,L in normal and arrhythmic ventricular cardiomyocytes induced by oubaine in rat exposed to amiodarone and different concentration of TMCC.
Results:
1. In normal ventricular cardiomyocytes of rat, TMCC (100,200,400μmol·L-1) decreased INa densities from (45.56±1.96) pA/pF to (42.42±4.75) pA/pF, (39.71±1.63) pA/pF, (37.59±4.75) pA/pF (n=5, p<0.01), respectively. The inhibition was in a concentration-dependent manner.24.24μmol·L-1 amiodarone decreased INa densities to (34.23±1.33) pA/pF (n=5,P<0.01). The INa I-V curve was shifted upwards by TMCC and amiodarone without changes of their active, peak and reverse potentials. TMCC and amiodarone turned INa steady-state activation and inactivation curves to right, which made activate and inactivate slowly.
2. In arrhythmic ventricular cardiomyocytes of rat induced by 5μmol·L-1 oubaine the INa density decreased from (45.56±1.96)pA/pF to(34.74±1.61) pA/pF(n=5, P<0.01), which was restored to (39.57.42±1.96) pA/pF, (36.61±2.47) pA/pF, (32.95±1.18) pA/pF(n=5,P<0.01) by TMCC (100,200,400μmol·L-1). The the INa density decreased to (28.47±1.65) pA/pF (n=5, P<0.01) by 24.24μmol·L-1 amiodarone. The I-V curve upward shift induced by 5μmol·L-1oubaine was inhibited by TMCC(100,200μmol·L-1) while TMCC(400μmol·L-1)and amiodarone made this shift further. INa steady-state activation and inactivation curve was shifted to the right by 5μmol·L-1 oubaine.
3. In normal ventricular cardiomyocytes of rat, TMCC (100,200,400μmol·L-1) changed ICa,L densities from (-4.31±1.62)pA/pF to (4.02±0.75)pA/pF, (4.59±0.30) pA/pF, (5.17±0.20) pA/pF, respectively.400μmol·L-1TMCC increased ICa,L densities significantly (n=5, P<0.01).Amiodarone decreased ICa,L densities to (2.84±0.19) pA/pF (n=5, P<0.01). The ICa,L I-V curve was shifted downwards by 400μmol·L-1TMCC, while upwards by amiodarone.TMCC turned the ICa,L steady-state activation curve to left, while turned inactivation curve to right. Amiodarone turned the Ica,L steady-state activation curve to right, while turned inactivation curve to left..
4. In arrhythmic ventricular cardiomyocytes induced by 5μmol·L-1 oubaine the current density decreased from (4.31±1.62) pA/pF to (2.89±0.52) pA/pF, TMCC (100, 200,400μmol·L-1) could inhibit the action of oubaine and made the I-V curve upper shift in a concentration-dependent manner. The ICa,L densities was restored to (2.86±0.65) pA/pF, (3.87±0.57) pA/pF, (4.48±0.91) pA/pF(n=5,P<0.01), respectively.24.24μmol·L-1 amidodarone restored ICa,L densities to (2.55±0.49) pA/pF (n=5, P<0.01).5μmol·L-1 oubaine turned ICa,L steady-state activation curve to right, while inactivation curve to left. TMCC and amiodarone can make them normal.
Conclusion:
1. TMCC inhibits INa in a concentration-dependent manner in normal cardiomyocytes, meanwhile, TMCC can restore INa to normal in ventricular cardiomyocytes.
2. TMCC of lower concentration inhibits ICa,L which TMCC of high concen-tration inhances ICa,L in a biphasic manner in normal myocardiocytes.TMCC restores ICa,L in ventricular myocardiocytes.
3. The affection on INa and ICa,L may attribute to the antiarrhythmic effect of TMCC.
4. Compared with amiodarone, TMCC is less likely to cause arrhymias.
方法：酶解法急性分离大鼠单个心室肌细胞,以5μmol·L-1哇巴因诱发细胞水平心律失常,采用全细胞膜片钳技术,在电压钳模式下记录不同浓度的牛磺酸镁、胺碘酮对正常心室肌细胞及哇巴因所致大鼠心室细胞心律失常模型的INa和Ica,L的影响。
结果：
1、TMCC (100,200,400μmol·L-1)使大鼠心室肌细胞INa电流密度由给药前的(45.56±1.96)pA/pF分别减少到(42.42±4.75) pA/pF,(39.71±1.63)pA/pF, (37.59±4.75) pA/pF (n=5,p<0.01),抑制呈浓度依赖性。24.24μmol·L-1胺碘酮则使电流密度减小到(34.23±1.33) pA/pF (n=5, P<0.01)。TMCC和胺碘酮均使INa的电流-电压曲线上移,但不改变其激活电位、峰值电位和反转电位。TMCC和胺碘酮均使INa激活曲线右移,使激活减慢。TMCC及胺碘酮对INa失活曲线的影响是使之右移,失活减慢。
2、5μmol·L-1哇巴因使大鼠心室肌细胞钠电流密度从(45.56±1.96)pA/pF下降至(34.74±1.61)pA/pF(n=5,P<0.01),使INa的电流-电压曲线上移。TMCC (100, 200,400μmol·L-1)作用后使电流密度分别恢复为(39.57.42±1.96) pA/pF, (36.61±2.47) pA/pF, (32.95±1.18) pA/pF(n=5,P<0.01)。24.24μmol·L-1胺碘酮则使其变为(28.47±1.65) pA/pF (n=5,P<0.01)。TMCC (100,200μmol·L-1)可对抗哇巴因引起的INa的电流-电压曲线上移,TMCC (400μmol·L-1)和胺碘酮作用后均使上移的电流-电压曲线进一步上移。5μmol·L-1哇巴因使钠通道激活曲线失活曲线都右移,激活减慢快,失活也减慢。TMCC及胺碘酮作用后则使其右移。
3、TMCC (100,200,400μmol·L-1)使大鼠心室肌细胞ICa，L电流密度由给药前的(4.31±1.62) pA/pF改变为(4.02±0.75) pA/pF、(4.59±0.30) pA/pF、(5.17±0.20) pA/pF,其中400μmol·L-1显著升高钙电流(n=5,<0.01)。胺碘酮作用后的电流密度减小为(2.84±0.19)pA/pF(n=5,P<0.01).400μmol·L-1 TMCC使ICa,L的I-V曲线下移,100,200μmol·L-1 TMCC对I-V曲线影响不明显,胺碘酮则使I-V曲线上移。TMCC使钙通道激活曲线左移,激活加快；胺碘酮使曲线右移,激活减慢。TMCC使钙通道失活曲线右移,失活减慢；胺碘酮使曲线左移,失活加快。
4、哇巴因大鼠心室肌细胞钙电流密度从(4.31±1.62) pA/pF下降到(2.89±0.52) pA/pF (n=5, P<0.01),使ICa,L的电流-电压曲线上移。TMCC (100, 200,400μmol·L-1)作用后使电流密度分别恢复为(2.86±0.65)pA/pF, (3.87±0.57) pA/pF, (4.48±0.91)pA/pF。24.24μmol·L-1胺碘酮则使其变为(2.55±0.49) pA/pF (n=5,P<0.01)。TMCC使电流-电压曲线下移,胺碘酮使电流-电压曲线上移。5μmol·L-1哇巴因使激活曲线右移,失活曲线左移。TMCC和胺碘酮使激活、失活曲线恢复正常。
结论：
1、100,200,400μmol·L-1TMCC呈浓度依赖性抑制大鼠正常心肌细胞INa,在-45 mV除极电压时,与正常INa相比分别下降6.89%,12.84%(n=5,p<0.01),17.49%(n=5,p<0.01),使钠通道的激活延迟,使钠通道失活提前；可增强哇巴因引起的INa抑制作用,但影响较小。
2、TMCC对大鼠正常心肌细胞ICa,L呈双向作用,100μmol·L-1TMCC可抑制ICa,L, 400μmol·L-1TMCC可增强ICa,L; 100μmol·L-1TMCC可增强哇巴因引起的浓度抑制(1.03%,p>0.05),200,400μmol·L-1TMCC可对抗哇巴因引起ICa,L抑制,使其电流峰值分别增加33.91%和55.17%(p均小于0.01),浓度依赖性使钙通道激活提前,失活延迟。
3、TMCC通过对INa和Ica,L的作用而发挥抗心律失常作用。
4、与胺碘酮相比,TMCC对大鼠正常心肌细胞的IN。的抑制作用较温和,而且不会在钠通道处于抑制状态时加重这些通道的抑制；TMCC对钙的作用则表现为双向作用,TMCC可能是一种致心律失常作用弱于胺碘酮的化合物。
Objectives:To investigate the antiarrhythmic mechanism of TMCC,we observed the effect of TMCC on sodium current (INa) and L-type calcium current (ICa,L) in rat ventricular cardiomyocytes of arrhythmia induced by oubaine.
Methods:Enzymatic dissociation was used to get single rat ventricular myocytes and whole-cell patch clamp was used to record INa and ICa,L in normal and arrhythmic ventricular cardiomyocytes induced by oubaine in rat exposed to amiodarone and different concentration of TMCC.
Results:
1. In normal ventricular cardiomyocytes of rat, TMCC (100,200,400μmol·L-1) decreased INa densities from (45.56±1.96) pA/pF to (42.42±4.75) pA/pF, (39.71±1.63) pA/pF, (37.59±4.75) pA/pF (n=5, p<0.01), respectively. The inhibition was in a concentration-dependent manner.24.24μmol·L-1 amiodarone decreased INa densities to (34.23±1.33) pA/pF (n=5,P<0.01). The INa I-V curve was shifted upwards by TMCC and amiodarone without changes of their active, peak and reverse potentials. TMCC and amiodarone turned INa steady-state activation and inactivation curves to right, which made activate and inactivate slowly.
2. In arrhythmic ventricular cardiomyocytes of rat induced by 5μmol·L-1 oubaine the INa density decreased from (45.56±1.96)pA/pF to(34.74±1.61) pA/pF(n=5, P<0.01), which was restored to (39.57.42±1.96) pA/pF, (36.61±2.47) pA/pF, (32.95±1.18) pA/pF(n=5,P<0.01) by TMCC (100,200,400μmol·L-1). The the INa density decreased to (28.47±1.65) pA/pF (n=5, P<0.01) by 24.24μmol·L-1 amiodarone. The I-V curve upward shift induced by 5μmol·L-1oubaine was inhibited by TMCC(100,200μmol·L-1) while TMCC(400μmol·L-1)and amiodarone made this shift further. INa steady-state activation and inactivation curve was shifted to the right by 5μmol·L-1 oubaine.
3. In normal ventricular cardiomyocytes of rat, TMCC (100,200,400μmol·L-1) changed ICa,L densities from (-4.31±1.62)pA/pF to (4.02±0.75)pA/pF, (4.59±0.30) pA/pF, (5.17±0.20) pA/pF, respectively.400μmol·L-1TMCC increased ICa,L densities significantly (n=5, P<0.01).Amiodarone decreased ICa,L densities to (2.84±0.19) pA/pF (n=5, P<0.01). The ICa,L I-V curve was shifted downwards by 400μmol·L-1TMCC, while upwards by amiodarone.TMCC turned the ICa,L steady-state activation curve to left, while turned inactivation curve to right. Amiodarone turned the Ica,L steady-state activation curve to right, while turned inactivation curve to left..
4. In arrhythmic ventricular cardiomyocytes induced by 5μmol·L-1 oubaine the current density decreased from (4.31±1.62) pA/pF to (2.89±0.52) pA/pF, TMCC (100, 200,400μmol·L-1) could inhibit the action of oubaine and made the I-V curve upper shift in a concentration-dependent manner. The ICa,L densities was restored to (2.86±0.65) pA/pF, (3.87±0.57) pA/pF, (4.48±0.91) pA/pF(n=5,P<0.01), respectively.24.24μmol·L-1 amidodarone restored ICa,L densities to (2.55±0.49) pA/pF (n=5, P<0.01).5μmol·L-1 oubaine turned ICa,L steady-state activation curve to right, while inactivation curve to left. TMCC and amiodarone can make them normal.
Conclusion:
1. TMCC inhibits INa in a concentration-dependent manner in normal cardiomyocytes, meanwhile, TMCC can restore INa to normal in ventricular cardiomyocytes.
2. TMCC of lower concentration inhibits ICa,L which TMCC of high concen-tration inhances ICa,L in a biphasic manner in normal myocardiocytes.TMCC restores ICa,L in ventricular myocardiocytes.
3. The affection on INa and ICa,L may attribute to the antiarrhythmic effect of TMCC.
4. Compared with amiodarone, TMCC is less likely to cause arrhymias.
引文
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