以HERG基因表达模型为基础的药物在心脏复极方面的安全性评价
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摘要
药物致QT间期延长的副作用已成为威胁公众用药安全的重要问题,也是目前药物安全管理部门和药物公司广泛关注的药物心脏毒性问题。很多药物可以通过直接阻断心肌复极中的快速激活延迟整流钾通道电流(IKr),使得复极时程延长,导致QT间期延长,甚至发生尖端扭转性室性心动过速或心源性猝死；也可以通过干扰钾通道蛋白的表达,间接减少IKr,使得QT延长。药物对心脏复极的不良影响成为美国食品和药品管理局(FDA)终止药品上市的主要原因之一,并要求所有药物上市前必须进行这方面的评价。对IKr电流的测定成为判断药物是否能引起QT延长及是否易产生促心律失常作用的一个指标。因此,本研究拟从细胞离子通道、蛋白水平上建立一套临床前在体外评价药物对心脏复极影响的方法,并应用药物进行评估。据此,本研究设计了三个分实验。
第一部分：建立表达HERG基因的HEK293细胞模型,并培养出稳定转染的HERG-HEK293细胞株；
第二部分：用已知导致QT间期延长的药物西沙比利来测定该药对HERG通道电流的影响,进一步明确该通道的特性,并评价西沙比利对HERG通道蛋白的影响；
第三部分：评价我国的一类抗心律失常新药——盐酸关附甲素对HERG通道电流、通道动力学的影响,并对HERG基因F656C突变后的电流进行测定,明确药物与HERG通道结合位点；应用免疫蛋白印迹技术(Western blot)评价关附甲素对蛋白表达的影响。
第一部分：HERG-HEK293细胞表达模型的建立
目的：通过基因转染的方法把HERG基因转染进HEK293细胞,使之表达HERG通道钾电流及蛋白,达到建立HERG-HEK293细胞表达模型的目的。
方法：利用LipofectamineTM2000将pCDNA3.0-HERG和绿色荧光蛋白(GFP)瞬时转染进入HEK293细胞,利用膜片钳技术测定HERG-HEK293细胞上的HERG钾电流；应用G418对瞬时转染的阳性克隆细胞进行筛选,进而利用免疫蛋白印迹技术(Western blot)测定HERG-HEK293细胞的HERG蛋白的表达。
结果：LipofectamineTM2000介导的瞬时转染成功率在30-70%,该方法有效地将HERG基因转染进入HEK293细胞,并表达HERG介导HERG通道钾电流；G418可成功筛选HERG基因阳性的克隆细胞,使得瞬时转染的HERG-HEK293细胞达到稳定转染,并可用于Western blot的研究。
结论：荧光显微镜检查、膜片钳及Western blot研究证实该HERG-HEK293细胞表达模型的建立成功的。
第二部分：西沙比利对HERG基因表达的快速激活延迟整流钾通道电流及蛋白的影响
目的评价西沙比利对转染HERG基因表达的快速激活延迟整流钾电流(IKr)和蛋白的影响,探讨其致心律失常发生的机制。
方法使用脂质体介导的瞬时转染法把野生型HERG基因转染进人胚肾细胞(HEK293),采用全细胞膜片钳技术评价西沙比利对IKr通道电流和动力学的影响；使用G418筛选出稳定转染HERG的细胞,并用西沙比利进行干预,应用免疫蛋白印迹技术(Western blot)评价药物对蛋白的影响。
结果西沙比利对IKr通道的刺激电流(ⅠHERG)和尾电流(Itail)具有浓度和电压依赖性抑制作用,半数最大抑制浓度(IC50)分别14.5和3.9 nmol／L。西沙比利使ⅠHERG和Itail的最大峰值电位前移,但不改变激活电位；使激活曲线左移并加快通道的失活,但不改变通道失活后的恢复时间；西沙比利对HERG-HEK293细胞上的IKr通道蛋白无明显抑制。
结论西沙比利通过作用于通道的激活态及失活态抑制HERG钾电流,但不影响HERG通道蛋白的表达,从而使得心肌复极时程延长,导致心律失常发生。
第三部分：关附甲素对转染HERG基因表达的快速激活延迟整流钾通道电流和蛋白的影响[摘要]
目的评价关附甲素(GFA)对HERG基因表达的钾通道电流和蛋白的影响。
方法使用脂质体介导的瞬时转染法把野生型HERG基因转染入人胚肾细胞(HEK293),使之表达快速激活延迟整流钾电流(IKr),采用标准的全细胞膜片钳技术记录IKr通道电流,观察不同浓度的关附甲素对IKr的影响并进行通道动力学研究。采用定点突变技术使HERG基因产生F656C突变,并应用膜片钳进行药物对电流影响的测定。应用免疫蛋白印迹技术(Western blot)评价关附甲素对HERG钾通道蛋白的影响。
结果
1.关附甲素对IKr通道的峰电流IHERG具有浓度和电压依赖性抑制作用,半数最大抑制浓度(IC50)为465.95μmol／L；400μmol／L和1000μmol／L的关附甲素使IHERG的最大峰值电位前移,但不改变激活电位。25-400μmol／L的关附甲素对尾电流(Itail)抑制不明显,1、2.5和5mmol／L的关附甲素对抑制率分别为34.9%、58.0%和70.5%,IC50为1.64mmol／L。1mmol／L的关附甲素对Itail呈电压依赖性,并使得最大峰值电位前移,电流-电压曲线的形状产生变化,但对激活电位没有影响。关附甲素对HERG通道电流的抑制无时间依赖性。
2.关附甲素可以使得通道的激活曲线左移并能加快通道的失活过程,并且能在-60mV的电压上减慢通道失活后的恢复时间,而对去激活时间常数无明显影响。
3.关附甲素对F656C突变的HERG通道峰电流(ⅠHERG)和尾电流(Itail)具有抑制效应,但抑制程度比野生型HERG电流明显减弱,并使得激活曲线左移。
4.高浓度的关附甲素可抑制HERG钾通道蛋白的转运,且对F656C突变表达的HERG钾通道蛋白抑制更明显。
结论25～400μmol／L的关附甲素对IKr的抑制作用不明显,高浓度的关附甲素可以抑制]HERG电流,关附甲素主要是作用于HERG通道的失活态和激活态,并且主要是结合在HERG通道的S6区从而抑制钾电流。关附甲素不影响HERG蛋白的合成,但高浓度的关附甲素可抑制HERG蛋白的转运。
Drug-induced QT interval prolongation has become an important public health problem.And Drug Safety Authouities and Drug companies pay more and more attention to the drug cardiac toxicity. Many drugs induced QT interval prolongation by directly blocked the the rapidly activating delayed rectifier potassium current (ⅠKr).Besides, other drugs can inhibit potassium channel protein expression, which indirect reduceⅠKr.Indeed, many drugs have been withdrawn from the market by FDA because they lead to long QT syndrome and ventricular arrhythmias. Regulatory guidelines [CPMP/986/96 (1997) and ICH S7B (2005)] recommend conducting preclinical in vivo and in vitro studies to detect the QT-prolonging effects and arrhythmogenic potential of new drugs.
The investigation ofⅠKr has become an indicator for whether the drug can cause QT interval prolongation and proarrhythmia. The present study is to build up an in vitro method to detect the QT-prolonging effects base on ion channel currents and protein expression, and then evaluate drugs effects. The study is divided into three parts.
Part 1. To build up a HERG-HEK293 cell model by transfected of HERG gene into HEK293, and build up a stably transfected HERG-HEK 293 cells line.
Part 2. To evaluate the electrophysiogical effects of cisapride on the rapidly activating delayed rectifier potassium current (ⅠKr) encoded by the HERG gene with a whole-cell patch clamp technique, and study the effects of cisapride on the HERG protein trafficking by Western blot analysis.
Part 3. To investigate the effects of Guanfu base A (GFA) on the amplitude, concentration and voltage dependence, and the kinetics of HERG current. An HERG mutant at this position F656C, was also evaluated in this study. The HERG current was measured by the whole-cell patch clamp method. The effects of GFA on HERG protein trafficking were investigated by Western blot analysis.
Part 1. The transfection of HERG gene into HEK293 and the certification of HERG channel currents and protein
Objective:To set up the HERG-HEK293 cell line by transfected HERG gene into HEK293 cells, which can express the the rapidly activating delayed-rectifier K+ current (ⅠKr) and HERG protein.
Methods:The HEK293 cells were transient transfected by the pcDNA3.0-HERG gene and green fluorescin protein (GFP) using Lipofectamine 2000, and theⅠKr was measured by whole cell patch clamp techniques. Then screen by G418 to achieve stable transfection, and the HERG channel protein was detected by the Western blot analysis.
Results:Lipofectamine 2000 can transfected the pcDNA3.0-HERG gene inth HEK293 cells and the transient transfection efficiency was between 30-70%. Patch clamp study confirmed that HERG gene expressedⅠKr. G418 can be successfully screened HERG-HEK293 positive clone cells, making the cells stable expressed HERG protein and can be used for Western blot study Conclusions:Both the patch clamp study and Western blot analysis prove that this is an effective method for transfecting the HERG gene into HEK293 and expressing the HERG channel currents and protein.
Part 2. The effects of cisapride on the HERG K+ channel current and protein trafficking
Objective To evaluate the electrophysiogical effects of cisapride on the rapidly activating delayed rectifier potassium current (ⅠKr) encoded by the HERG gene with a whole-cell patch clamp technique, and study the effects of cisapride on the HERG protein trafficking by Western blot analysis.
Methods Wild-type HERG cDNA plasmids were transfected into human embryonic kidney (HEK293) cells by lipofectamine method. The whole-cell patch clamp method was used to record the IKr and kinesics of channel gating. Used G418 to build up a stably transfected HERG-HEK 293 cells line, and studied the effects of cisapride on the protein expression.
Results Cisapride produced a concentration-and voltage-dependent blockage of theⅠHERG andⅠtail with IC50 (50% inhibitory concentration) of 14.5 and 3.9 nmol/L, respectively. Cisapride degraded peak current potential ofⅠHERG andⅠtail without altered activation threshold potential. The activation curve was shifted in a negative direction and accelerated channel inactivation by cisapride, but the time constants of recovery from inactivation were not significant change. Cisapride did not present significant influence on the IKr channel protein trafficking.
Conclusion Cisapride blocked HERG K+ channel via inactivated and open state, not influenced on the protein trafficking, which was the mechanism of drug inducing proarrhythmia.
Part 3. The effect of the novel anti-arrhythmia Guanfu base A on HERG K+ channel current and protein
Objective To evaluate the electrophysiogical effects of Guanfu base A (GFA) on the rapid delayed rectifier potassium current (ⅠKr) encoded by the HERG gene using patch clamp whole cell recording techniques, and study the effects of acehytisine hydrochloride on the HERG protein trafficking.
Methods Wild-type HERG cDNA plasmids were transfected into human embryonic kidney(HEK293) cells by lipofectamine method. The whole cell patch clamp method was used to record theⅠKr. Using Site-directed mutagenesis techniques to make a F656C mutation of HERG gene, and then study the effects of Guanfu base A on theⅠKr by patch clamp. The Western blot analysis was used to study the effects of Guanfu base A on the protein expression.
Results
1. GFA produced a concentration-dependent and voltage-dependent blockade of theⅠHERG with an IC50 (50% inhibitory concentration) of 465.95μmol/L. GFA (400 and 1000μmol/L) degraded peak current potential ofⅠHERG without altered activation threshold potential. GFA (25、100、400μmol/L) presented no significant inhibition effects ong theⅠtail, wheres, GFA at concentration of 1,2.5 and 5mmol/L inhibitedⅠtaii by 34.9%,58% and 70.5%, respectively. The IC50 forⅠtail was 1.64mmol/L. GFA (lmmol/L) produced voltage-dependent blockage of theⅠtail, degraded degraded peak current potential ofⅠtail without altered activation threshold potential. GFA showed no time-dependent blockade of HERG currents.
2. The activation curve was shifted in a negative direction and accelerated channel inactivation by GFA. Moreover, GFA slowed channel recovery from inactivation at above-60mV without no significant effects on the deactivation time constants.
3. GFA produced a concentration-dependent blockage of the F656C mutation HERG currents, including theⅠHERG andⅠtail.The activation curve was shifted in a negative direction by GFA. However, the F656C mutation in the S6 domain attenuated acehytisine hydrochloride inhibition of HERG current.
4. High concentration of GFA inhibited HERG K+channel protein trafficking, and F656C mutation enhanced the inhibition of protein trafficking.
Conclusion 25-400μmol/L GFA had little inhibitory effects onⅠKr current. High concentration of GFA blocked the HERG currents. GFA blocked HERG channel via inactivated and activated states. GFA inhibited HERG K+ channel current via S6 domain. In addtition, acehytisine hydrochloride didn't inhibit protein synthesis, but could inhibit protein trafficking at high concentration.
第一部分：建立表达HERG基因的HEK293细胞模型,并培养出稳定转染的HERG-HEK293细胞株；
第二部分：用已知导致QT间期延长的药物西沙比利来测定该药对HERG通道电流的影响,进一步明确该通道的特性,并评价西沙比利对HERG通道蛋白的影响；
第三部分：评价我国的一类抗心律失常新药——盐酸关附甲素对HERG通道电流、通道动力学的影响,并对HERG基因F656C突变后的电流进行测定,明确药物与HERG通道结合位点；应用免疫蛋白印迹技术(Western blot)评价关附甲素对蛋白表达的影响。
第一部分：HERG-HEK293细胞表达模型的建立
目的：通过基因转染的方法把HERG基因转染进HEK293细胞,使之表达HERG通道钾电流及蛋白,达到建立HERG-HEK293细胞表达模型的目的。
方法：利用LipofectamineTM2000将pCDNA3.0-HERG和绿色荧光蛋白(GFP)瞬时转染进入HEK293细胞,利用膜片钳技术测定HERG-HEK293细胞上的HERG钾电流；应用G418对瞬时转染的阳性克隆细胞进行筛选,进而利用免疫蛋白印迹技术(Western blot)测定HERG-HEK293细胞的HERG蛋白的表达。
结果：LipofectamineTM2000介导的瞬时转染成功率在30-70%,该方法有效地将HERG基因转染进入HEK293细胞,并表达HERG介导HERG通道钾电流；G418可成功筛选HERG基因阳性的克隆细胞,使得瞬时转染的HERG-HEK293细胞达到稳定转染,并可用于Western blot的研究。
结论：荧光显微镜检查、膜片钳及Western blot研究证实该HERG-HEK293细胞表达模型的建立成功的。
第二部分：西沙比利对HERG基因表达的快速激活延迟整流钾通道电流及蛋白的影响
目的评价西沙比利对转染HERG基因表达的快速激活延迟整流钾电流(IKr)和蛋白的影响,探讨其致心律失常发生的机制。
方法使用脂质体介导的瞬时转染法把野生型HERG基因转染进人胚肾细胞(HEK293),采用全细胞膜片钳技术评价西沙比利对IKr通道电流和动力学的影响；使用G418筛选出稳定转染HERG的细胞,并用西沙比利进行干预,应用免疫蛋白印迹技术(Western blot)评价药物对蛋白的影响。
结果西沙比利对IKr通道的刺激电流(ⅠHERG)和尾电流(Itail)具有浓度和电压依赖性抑制作用,半数最大抑制浓度(IC50)分别14.5和3.9 nmol／L。西沙比利使ⅠHERG和Itail的最大峰值电位前移,但不改变激活电位；使激活曲线左移并加快通道的失活,但不改变通道失活后的恢复时间；西沙比利对HERG-HEK293细胞上的IKr通道蛋白无明显抑制。
结论西沙比利通过作用于通道的激活态及失活态抑制HERG钾电流,但不影响HERG通道蛋白的表达,从而使得心肌复极时程延长,导致心律失常发生。
第三部分：关附甲素对转染HERG基因表达的快速激活延迟整流钾通道电流和蛋白的影响[摘要]
目的评价关附甲素(GFA)对HERG基因表达的钾通道电流和蛋白的影响。
方法使用脂质体介导的瞬时转染法把野生型HERG基因转染入人胚肾细胞(HEK293),使之表达快速激活延迟整流钾电流(IKr),采用标准的全细胞膜片钳技术记录IKr通道电流,观察不同浓度的关附甲素对IKr的影响并进行通道动力学研究。采用定点突变技术使HERG基因产生F656C突变,并应用膜片钳进行药物对电流影响的测定。应用免疫蛋白印迹技术(Western blot)评价关附甲素对HERG钾通道蛋白的影响。
结果
1.关附甲素对IKr通道的峰电流IHERG具有浓度和电压依赖性抑制作用,半数最大抑制浓度(IC50)为465.95μmol／L；400μmol／L和1000μmol／L的关附甲素使IHERG的最大峰值电位前移,但不改变激活电位。25-400μmol／L的关附甲素对尾电流(Itail)抑制不明显,1、2.5和5mmol／L的关附甲素对抑制率分别为34.9%、58.0%和70.5%,IC50为1.64mmol／L。1mmol／L的关附甲素对Itail呈电压依赖性,并使得最大峰值电位前移,电流-电压曲线的形状产生变化,但对激活电位没有影响。关附甲素对HERG通道电流的抑制无时间依赖性。
2.关附甲素可以使得通道的激活曲线左移并能加快通道的失活过程,并且能在-60mV的电压上减慢通道失活后的恢复时间,而对去激活时间常数无明显影响。
3.关附甲素对F656C突变的HERG通道峰电流(ⅠHERG)和尾电流(Itail)具有抑制效应,但抑制程度比野生型HERG电流明显减弱,并使得激活曲线左移。
4.高浓度的关附甲素可抑制HERG钾通道蛋白的转运,且对F656C突变表达的HERG钾通道蛋白抑制更明显。
结论25～400μmol／L的关附甲素对IKr的抑制作用不明显,高浓度的关附甲素可以抑制]HERG电流,关附甲素主要是作用于HERG通道的失活态和激活态,并且主要是结合在HERG通道的S6区从而抑制钾电流。关附甲素不影响HERG蛋白的合成,但高浓度的关附甲素可抑制HERG蛋白的转运。
Drug-induced QT interval prolongation has become an important public health problem.And Drug Safety Authouities and Drug companies pay more and more attention to the drug cardiac toxicity. Many drugs induced QT interval prolongation by directly blocked the the rapidly activating delayed rectifier potassium current (ⅠKr).Besides, other drugs can inhibit potassium channel protein expression, which indirect reduceⅠKr.Indeed, many drugs have been withdrawn from the market by FDA because they lead to long QT syndrome and ventricular arrhythmias. Regulatory guidelines [CPMP/986/96 (1997) and ICH S7B (2005)] recommend conducting preclinical in vivo and in vitro studies to detect the QT-prolonging effects and arrhythmogenic potential of new drugs.
The investigation ofⅠKr has become an indicator for whether the drug can cause QT interval prolongation and proarrhythmia. The present study is to build up an in vitro method to detect the QT-prolonging effects base on ion channel currents and protein expression, and then evaluate drugs effects. The study is divided into three parts.
Part 1. To build up a HERG-HEK293 cell model by transfected of HERG gene into HEK293, and build up a stably transfected HERG-HEK 293 cells line.
Part 2. To evaluate the electrophysiogical effects of cisapride on the rapidly activating delayed rectifier potassium current (ⅠKr) encoded by the HERG gene with a whole-cell patch clamp technique, and study the effects of cisapride on the HERG protein trafficking by Western blot analysis.
Part 3. To investigate the effects of Guanfu base A (GFA) on the amplitude, concentration and voltage dependence, and the kinetics of HERG current. An HERG mutant at this position F656C, was also evaluated in this study. The HERG current was measured by the whole-cell patch clamp method. The effects of GFA on HERG protein trafficking were investigated by Western blot analysis.
Part 1. The transfection of HERG gene into HEK293 and the certification of HERG channel currents and protein
Objective:To set up the HERG-HEK293 cell line by transfected HERG gene into HEK293 cells, which can express the the rapidly activating delayed-rectifier K+ current (ⅠKr) and HERG protein.
Methods:The HEK293 cells were transient transfected by the pcDNA3.0-HERG gene and green fluorescin protein (GFP) using Lipofectamine 2000, and theⅠKr was measured by whole cell patch clamp techniques. Then screen by G418 to achieve stable transfection, and the HERG channel protein was detected by the Western blot analysis.
Results:Lipofectamine 2000 can transfected the pcDNA3.0-HERG gene inth HEK293 cells and the transient transfection efficiency was between 30-70%. Patch clamp study confirmed that HERG gene expressedⅠKr. G418 can be successfully screened HERG-HEK293 positive clone cells, making the cells stable expressed HERG protein and can be used for Western blot study Conclusions:Both the patch clamp study and Western blot analysis prove that this is an effective method for transfecting the HERG gene into HEK293 and expressing the HERG channel currents and protein.
Part 2. The effects of cisapride on the HERG K+ channel current and protein trafficking
Objective To evaluate the electrophysiogical effects of cisapride on the rapidly activating delayed rectifier potassium current (ⅠKr) encoded by the HERG gene with a whole-cell patch clamp technique, and study the effects of cisapride on the HERG protein trafficking by Western blot analysis.
Methods Wild-type HERG cDNA plasmids were transfected into human embryonic kidney (HEK293) cells by lipofectamine method. The whole-cell patch clamp method was used to record the IKr and kinesics of channel gating. Used G418 to build up a stably transfected HERG-HEK 293 cells line, and studied the effects of cisapride on the protein expression.
Results Cisapride produced a concentration-and voltage-dependent blockage of theⅠHERG andⅠtail with IC50 (50% inhibitory concentration) of 14.5 and 3.9 nmol/L, respectively. Cisapride degraded peak current potential ofⅠHERG andⅠtail without altered activation threshold potential. The activation curve was shifted in a negative direction and accelerated channel inactivation by cisapride, but the time constants of recovery from inactivation were not significant change. Cisapride did not present significant influence on the IKr channel protein trafficking.
Conclusion Cisapride blocked HERG K+ channel via inactivated and open state, not influenced on the protein trafficking, which was the mechanism of drug inducing proarrhythmia.
Part 3. The effect of the novel anti-arrhythmia Guanfu base A on HERG K+ channel current and protein
Objective To evaluate the electrophysiogical effects of Guanfu base A (GFA) on the rapid delayed rectifier potassium current (ⅠKr) encoded by the HERG gene using patch clamp whole cell recording techniques, and study the effects of acehytisine hydrochloride on the HERG protein trafficking.
Methods Wild-type HERG cDNA plasmids were transfected into human embryonic kidney(HEK293) cells by lipofectamine method. The whole cell patch clamp method was used to record theⅠKr. Using Site-directed mutagenesis techniques to make a F656C mutation of HERG gene, and then study the effects of Guanfu base A on theⅠKr by patch clamp. The Western blot analysis was used to study the effects of Guanfu base A on the protein expression.
Results
1. GFA produced a concentration-dependent and voltage-dependent blockade of theⅠHERG with an IC50 (50% inhibitory concentration) of 465.95μmol/L. GFA (400 and 1000μmol/L) degraded peak current potential ofⅠHERG without altered activation threshold potential. GFA (25、100、400μmol/L) presented no significant inhibition effects ong theⅠtail, wheres, GFA at concentration of 1,2.5 and 5mmol/L inhibitedⅠtaii by 34.9%,58% and 70.5%, respectively. The IC50 forⅠtail was 1.64mmol/L. GFA (lmmol/L) produced voltage-dependent blockage of theⅠtail, degraded degraded peak current potential ofⅠtail without altered activation threshold potential. GFA showed no time-dependent blockade of HERG currents.
2. The activation curve was shifted in a negative direction and accelerated channel inactivation by GFA. Moreover, GFA slowed channel recovery from inactivation at above-60mV without no significant effects on the deactivation time constants.
3. GFA produced a concentration-dependent blockage of the F656C mutation HERG currents, including theⅠHERG andⅠtail.The activation curve was shifted in a negative direction by GFA. However, the F656C mutation in the S6 domain attenuated acehytisine hydrochloride inhibition of HERG current.
4. High concentration of GFA inhibited HERG K+channel protein trafficking, and F656C mutation enhanced the inhibition of protein trafficking.
Conclusion 25-400μmol/L GFA had little inhibitory effects onⅠKr current. High concentration of GFA blocked the HERG currents. GFA blocked HERG channel via inactivated and activated states. GFA inhibited HERG K+ channel current via S6 domain. In addtition, acehytisine hydrochloride didn't inhibit protein synthesis, but could inhibit protein trafficking at high concentration.
引文
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[1]Lee SY, Kim YJ, Kim KT, Choe H, Jo SH. Blockade of HERG human K+channels and IKr of guinea-pig cardiomyocytes by the antipsychotic drug clozapine. Br J Pharmacol.2006 Jun; 148(4): 499-509.
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[4]Rajamani S, Eckhardt LL, Valdivia CR, Klemens CA, Gillman BM, Anderson CL, et al. Drug-induced long QT syndrome:hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine. Br J Pharmacol.2006 Nov; 149(5):481-9.
[5]Takemasa H, Nagatomo T, Abe H, Kawakami K, Igarashi T, Tsurugi T, et al. Coexistence of hERG current block and disruption of protein trafficking in ketoconazole-induced long QT syndrome. Br J Pharmacol.2008 Feb; 153(3):439-47.
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[8]Zhou Z, Gong Q, Ye B, Fan Z, Makielski JC, Robertson GA, et al. Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophys J.1998 Jan; 74(1): 230-41.
[9]黄兴福,戴研,杨艳敏,等.盐酸关附甲素对转染HERG基因表达的快速激活延迟整流钾通道电流的影响[中华心律失常学杂志.2008；12(3)：169-74.
[10]Kiehn J, Lacerda AE, Wible B, Brown AM. Molecular physiology and pharmacology of HERG. Single-channel currents and block by dofetilide. Circulation.1996 Nov 15; 94(10):2572-9.
[11]Karle CA, Kreye VA, Thomas D, Rockl K, Kathofer S, Zhang W, et al. Antiarrhythmic drug carvedilol inhibits HERG potassium channels. Cardiovasc Res.2001 Feb 1; 49(2):361-70.
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[1]Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, et al. Prevention of torsade de pointes in hospital settings:a scientific statement from the American Heart Association and the American College of Cardiology Foundation. Circulation.2010 Mar 2; 121(8):1047-60.
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[3]Lee SY, Kim YJ, Kim KT, Choe H, Jo SH. Blockade of HERG human K+ channels and IKr of guinea-pig cardiomyocytes by the antipsychotic drug clozapine. Br J Pharmacol.2006 Jun; 148(4): 499-509.
[4]Huang X, Yang Y, Zhu J, Dai Y, Pu J. The effects of a novel anti-arrhythmic drug, acehytisine hydrochloride, on the human ether-a-go-go related gene K channel and its trafficking. Basic Clin Pharmacol Toxicol.2009 Feb; 104(2):145-54.
[5]van der Heyden MA, Smits ME, Vos MA. Drugs and trafficking of ion channels:a new pro-arrhythmic threat on the horizon? Br J Pharmacol.2008 Feb; 153(3):406-9.
[6]Hancox JC, McPate MJ, El Harchi A, Zhang YH. The hERG potassium channel and hERG screening for drug-induced torsades de pointes. Pharmacol Ther.2008 Aug; 119(2):118-32.
[7]Rajamani S, Eckhardt LL, Valdivia CR, Klemens CA, Gillman BM, Anderson CL, et al. Drug-induced long QT syndrome:hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine. Br J Pharmacol.2006 Nov; 149(5):481-9.
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[1]Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, et al. Prevention of torsade de pointes in hospital settings:a scientific statement from the American Heart Association and the American College of Cardiology Foundation. Circulation.2010 Mar 2; 121(8):1047-60.
[2]Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death:a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death):developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation.2006 Sep 5; 114(10):e385-484.
[3]Lee SY, Kim YJ, Kim KT, Choe H, Jo SH. Blockade of HERG human K+ channels and IKr of guinea-pig cardiomyocytes by the antipsychotic drug clozapine. Br J Pharmacol.2006 Jun; 148(4): 499-509.
[4]Huang X, Yang Y, Zhu J, Dai Y, Pu J. The effects of a novel anti-arrhythmic drug, acehytisine hydrochloride, on the human ether-a-go-go related gene K channel and its trafficking. Basic Clin Pharmacol Toxicol.2009 Feb; 104(2):145-54.
[5]van der Heyden MA, Smits ME, Vos MA. Drugs and trafficking of ion channels:a new pro-arrhythmic threat on the horizon? Br J Pharmacol.2008 Feb; 153(3):406-9.
[6]Hancox JC, McPate MJ, El Harchi A, Zhang YH. The hERG potassium channel and hERG screening for drug-induced torsades de pointes. Pharmacol Ther.2008 Aug; 119(2):118-32.
[7]Rajamani S, Eckhardt LL, Valdivia CR, Klemens CA, Gillman BM, Anderson CL, et al. Drug-induced long QT syndrome:hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine. Br J Pharmacol.2006 Nov; 149(5):481-9.
[8]Takemasa H, Nagatomo T, Abe H, Kawakami K, Igarashi T, Tsurugi T, et al. Coexistence of hERG current block and disruption of protein trafficking in ketoconazole-induced long QT syndrome. Br J Pharmacol.2008 Feb; 153(3):439-47.
[9]Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia:HERG encodes the IKr potassium channel. Cell.1995 Apr 21; 81(2): 299-307.
[10]Kiehn J, Lacerda AE, Wible B, Brown AM. Molecular physiology and pharmacology of HERG. Single-channel currents and block by dofetilide. Circulation.1996 Nov 15; 94(10):2572-9.
[11]Karle CA, Kreye VA, Thomas D, Rockl K, Kathofer S, Zhang W, et al. Antiarrhythmic drug carvedilol inhibits HERG potassium channels. Cardiovasc Res.2001 Feb 1; 49(2):361-70.
[12]梁岩,朱俊,杨艳敏等.盐酸关附甲素在五指山小型猪急性缺血模型中的电生理学作用.中华心血管病杂志.2006；34(11)：1035-9.
[13]梁岩,朱俊,杨艳敏等.盐酸关附甲素在五指山小型猪心肌梗死后慢性心功能异常模型中的电生理学作用.中国心脏起搏与心电生理杂志.2007；21(3)：251-5.
[14]高鑫,朱俊,杨艳敏,等.盐酸关附甲素与普罗帕酮对比终止阵发性室上性心动过速的随机双盲多中心试验.中华心血管病杂志.2007；35(2)：151-4.
[15]杨艳敏,朱俊,高鑫,等.盐酸关附甲素注射液治疗室性心律失常的多中心随机开放试验.中华心律失常学杂志.2006；10(2)：130-4.
[16]杨艳敏,朱俊,高鑫,等.盐酸关附甲素注射液治疗室性心律失常的多中心随机双盲试验.中华心血管病杂志.2006；34(4)：329-32.
[17]韩智红,吴学思,朱晓玲,等.盐酸关附甲素注射液终止室上性心动过速的疗效.中国新药杂志.2003；12(11)：939-40.
[18]高鑫,浦介麟,杨艳敏,等.盐酸关附甲素对大鼠心室肌细胞膜L型钙通道(ICa-L)的影响.中国新药杂志.2006；15(22)：1926-9.
[19]丽英,杨艳敏,浦介麟,等.盐酸关附甲素对豚鼠和大鼠心肌细胞钾通道的阻断作用.中国心脏起搏与心电生理杂志.2006；20(3)：255-8.
[20]丽英,杨艳敏,浦介麟,等.盐酸关附甲素对豚鼠心室肌细胞膜钠通道的阻断作用.中华心律失常学杂志.2007；11(1)：47-52.
[21]Milnes JT, Witchel HJ, Leaney JL, Leishman DJ, Hancox JC. hERG K+ channel blockade by the antipsychotic drug thioridazine:An obligatory role for the S6 helix residue F656. Biochem Biophys Res Commun.2006 Dec 8; 351(1):273-80.
[22]Kikuchi K, Nagatomo T, Abe H, Kawakami K, Duff HJ, Makielski JC, et al. Blockade of HERG cardiac K+ current by antifungal drug miconazole. Br J Pharmacol.2005 Mar; 144(6):840-8.
[23]Mitcheson JS, Chen J, Sanguinetti MC. Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate. J Gen Physiol.2000 Mar; 115(3):229-40.
[24]Zhou Z, Gong Q, Ye B, Fan Z, Makielski JC, Robertson GA, et al. Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophys J.1998 Jan; 74(1): 230-41.
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