雷诺嗪对豚鼠心律失常及心功能影响的实验研究
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摘要
目的:缺血性心脏病多合并心律失常及心功能不全,最近研究发现心肌缺血时出现持续晚钠电流,从理论上讲如果对晚钠电流进行抑制,不但减少心绞痛发作,而且能够减少心律失常的发生、保护心功能,是一个全新机制的多靶点的治疗冠心病用药。本文拟通过晚钠电流抑制剂---雷诺嗪(Ranolazine)对豚鼠心脏乳头肌动作电位(AP)及收缩力,对豚鼠心室肌细胞钠电流(INa+)和晚钠电流(INa/L)及延迟整流钾电流(Ik+)的影响,配合其对钙电流(L-ICa)阻滞作用的研究,探讨雷诺嗪对豚鼠在体、离体缺血-再灌注模型的心功能及心律失常的影响及其作用机制。
方法:通过在体缺血再灌注及离体Langendorff模型灌流方法,观察雷诺嗪对SOD、MDA、再灌注心律失常影响;血流动力学改变;心肌组织中钙离子含量;常规玻璃微电极法记录豚鼠乳头肌动作电位,观察模拟缺氧条件下的雷诺嗪对动作电位参数APA、APD50、APD90及心肌收缩力的影响;采用主动脉逆行灌流法酶解分离豚鼠单个心室肌细胞,全细胞膜片钳技术记录正常钠电流(INa+)、晚钠电流(INa/L)、迟整流钾电流(Ik+)和L型钙通道电流(L-Ica)作为对照,观察不同剂量的雷诺嗪对钠电流(INa+)、晚钠电流(INa/L)和延迟整流钾电流(Ik+)及L型钙通道电流(L-Ica)的影响。
结果:雷诺嗪可增强SOD活性,可以对抗H2O2模拟的缺血-再灌注损伤过程的作用,减少再灌注心律失常;可降低H2O2引起的豚鼠乳头肌动作电位动时程的增加和增强心肌收缩力,对动作电位振幅(APA)无影响;改善在体心肌缺血再灌注的LVEDP,不影响心率;可以改善离体心肌LVDP和士dp/dPmax等心肌收缩性指标,并且呈剂量依赖性;能够降低缺血-再灌注受损心肌组织的钙含量;中大剂量雷诺嗪可降低晚钠电流(INa/L);大剂量雷诺嗪可以可明显降低豚鼠心室肌细胞钠电流(INa+)、延迟整流钾电流(Ik+)和L型钙通道电流(L-Ica)幅值,且具有剂量依赖性。
当加入雷诺嗪1μM·L-1、10μM·L-1和100μg·L-1 3分钟后,与正常对照组比较,各离子电流分别为:①、钠其峰值电流量和中剂量分别为(99.50±11.13和96.38+-10.35 pA/pF,n=6)无统计学意义(p>0.05),大剂量峰值电流为(79.88±9.88,pA/pF,n=6)具有显著的统计学意义(p<0.05),翻转电位约在+10 - +20mV;②、小剂量对晚钠电流峰值成份为(3.96±0.23 ,pA/pF,n=6) p>0.05)中剂量和大剂量峰值电流为(3.40±0.24和3.03±0.21,pA/pF,n=6)(p<0.01和P<0.001);与正常组相比H2O2使心室肌细胞通道开放时间,开放概率明显增加(p<0.01),关闭时间明显降低(p<0.01);③、钾峰值电流小剂量和中剂量分别为(21.67±3.78和18.56±4.78 pA/pF,n=6)无统计学意义(p>0.05),大剂量为(18.00±2.78 pA/pF,n=6 )具有显著的统计学意义(p<0.05);通道开放时间,开放概率以及关闭时间与正常组相比无统计学意义(p>0.05)。④、钙峰值电流分别为(-310.5±60.6、-270.6±50.2和-210.3±30.5 pA,n=8),大剂量组具有统计学意义(p<0.01)。
结论:
1雷诺嗪可减少再灌注心律失常、降低LVEDP水平、改善心肌僵硬度,减少缺血-再灌注心肌组织的钙含量,能改善心脏舒张功能。
2雷诺嗪可降低H2O2引起的豚鼠乳头肌动作电位动时程的增加,且呈剂量依赖性,可改善H2O2引起的豚鼠的心肌收缩力降低。
3雷诺嗪大剂量(100μg·L-1)可以抑制快钠通道,有Ⅰ类抗心律失常药物的特性,小剂量对快钠通道无明显昨用;中、大剂量(10μg·L-1以上)可明显抑制晚钠通道,改善缺血心肌心功能及抑制心律失常。
4雷诺嗪(100μg·L-1)可明显抑制钾通道,并呈剂量依赖性,可以抗室性、房性心律失常,类似Ⅲ类抗心律失常药物。
5雷诺嗪可剂量依赖性的降低豚鼠心室肌细胞L-Ica幅值。阻滞经L型钙通道的Ca2+内流,降低胞浆内的Ca2+浓度,改善心脏舒张功能。
As an effective anti-ischemic drug, ranolazine can inhibit late sodium channel to prevent the sodium and calcium overload caused by myocardial ischemia, and effectively improve the heart disfunction and barrier of energy metabolism caused by myocardial ischemia ,without the fluctuations of patients’heart rate and blood pressure ,who have angina and myocardial infarction, having a unique protection of ischemic myocardium. Recently studies show that the use of ranolazine in the treatment of angina may be achieved through the inhibition of myocardial cells late sodium current (INa), and reducing intracellular calcium overload. When cardiac action potential occurs, the sodium ions result in rapid depolarization or peak of the action potential through the cardiac membrane sodium channels into the cell. The open of sodium channel is very short, following a rapid inactivation, and closes in the stage of platform. However, there is a small part of the open of sodium channels is not completely inactivated, and persistent in the whole stage of plateau, when a typical sodium channel close.
Delaying the open of the sodium channel allows the slow flow of sodium ions into the cell (in the systolic).Studies show that myocardial cell membrane sodium channel slow and cardiovascular diseases, especially ischemic heart disease and its related diseases are closely linked in the state of the occurrence and development. Undrovinas AI etc. detected that the concentration of ranolazine in the slow sodium channel and the peak current of sodium ions’s half-inhibitory (Ic50) is 6.5μM·L-1and 244μM·L-1, by comparing the use of ranolazine in the slow sodium channel with it in the sodium peak current in the of chronic heart failure canine’s isolated ventricular muscle. They believed that ranolazine could selectively inhibit slow sodium channel. Based on the experimental preparation, conditions, and different species, the IC50 ranges from 5μM·L-1 to 21μM·L-1.
Associated with an imbalance of oxygen supply and demand, the destruction of the environment’s homeostasis of cardiac cells’sodium and calcium ion in pathological conditions, sodium outflow’s reduction and its inflow’s raise will lead to sodium overload in myocardial cells. Result in a large number of intracellular accumulation of sodium ions, through the Na + / Ca + exchange, inducing calcium overload, leading the extension of action potential and inducing the abnormalities of its relaxtion in early after depolarization. The ventricular repolarization and contractile function of the patients with heart failure are often abnormal, these anomalies result in the disorder of the cardiac excitation-contraction coupling’s process, destructing the intracellular sodium and calcium homeostasis. Abnormal energy metabolism also plays a crucial role in the heart failure and left ventricular disfunction associating with it. The study found that the slow sodium channel of myocardial cells in dogs with heart failure tripled. Ranolazine can reduce the time of late sodium channel opening, reverse the prolongation of action potential , inhibit early after depolarization, and end the ventricular tachycardia by the effects of antiarrhythmic,Chandle MP etc. detected that short-term use of Ranolazine and dobutamine in dogs with chronic heart failure can increase the stroke volume, cardiac output, ejection fraction and so on. Ranolazine improves left ventricular function, makes mechanical efficiency of left ventricular increasing significantly, without the raise of myocardial oxygen consumption. In summary,Ranolazine is a new anti-ischemic mechanism,It is still under study, In particular, still no for clinical ,Our experimental study will provide a richer and more systematic clinical basis of clinical application.
Patch-clamp technique is a received cutting-edge technology of cell electrophysiological studies in the world, which makes a direct study of cell membrane ion channel’s current characteristics become reality. The subjects use whole-cell patch-clamp technique to study the effects of ranolazine on ion channels, and analyze the possible mechanism of anti-arrhythmia and improvement of cardiac function.Some studies confirmed that the transient outward potassium current is the most important repolarization currents in human and rat myocardium. The late sodium current mainly occurs in the plateau, therefore, this study made guinea pigs experimental animals for research.
This study analyzed the mechanism of antiarrhythmic effects and improvement of cardiac function with the use of ranolazine ,by observing the its influence of cardiac function and arrhythmia in vivo and vitro ischemia - reperfusion of guinea pig model, the its influence on the guinea pig heart papillary muscle action potential (AP) and contractile force, and its influence on right sodium current(INa +) , the late sodium current (INa / L) and delayed rectifier potassium current (Ik +) of guinea pig ventricular myocytes with the combination of the block of calcium current(L-ICa).
There is high SOD activity and low content of MDA in serum of vivo myocardial ischemia - reperfusion injury model of the sham group of guinea pig with the use of ranolazine. The SOD activity of Ranolazine group is higher than ischemia-reperfusion model group (P <0.05), while the ranolazine group can significantly reduce serum MDA levels (P <0.05). MDA content in sham-operated group is 2.37±0.71 nmol / ml, while the MDA content in ischemia-reperfusion group was significantly higher (7.21 land 1.65 nmol / ml). After the intervention of ranolazine, MDA contents were decreased to 4.52±0.61nmol / ml in Ranolazine iv group and 3.07±0.56nmol/ml in ranolazine infusion group. There is a contrary of SOD activity, the control group up to 107.66±13.10 nmol / ml, ischemia-reperfusion group a minimum of 74.65±8.05nmol/ml, but ranolazine treatment group were back to 98.91 Soil 6.13 nmol / ml (Reynolds hydrochloride iv group) and 114.11±9.38 nmol / ml (ranolazine infusion group). There was a significant difference of MDA content and SOD activity among ranolazine iv group, ranolazine infusion group and the ischemia-reperfusion group (p <0.05). Ranolazine can improve the body's ability to eliminate free radicals and inhibit lipid peroxidation. Large doses of ranolazine have a significant inhibition on arrhythmia induced by ischemia-reperfusion. Ranolazine iv group and ranolazine continuous infusion group both can low LVEDP, especially the latter. LVEDP is an important indicator reflecting the degree of ventricular myocardial contracture and rigid. Diastolic heart failure results from left ventricular impairment in diastolic filling period ,reduction of stroke volume and the raise of left ventricular end-diastolic pressure leaded by the increasing myocardial stiffness. Therefore, Ranolazine can improves diastolic function and be applied to diastolic heart failure. Ranolazine can protect vivo ischemia-reperfusion’s injury , reduce reperfusion arrhythmias, and improve cardiac function, especially cardiac diastolic function.
Ranolazine increases LVDP, + dp / dtmax, -dp/dtmax, and reduces myocardial reperfusion at the end of the Ca2 + concentration in the protective effect of vitro simulated ischemia - reperfusion injury cardiac function. Both are dose-dependent. LVDP, dp / dtmax reflects the left ventricular systolic function, -dp/dtmax reflects left ventricular diastolic function. These shows that ranolazine can be against with the reduction of cardiac function induced by isolated myocardial ischemia-reperfusion. At the same time it can reduce the myocardial Ca2 + content of myocardial tissue. That confirmed Ranolazine can inhibit the calcium overload induced by myocardial ischemia - reperfusion. Ranolazine can effectively improve the ischemia and angina and left ventricular decompensation, then increase cardiac contractility and improve diastolic function.
APD50 and APD90, compared with the simple perfusion with H2O2 significantly reduced action potential duration (p < 0.05 and p <0.01), after ranolazine (1Μ) + H2O2 perfusion with 3 minutes in the experiments of muscle action potentials and contractile force of guinea pig papillary by using ranolazine. Compared APD50 and APD90 with perfusion with H2O2 alone, there is a significant reduction in action potential duration (p <0.05 and p <0.001) after TTX (2μΜ) + H2O2 perfusion with 3 minutes. H2O2 group contractile force decreased significantly (80.66±6.53)%, (p <0.05), by the comparison between Ranolazine group and the normal group. Amplitude of papillary muscle contraction in ranolazine (10uM) + H2O2 group and TTX (2uM) + H2O2 group compared with the control group has no significant statistical significance (93.00±6.63 and 93.67±6.12)%, (P> 0.05). Intervention of H2O2-induced guinea pig ventricular myocytes by use of ranolazine can reduce the extension of the cell action potentials. Ranolazine reduces guinea pig papillary muscle action potential duration induced by H2O2 and enhance myocardial contractile force. The result is as same as it by using TTX. Further illustrates ranolazine can inhibit the arrhythmias and improve cardiac function. All these guide us to do further study about the mechanism of ranolazine in the level of ion channels. We can observe the ranolazine’s effect on cardiac ion channel currents in cells with the application of patch-clamp technique. After adding ranolazine 1μM ? L-1, 10μM ? L-1, and 100μg ? L-1 3 minutes later, comparing with the normal control group, the peak amount of current and medium doses of sodium, respectively (99.50±11.13和96.38±10.35, pA / pF, n = 8) ,has no statistical significance (p> 0.05); the high-dose peak current (79.88±9.88, pA / pF, n = 8) with a significant statistical significance (p <0.05, reversal potential around +10 - +20 mV; compared with normal ventricular myocytes on the opening hours by using H2O2, probability of open increased significantly (p <0.01), closing time significantly lower (p <0.01); however, opening hours, probability of and closing time of the ranolazine group compared with the normal group have no statistical significance (p> 0.05).It shows that ranolazine can inhibit the fast high-dose sodium currents, and the high-dose ranolazine can block the increase of sodium current induced by a hydrogen peroxide
(the late sodium current). It has a dose-dependent manner and be as similar as the role of tetrodotoxin.
After adding Ranolazine 1μM ? L-1, 10μM ? L-1, and 100μg ? L-1 3 minutes later, the low-dose and medium dose of peak potassium currents, respectively (21.67±3.78 and 18.56±4.78 pA / pF , n = 8) no statistical significance (p> 0.05), and large dose (18.00±2.78 pA / pF, n = 8) has significant statistical significance. Large dose of Ranolazine can inhibit the potassium channels with a dose-dependent manner.It indicates that ranolazine has a role of anti-ventricular arrhythmias and anti-atrial arrhythmia, similar with classⅢantiarrhythmic drug.
We found that medium and large doses of ranolazine have inhibition on ventricular myocytes of L-type calcium ion channels. After adding ranolazine 1,10 and 100μg ? L-1 3 minutes later, , the peak sodium current (respectively 3.98±0.75、3.85±0.71和3.53±0.58,pA/pF n=8), group with 200μg ? L -1 was statistically significant (p <0.01). The reduction of guinea pig ventricular myocytes L-Ica’s amplitude by Ranolazine is dose-dependent when Reversal potential is at about +50 - +60 mV. Ranolazine can blocked Ca2 + influx of the L-type calcium channels, reduce the concentration of Ca2 + in the cytoplasm, and inhibit cardiac myocyte excitation-contraction coupling. So myocardial contractile force weak as a negative inotropic effect, it can make the power of heart reduce while a corresponding reduction in myocardial oxygen consumption. It played a role in protection of ischemic myocardium, while it also reduce calcium overload. However we need further experiments.
In summary, we found that ranolazine has a effect of inhibition in the majority cardiac ion channels of cells, as classⅢantiarrhythmic drugs like amiodarone. Ranolazine also can improve cardiac function, especially left ventricular diastolic function. There will be a very good prospects of it in clinical application . Ranolazine can effectively improve the ischemia and angina, and improveleft ventricular decompensation, particularly those with diastolic dysfunction and arrhythmia. So we expect that ranolazine may become a new category of drug with the effect of anti-arrhythmia and treating heart failure in future. There is a need to conduct more in-depth study.
方法:通过在体缺血再灌注及离体Langendorff模型灌流方法,观察雷诺嗪对SOD、MDA、再灌注心律失常影响;血流动力学改变;心肌组织中钙离子含量;常规玻璃微电极法记录豚鼠乳头肌动作电位,观察模拟缺氧条件下的雷诺嗪对动作电位参数APA、APD50、APD90及心肌收缩力的影响;采用主动脉逆行灌流法酶解分离豚鼠单个心室肌细胞,全细胞膜片钳技术记录正常钠电流(INa+)、晚钠电流(INa/L)、迟整流钾电流(Ik+)和L型钙通道电流(L-Ica)作为对照,观察不同剂量的雷诺嗪对钠电流(INa+)、晚钠电流(INa/L)和延迟整流钾电流(Ik+)及L型钙通道电流(L-Ica)的影响。
结果:雷诺嗪可增强SOD活性,可以对抗H2O2模拟的缺血-再灌注损伤过程的作用,减少再灌注心律失常;可降低H2O2引起的豚鼠乳头肌动作电位动时程的增加和增强心肌收缩力,对动作电位振幅(APA)无影响;改善在体心肌缺血再灌注的LVEDP,不影响心率;可以改善离体心肌LVDP和士dp/dPmax等心肌收缩性指标,并且呈剂量依赖性;能够降低缺血-再灌注受损心肌组织的钙含量;中大剂量雷诺嗪可降低晚钠电流(INa/L);大剂量雷诺嗪可以可明显降低豚鼠心室肌细胞钠电流(INa+)、延迟整流钾电流(Ik+)和L型钙通道电流(L-Ica)幅值,且具有剂量依赖性。
当加入雷诺嗪1μM·L-1、10μM·L-1和100μg·L-1 3分钟后,与正常对照组比较,各离子电流分别为:①、钠其峰值电流量和中剂量分别为(99.50±11.13和96.38+-10.35 pA/pF,n=6)无统计学意义(p>0.05),大剂量峰值电流为(79.88±9.88,pA/pF,n=6)具有显著的统计学意义(p<0.05),翻转电位约在+10 - +20mV;②、小剂量对晚钠电流峰值成份为(3.96±0.23 ,pA/pF,n=6) p>0.05)中剂量和大剂量峰值电流为(3.40±0.24和3.03±0.21,pA/pF,n=6)(p<0.01和P<0.001);与正常组相比H2O2使心室肌细胞通道开放时间,开放概率明显增加(p<0.01),关闭时间明显降低(p<0.01);③、钾峰值电流小剂量和中剂量分别为(21.67±3.78和18.56±4.78 pA/pF,n=6)无统计学意义(p>0.05),大剂量为(18.00±2.78 pA/pF,n=6 )具有显著的统计学意义(p<0.05);通道开放时间,开放概率以及关闭时间与正常组相比无统计学意义(p>0.05)。④、钙峰值电流分别为(-310.5±60.6、-270.6±50.2和-210.3±30.5 pA,n=8),大剂量组具有统计学意义(p<0.01)。
结论:
1雷诺嗪可减少再灌注心律失常、降低LVEDP水平、改善心肌僵硬度,减少缺血-再灌注心肌组织的钙含量,能改善心脏舒张功能。
2雷诺嗪可降低H2O2引起的豚鼠乳头肌动作电位动时程的增加,且呈剂量依赖性,可改善H2O2引起的豚鼠的心肌收缩力降低。
3雷诺嗪大剂量(100μg·L-1)可以抑制快钠通道,有Ⅰ类抗心律失常药物的特性,小剂量对快钠通道无明显昨用;中、大剂量(10μg·L-1以上)可明显抑制晚钠通道,改善缺血心肌心功能及抑制心律失常。
4雷诺嗪(100μg·L-1)可明显抑制钾通道,并呈剂量依赖性,可以抗室性、房性心律失常,类似Ⅲ类抗心律失常药物。
5雷诺嗪可剂量依赖性的降低豚鼠心室肌细胞L-Ica幅值。阻滞经L型钙通道的Ca2+内流,降低胞浆内的Ca2+浓度,改善心脏舒张功能。
As an effective anti-ischemic drug, ranolazine can inhibit late sodium channel to prevent the sodium and calcium overload caused by myocardial ischemia, and effectively improve the heart disfunction and barrier of energy metabolism caused by myocardial ischemia ,without the fluctuations of patients’heart rate and blood pressure ,who have angina and myocardial infarction, having a unique protection of ischemic myocardium. Recently studies show that the use of ranolazine in the treatment of angina may be achieved through the inhibition of myocardial cells late sodium current (INa), and reducing intracellular calcium overload. When cardiac action potential occurs, the sodium ions result in rapid depolarization or peak of the action potential through the cardiac membrane sodium channels into the cell. The open of sodium channel is very short, following a rapid inactivation, and closes in the stage of platform. However, there is a small part of the open of sodium channels is not completely inactivated, and persistent in the whole stage of plateau, when a typical sodium channel close.
Delaying the open of the sodium channel allows the slow flow of sodium ions into the cell (in the systolic).Studies show that myocardial cell membrane sodium channel slow and cardiovascular diseases, especially ischemic heart disease and its related diseases are closely linked in the state of the occurrence and development. Undrovinas AI etc. detected that the concentration of ranolazine in the slow sodium channel and the peak current of sodium ions’s half-inhibitory (Ic50) is 6.5μM·L-1and 244μM·L-1, by comparing the use of ranolazine in the slow sodium channel with it in the sodium peak current in the of chronic heart failure canine’s isolated ventricular muscle. They believed that ranolazine could selectively inhibit slow sodium channel. Based on the experimental preparation, conditions, and different species, the IC50 ranges from 5μM·L-1 to 21μM·L-1.
Associated with an imbalance of oxygen supply and demand, the destruction of the environment’s homeostasis of cardiac cells’sodium and calcium ion in pathological conditions, sodium outflow’s reduction and its inflow’s raise will lead to sodium overload in myocardial cells. Result in a large number of intracellular accumulation of sodium ions, through the Na + / Ca + exchange, inducing calcium overload, leading the extension of action potential and inducing the abnormalities of its relaxtion in early after depolarization. The ventricular repolarization and contractile function of the patients with heart failure are often abnormal, these anomalies result in the disorder of the cardiac excitation-contraction coupling’s process, destructing the intracellular sodium and calcium homeostasis. Abnormal energy metabolism also plays a crucial role in the heart failure and left ventricular disfunction associating with it. The study found that the slow sodium channel of myocardial cells in dogs with heart failure tripled. Ranolazine can reduce the time of late sodium channel opening, reverse the prolongation of action potential , inhibit early after depolarization, and end the ventricular tachycardia by the effects of antiarrhythmic,Chandle MP etc. detected that short-term use of Ranolazine and dobutamine in dogs with chronic heart failure can increase the stroke volume, cardiac output, ejection fraction and so on. Ranolazine improves left ventricular function, makes mechanical efficiency of left ventricular increasing significantly, without the raise of myocardial oxygen consumption. In summary,Ranolazine is a new anti-ischemic mechanism,It is still under study, In particular, still no for clinical ,Our experimental study will provide a richer and more systematic clinical basis of clinical application.
Patch-clamp technique is a received cutting-edge technology of cell electrophysiological studies in the world, which makes a direct study of cell membrane ion channel’s current characteristics become reality. The subjects use whole-cell patch-clamp technique to study the effects of ranolazine on ion channels, and analyze the possible mechanism of anti-arrhythmia and improvement of cardiac function.Some studies confirmed that the transient outward potassium current is the most important repolarization currents in human and rat myocardium. The late sodium current mainly occurs in the plateau, therefore, this study made guinea pigs experimental animals for research.
This study analyzed the mechanism of antiarrhythmic effects and improvement of cardiac function with the use of ranolazine ,by observing the its influence of cardiac function and arrhythmia in vivo and vitro ischemia - reperfusion of guinea pig model, the its influence on the guinea pig heart papillary muscle action potential (AP) and contractile force, and its influence on right sodium current(INa +) , the late sodium current (INa / L) and delayed rectifier potassium current (Ik +) of guinea pig ventricular myocytes with the combination of the block of calcium current(L-ICa).
There is high SOD activity and low content of MDA in serum of vivo myocardial ischemia - reperfusion injury model of the sham group of guinea pig with the use of ranolazine. The SOD activity of Ranolazine group is higher than ischemia-reperfusion model group (P <0.05), while the ranolazine group can significantly reduce serum MDA levels (P <0.05). MDA content in sham-operated group is 2.37±0.71 nmol / ml, while the MDA content in ischemia-reperfusion group was significantly higher (7.21 land 1.65 nmol / ml). After the intervention of ranolazine, MDA contents were decreased to 4.52±0.61nmol / ml in Ranolazine iv group and 3.07±0.56nmol/ml in ranolazine infusion group. There is a contrary of SOD activity, the control group up to 107.66±13.10 nmol / ml, ischemia-reperfusion group a minimum of 74.65±8.05nmol/ml, but ranolazine treatment group were back to 98.91 Soil 6.13 nmol / ml (Reynolds hydrochloride iv group) and 114.11±9.38 nmol / ml (ranolazine infusion group). There was a significant difference of MDA content and SOD activity among ranolazine iv group, ranolazine infusion group and the ischemia-reperfusion group (p <0.05). Ranolazine can improve the body's ability to eliminate free radicals and inhibit lipid peroxidation. Large doses of ranolazine have a significant inhibition on arrhythmia induced by ischemia-reperfusion. Ranolazine iv group and ranolazine continuous infusion group both can low LVEDP, especially the latter. LVEDP is an important indicator reflecting the degree of ventricular myocardial contracture and rigid. Diastolic heart failure results from left ventricular impairment in diastolic filling period ,reduction of stroke volume and the raise of left ventricular end-diastolic pressure leaded by the increasing myocardial stiffness. Therefore, Ranolazine can improves diastolic function and be applied to diastolic heart failure. Ranolazine can protect vivo ischemia-reperfusion’s injury , reduce reperfusion arrhythmias, and improve cardiac function, especially cardiac diastolic function.
Ranolazine increases LVDP, + dp / dtmax, -dp/dtmax, and reduces myocardial reperfusion at the end of the Ca2 + concentration in the protective effect of vitro simulated ischemia - reperfusion injury cardiac function. Both are dose-dependent. LVDP, dp / dtmax reflects the left ventricular systolic function, -dp/dtmax reflects left ventricular diastolic function. These shows that ranolazine can be against with the reduction of cardiac function induced by isolated myocardial ischemia-reperfusion. At the same time it can reduce the myocardial Ca2 + content of myocardial tissue. That confirmed Ranolazine can inhibit the calcium overload induced by myocardial ischemia - reperfusion. Ranolazine can effectively improve the ischemia and angina and left ventricular decompensation, then increase cardiac contractility and improve diastolic function.
APD50 and APD90, compared with the simple perfusion with H2O2 significantly reduced action potential duration (p < 0.05 and p <0.01), after ranolazine (1Μ) + H2O2 perfusion with 3 minutes in the experiments of muscle action potentials and contractile force of guinea pig papillary by using ranolazine. Compared APD50 and APD90 with perfusion with H2O2 alone, there is a significant reduction in action potential duration (p <0.05 and p <0.001) after TTX (2μΜ) + H2O2 perfusion with 3 minutes. H2O2 group contractile force decreased significantly (80.66±6.53)%, (p <0.05), by the comparison between Ranolazine group and the normal group. Amplitude of papillary muscle contraction in ranolazine (10uM) + H2O2 group and TTX (2uM) + H2O2 group compared with the control group has no significant statistical significance (93.00±6.63 and 93.67±6.12)%, (P> 0.05). Intervention of H2O2-induced guinea pig ventricular myocytes by use of ranolazine can reduce the extension of the cell action potentials. Ranolazine reduces guinea pig papillary muscle action potential duration induced by H2O2 and enhance myocardial contractile force. The result is as same as it by using TTX. Further illustrates ranolazine can inhibit the arrhythmias and improve cardiac function. All these guide us to do further study about the mechanism of ranolazine in the level of ion channels. We can observe the ranolazine’s effect on cardiac ion channel currents in cells with the application of patch-clamp technique. After adding ranolazine 1μM ? L-1, 10μM ? L-1, and 100μg ? L-1 3 minutes later, comparing with the normal control group, the peak amount of current and medium doses of sodium, respectively (99.50±11.13和96.38±10.35, pA / pF, n = 8) ,has no statistical significance (p> 0.05); the high-dose peak current (79.88±9.88, pA / pF, n = 8) with a significant statistical significance (p <0.05, reversal potential around +10 - +20 mV; compared with normal ventricular myocytes on the opening hours by using H2O2, probability of open increased significantly (p <0.01), closing time significantly lower (p <0.01); however, opening hours, probability of and closing time of the ranolazine group compared with the normal group have no statistical significance (p> 0.05).It shows that ranolazine can inhibit the fast high-dose sodium currents, and the high-dose ranolazine can block the increase of sodium current induced by a hydrogen peroxide
(the late sodium current). It has a dose-dependent manner and be as similar as the role of tetrodotoxin.
After adding Ranolazine 1μM ? L-1, 10μM ? L-1, and 100μg ? L-1 3 minutes later, the low-dose and medium dose of peak potassium currents, respectively (21.67±3.78 and 18.56±4.78 pA / pF , n = 8) no statistical significance (p> 0.05), and large dose (18.00±2.78 pA / pF, n = 8) has significant statistical significance. Large dose of Ranolazine can inhibit the potassium channels with a dose-dependent manner.It indicates that ranolazine has a role of anti-ventricular arrhythmias and anti-atrial arrhythmia, similar with classⅢantiarrhythmic drug.
We found that medium and large doses of ranolazine have inhibition on ventricular myocytes of L-type calcium ion channels. After adding ranolazine 1,10 and 100μg ? L-1 3 minutes later, , the peak sodium current (respectively 3.98±0.75、3.85±0.71和3.53±0.58,pA/pF n=8), group with 200μg ? L -1 was statistically significant (p <0.01). The reduction of guinea pig ventricular myocytes L-Ica’s amplitude by Ranolazine is dose-dependent when Reversal potential is at about +50 - +60 mV. Ranolazine can blocked Ca2 + influx of the L-type calcium channels, reduce the concentration of Ca2 + in the cytoplasm, and inhibit cardiac myocyte excitation-contraction coupling. So myocardial contractile force weak as a negative inotropic effect, it can make the power of heart reduce while a corresponding reduction in myocardial oxygen consumption. It played a role in protection of ischemic myocardium, while it also reduce calcium overload. However we need further experiments.
In summary, we found that ranolazine has a effect of inhibition in the majority cardiac ion channels of cells, as classⅢantiarrhythmic drugs like amiodarone. Ranolazine also can improve cardiac function, especially left ventricular diastolic function. There will be a very good prospects of it in clinical application . Ranolazine can effectively improve the ischemia and angina, and improveleft ventricular decompensation, particularly those with diastolic dysfunction and arrhythmia. So we expect that ranolazine may become a new category of drug with the effect of anti-arrhythmia and treating heart failure in future. There is a need to conduct more in-depth study.
引文
[1]January CT, Riddle J M. Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current [J]. Circ Res,1989,64(5), 977?990.
[2]Zeng J, Rudy Y. Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence [J]. J Biophys ,1995,68(3), 949?964.
[3]Maltsev VA, Sabbah H N, Higgins RS, et al. Novel, ultraslow inactivating sodium current in human ventricularcardiomyocytes[J]. Circulation ,1998,98(23), 2545?2552.
[4]Wagner S, Dybkova N, Rasenack E C, et al. Ca/calmodulin-dependent protein kinase II regulates cardiac Na channels[J]. J Clin Invest, 2006,116(12), 3127?3138.
[5]Attwell D, Cohen IS, Eisner DA, et al. The steady state TTXsensitive (“window”) sodium current in cardiac Purkinje fibres[J]. Pflugers Arch ,1979,379,137?142.
[6]Colatsky TJ. Mechanism of action of lidocaine and quinidine on action potential duration in rabbit cardiac Purkinje fibers. Effects on steady state Na+ currents? [J]. Circ Res ,1982,50(1), 17?27.
[7]Wang DW, Kiyosue T, Sato T, et al. Comparison of the effects of class I antiarrhythmic drugs, cibenzoline, mexiletine and flecainide on the delayed rectifier K+ current of guinea-pig ventricular myocytes[J]. J Mol Cell Cardiol ,1996,28(5), 893?903.
[8]Patlak JB, Ortiz M. Slow currents through single sodium channels of the adult rat heart[J]. J Gen Physiol ,1985,86(1), 89?104.
[9]Berecki G, Zegers JG, Bhuiyan ZA, et al. Long-QT syndrome-related sodium channel mutations probed by the dynamic action potential clamp technique[J]. J Physiol, 2006,570(2), 237?250.
[10]Maltsev VA, Undrovinas AI. A multi-modal composition of the late Na+current in human ventricular cardiomyocytes[J]. Cardiovasc Res ,2006,69(1), 116?127.
[11]Zilberter Y, Starmer CF, Starobin J, et al. Late Na channels in cardiac cells: the physiological role of background Na channels[J]. Biophys J ,1994,67(1), 153?160.
[12]Maltsev VA, Sabbah HN, Undrovinas AI. Late sodium current is a novel target for amiodarone: studies in failing human myocardium[J]. J Mol Cell Cardiol ,2001,33,923?932.
[13]Zygmunt AC, Eddlestone GT, Thomas GP, et al. Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle[J]. Am J Physiol Heart Circ Physiol, 2001,281(2), H689?H697.
[14]Gintant GA, Datyner NB, Cohen IS. Slow inactivation of a tetrodotoxinsensitive current in canine cardiac Purkinje fibers[J]. Biophys J ,1984,45(3), 509?512.
[15]Vassalle M, Bocchi L, Du F. A slowly inactivating sodium current (INa2) in the plateau range in canine cardiac Purkinje single cells[J]. Exp Physiol, 2007,92(1), 161?173.
[16]Sakmann BF, Spindler AJ, Bryant SM, et al. Distribution of a persistent sodium current across the ventricular wall in guinea pigs[J]. Circ Res ,2000,87(10),910?914.
[17]Saint DA. The role of the persistent Na(+) current during cardiac ischemia and hypoxia[J]. J Cardiovasc Electrophysiol ,2006, 17(Suppl 1), S96?S103.
[18]Undrovinas AI, Maltsev VA, Kyle JW, et al.Gating of the late Na+ channel in normal and failing human myocardium[J]. J Mol Cell Cardiol,2002,34(11), 1477?1489.
[19]Maltsev VA, Sabbah HN, Tanimura M, et al.Relationship between action potential, contraction–relaxation pattern, and intracellular Ca2+ transient in cardiomyocytes of dogs with chronic heart failure[J].Cell Mol Life Sci ,1998,54(6), 597?605.
[20]Maltsev VA., Silverman N, Sabbah HN, et al. Chronic heart failure slows late sodium current in human and canine ventricular myocytes: implications for repolarization variability[J]. Eur J Heart Fail,2007,9(3),219?227.
[21]Bennett PB, Yazawa K, Makita N, et al. Molecular mechanism for an inherited cardiac arrhythmia[J]. Nature ,1995,376, 683?685.
[22]Wang DW, Yazawa K, George AL, et al. Characterization of human cardiac Na+ channel mutations in the congenital long QT syndrome[J]. Proc Natl Acad Sci U S A,1996,93, 13200?13205.
[23]Clancy CE, Tateyama M, Liu H, et al. Non-equilibrium gating in cardiac Na+ channels: an original mechanism of arrhythmia[J]. Circulation ,2003,107(17), 2233?2237.
[24]Abriel H, Kass RS. Regulation of the voltage-gated cardiac sodium channel Nav1.5 by interacting proteins. Trends Cardiovasc Med ,2005,15(1), 35?40.
[25]Meadows LS, Isom LL. Sodium channels as macromolecular complexes:implications for inherited arrhythmia syndromes[J]. Cardiovasc Res ,2005, 67(3), 448?458.
[26]Mohler PJ, Schott JJ, Gramolini AO, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death[J]. Nature ,2003, 421(6923), 634?639.
[27]Vatta M, Ackerman MJ, Ye B, et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome[J]. Circulation ,2006,114(2006), 2104?2112.
[28]Priori SG, Corr PB. Mechanisms underlying early and delayed afterdepolarizations induced by catecholamines[J]. Am J Physiol ,1990,258(1990), H1796?H1805.
[29]Burashnikov A, Antzelevitch C. Late-phase 3 EAD. A unique mechanism contributing to initiation of atrial fibrillation[J]. Pacing Clin Electrophysiol ,2006,29(3), 290?295.
[30]Undrovinas AI, Belardinelli L, Undrovinas NA, et al. Ranolazine improves abnormal repolarization and contraction in left ventricular myocytes of dogs with heart failure by inhibiting late sodium current[J]. J Cardiovasc Electrophysiol ,2006,17(Suppl 1), S169?S177.
[31]Chauhan VS, Tuvia S, Buhusi M, et al.Abnormal cardiac Na(+) channel properties and QT heart rate adaptation in neonatal ankyrin(B) knockout mice[J]. Circ Res, 2000,86(4), 441?447.
[32]Chen C, Bharucha V, Chen Y, et al.Reduced sodium channel density, altered voltage dependence of inactivation,and increased susceptibility to seizures in mice lacking sodium channel beta 2-subunits[J]. Proc Natl Acad Sci U S A ,2002, 99(26), 17072?17077.
[33]Waxman SG. Neurobiology: a channel sets the gain on pain[J].Nature ,2006,444, 831?832.
[34]Lehmann-Horn F, Jurkat-Rott K. Voltage-gated ion channels and hereditarydisease[J]. Physiol Rev, 1999,79(4), 1317?1372.
[35]Macianskiene R, Bito V, Raeymaekers L, et al.Action potential changes associated with a slowed inactivation of cardiac voltage-gated sodium channels by KB130015[J]. Br J Pharmacol , 2003,139(8), 1469?1479.
[36]Undrovinas AI, Maltsev VA, Sabbah HN. Repolarization abnormalities in cardiomyocytes of dogs with chronic heart failure: role of sustained inward current[J]. Cell Mol Life Sci, 1999,55(3), 494?505.
[37]Valdivia CR, Chu WW, Pu J, et al. Increased late sodium current in myocytes from a canine heart failure model and from failing human heart[J]. J Mol Cell Cardiol ,2005,38(3),475?483.
[38]Ward CA, Giles WR. Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes[J]. J Physiol, 1997,500(Pt 3), 631?642.
[39]Ma JH, Luo AT, Zhang PH. Effect of hydrogen peroxide on persistent sodium current in guinea pig ventricular myocytes[J]. Acta Pharmacol Sin ,2005,26,828?834.
[40]Song Y, Shryock JC, Wagner S, et al. Blocking late sodium current reduces hydrogen peroxide-induced arrhythmogenic activity and contractile dysfunction[J]. J Pharmacol Exp Ther ,2006,318(1), 214?222.
[41]Ahern GP,Hsu SF, Klyachko VA, et al. Induction ofpersistent sodium current by exogenous and endogenous nitric oxide[J]. J Biol Chem ,2000,275, 28810?28815.
[42]Tateyama M, Liu H, Yang AS, et al. Structural effects of an LQT-3 mutation on heart Na+ channel gating[J]. Biophys J,2004, 86(3), 1843?1851.
[43]Hammarstrom AK, Gage PW. Hypoxia and persistent sodium current[J]. Eur Biophys J, 2002,31(5), 323?330.
[44]Ferrari R. Oxygen-free radicals at myocardial level: effects of ischaemia and reperfusion[J]. Adv Exp Med Biol,1994, 366, 99?111.
[45]Pacher P, Schulz R, Liaudet L, et al.Nitrosative stress and pharmacological modulation of heart failure[J]. Trends Pharmacol Sci ,2005,26(6), 302?310.
[46]Wu J, Corr PB. Palmitoyl carnitine modifies sodium currents and induces transient inward current in ventricular myocytes[J]. Am J Physiol ,1994, 266(3,Pt2), H1034?H1046.
[47]Gautier M, Zhang H, Fearon IM.Peroxynitrite formation mediates LPCinduced augmentation of cardiac late sodium currents[J]. J Mol Cell Cardiol ,2008,44(2), 241?251.
[48]Kohlhardt M, Fichtner H, Frobe U. Metabolites of the glycolytic pathway modulate the activity of single cardiac Na+ channels[J]. FASEB,1989, J 3(8), 1963?1967.
[49]Tan HL, Kupershmidt S, Zhang R, et al. A calcium sensor in the sodium channel modulates cardiac excitability[J]. Nature,2002, 415, 442?447.
[50]Bezzina C, Veldkamp M.W, van Den Berg MP, et al. A single Na(+) channel mutation causing both long-QT and Brugada syndromes[J]. Circ Res ,1999,85(12), 1206?1213.
[51]Zong XG, Dugas M, Honerjager P. Relation between veratridine reaction dynamics and macroscopic Na current in single cardiac cells[J]. J Gen Physiol ,1992,99(5), 683?697.
[52]Wang SY, Wang GK. Voltage-gated sodium channels as primary targets of diverse lipid-soluble neurotoxins[J]. Cell Signal ,2003,15(2), 151?159.
[53]Spencer CI, Yuill KH, Borg JJ, et al. Actions of pyrethroid insecticides on sodium currents, action potentials, and contractile rhythm in isolatedmammalian ventricularmyocytes and perfused hearts[J]. J Pharmacol Exp Ther ,2001,298(3), 1067?1082.
[54]Soderlund DM, Clark JM, Sheets LP, et al. Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment[J]. Toxicology ,2002,171(1), 3?59.
[55]Spencer CI., Sham JS. Mechanisms underlying the effects of the pyrethroid tefluthrin on action potential duration in isolated rat ventricular myocytes[J].J Pharmacol Exp Ther ,2005,315(1), 16?23.
[56]Honerjager P. Cardioactive substances that prolong the open state of sodium channels[J]. Rev Physiol Biochem Pharmacol ,1982,92, 1?74.
[57]Hoey A, Amos GJ, Ravens U. Comparison of the action potential prolonging and positive inotropic activity of DPI 201-106 and BDF 9148 in human ventricular myocardium[J]. J Mol Cell Cardiol ,1994,26, 985?994.
[58]Yuill KH, Convery MK, Dooley PC, et al. Effects of BDF 9198 on action potentials and ionic currents from guinea-pig isolated ventricular myocytes[J]. Br J Pharmacol ,2000,130, 1753?1766.
[59]Fu LY, Li Y, Cheng L, Zhou HY, et al. Effect of sea anemone toxin anthopleurin-Q on sodium current in guinea pig ventricular myocytes[J]. Acta Pharmacol Sin,2001, 22(12), 1107?1112.
[60]Schreibmayer W, Kazerani H,Tritthart HA. A mechanistic interpretation of the action of toxin II from Anemonia sulcata on the cardiac sodium channel[J]. Biochim Biophys Acta ,1987,901(2), 273?282.
[61]Chahine M, Plante E, Kallen RG. Sea anemone toxin (ATX II) modulation of heart and skeletal muscle sodium channel alpha-subunits expressed in tsA201cells[J]. J Membr Biol, 1996,152(1), 39?48.
[62]Mantegazza M, Franceschetti S, Avanzini G. Anemone toxin (ATX II)-induced increase in persistent sodium current: effects on the firing properties of rat neocortical pyramidal75
[63]Sicouri S, Antzelevitch D, Heilmann C, et al. Effects of sodium channel block with mexiletine to reverse action potential prolongation in in vitro models of the long term QT syndrome[J]. J Cardiovasc Electrophysiol ,1997,8(11), 1280?1290.
[64]Nagatomo T, January CT, Makielski JC. Preferential block of late sodium current in the LQT3 DeltaKPQ mutant by the class I(C) antiarrhythmic flecainide[J]. Mol Pharmacol,2000, 57(1), 101?107.
[65]Fredj S, Sampson KJ, Liu H, et al. Molecular basis of ranolazine block of LQT-3 mutant sodium channels: evidence for site of action[J]. Br J Pharmacol ,2006,148(1),16?24.
[66]Sicouri S, Glass A, Belardinelli L, et al. Antiarrhythmic effects of ranolazine in canine pulmonary vein sleeve preparations[J]. Heart Rhythm ,2008,5(7), 1019?1026.
[67]、Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties[J]. Circulation , 2004,110(8), 904?910.
[68]Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine[J]. Heart ,2006,92(Suppl 4), iv6?iv14.
[69]Tian XL, Yong SL,Wan X, et al. Mechanisms by which SCN5A mutation N1325S causes cardiac arrhythmias and sudden death in vivo[J]. Cardiovasc Res ,2004,61(2), 256?267.
[70]Wu L, Shryock JC, Song Y, et al. An increase in late sodium current potentiates the proarrhythmic activities of low-risk QT-prolonging drugs in female rabbit hearts[J]. J Pharmacol Exp Ther,2006, 316(2), 718?726.
[71] Wu L, Rajamani S, Shryock JC, et al. Augmentation of late sodium current unmasks the proarrhythmic effects of amiodarone[J]. Cardiovasc Res,2007, 77(3), 481?488.
[72]Lathrop DA, Varro A. The combined electrophysiological effects of lignocaine and sotalol in canine isolated cardiac Purkinje fibres are rate-dependent[J].Br J Pharmacol,1990, 99(1), 124?130.
[73]Thomsen MB, Verduyn SC, Stengl M, et al. Increased short-term variability of repolarization predicts d-sotalolinduced torsades de pointes in dogs[J]. Circulation ,2004,110(16), 2453?2459.
[74]Hondeghem LM, Carlsson L, Duker G. Instability and triangulation of the action potentialpredict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic[J]. Circulation ,2001,103(15), 2004?2013.
[75]Lu HR, Vlaminckx E, Van Ammel K, et al. Drug-induced long QT in isolated rabbit Purkinje fibers: importance of action potential duration, triangulation and early afterdepolarizations[J]. Eur J Pharmacol ,2002,452(2), 183?192.
[76]Shimizu W, Antzelevitch C. Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsade despointes in LQT2 and LQT3 models of the long-QT syndrome[J]. Circulation ,1997,96(6),2038?2047.
[77]Studenik CR, Zhou Z, January CT. Differences in action potential and early afterdepolarization properties in LQT2 and LQT3 models of long QT syndrome[J]. Br J Pharmacol ,2001,132(1), 85?92.
[78]Abrahamsson C, Carlsson L, Duker G. Lidocaine and nisoldipine attenuate almokalant- induced dispersion of repolarization and early afterdepolarizations in vitro[J]. J Cardiovasc Electrophysiol 1996,7(11),1074?1081.
[79]Belardinelli L, Antzelevitch C, Vos MA. Assessing predictors of druginduced torsade de pointes[J]. Trends Pharmacol Sci ,2003,24(12), 619?625.
[80]Tomaselli GF, Beuckelmann DJ, Calkins HG, et al. Sudden cardiac death in heart failure[J]. The role of abnormal repolarization. Circulation ,1994,90(5), 2534?2539.
[81]Roden DM. Long QT syndrome: reduced repolarization reserve and the genetic link[J]. J Intern Med ,2006,259(1), 59?69.
[82]Ueda N, Zipes DP, Wu J.Prior ischemia enhances arrhythmogenicity in isolated canine ventricular wedge model of long QT3[J]. Cardiovasc Res,2004, 63(1), 69?76.
[83]Kaprielian R, Wickenden AD, Kassiri Z, et al. Relationship between K+ channel down- regulation and [Ca2+]i in rat ventricular myocytes following myocardial infarction[J]. J Physiol ,1999,517(Pt 1), 229?245.
[84]Lei M, Zhang H, Grace AA, Huang CL. SCN5A and sinoatrial node pacemaker function[J]. Cardiovasc Res ,2007,74(3), 356?365.
[85]Veldkamp MW, Wilders R, Baartscheer A, et al. Contribution of sodium channel mutations to bradycardia and sinus node dysfunction in LQT3 families[J]. Circ Res,2003, 92(9), 976?983.
[86]Levi AJ, Dalton GR, Hancox JC, et al. Role of intracellular sodium overload in the genesis of cardiac arrhythmias[J].J Cardiovasc Electrophysiol ,1997,8(6), 700?721.
[87]Makielski JC, Farley AL. Na(+) current in human ventricle: implications for sodium loading and homeostasis[J]. J Cardiovasc Electrophysiol,2006, 17(Suppl 1), S15?S20.
[88]Pieske B, Houser SR. [Na+]i handling in the failing human heart[J]. Cardiovasc Res ,2003,57(4), 874?886.
[89]Li L, DeSantiago J, Chu G, et al.Phosphorylation of phospholamban and troponin I in beta-adrenergic-induced acceleration of cardiac relaxation[J]. Am J Physiol Heart Circ Physiol ,2000,278(3), H769?H779.
[90]Bers DM. Cardiac inotropy and Ca mismanagement. In D. M. Bers ,Editor, Excitation–contraction coupling and cardiac contractile force (2nd ed). [M] Boston:Kluwer Academic Publishers. 2002,273?331.
[91]Vassalle M, Lin CI. Calcium overload and cardiac function[J]. J Biomed Sci ,2004,11(5), 542?565.
[92]Sipido KR. Calcium overload, spontaneous calcium release, and ventricular arrhythmias[J]. Heart Rhythm ,2006,3(8), 977?979.
[93]Gyorke S, Gyorke I, Lukyanenko V, et al. Regulation of sarcoplasmic reticulum calcium release by luminal calcium in cardiac muscle[J]. Front Biosci ,2002, 7, d1454?d1463.
[94]Zaza A, Rocchetti M, Brioschi A, et al. Dynamic Ca2+- induced inward rectification of K+ current during the ventricular action potential[J]. Circ Res ,1998,82(9), 947?956.
[95]Choi BR, Burton F, Salama G. Cytosolic Ca2+ triggers early afterdepolarizations and Torsade de Pointes in rabbit hearts with type 2 long QTsyndrome[J]. J Physiol,2002, 543(2), 615?631.
[96]Wan X, Laurita KR, Pruvot EJ, et al. Molecular correlates of repolarization alternans in cardiac myocytes[J]. J Mol Cell Cardiol,2005, 39(3), 419?428.
[97]Maier LS, Zhang T, Chen L, et al. Transgenic CaMKIIdeltaC overexpression uniquely alters cardiac myocyte Ca2+handling: reduced SR Ca2+ load and activated SR Ca2+ release[J]. Circ Res ,2003,92(8), 904?911.
[98]Kranias EG. Regulation of Ca2+ transport by cyclic 3′,5′-AMP-dependent and calcium-calmodulin-dependent phosphorylation of cardiac sarcoplasmic reticulum[J].Biochim Biophys Acta,1985, 844(2), 193?199.
[99]Wagner S, Dybkova N, Rasenack EC, et al. Ca/calmodulin-dependent protein kinase II regulates cardiac Na channels[J]. J Clin Invest 2006,116,3127-3138.
[100]Wilkins BJ, Molkentin JD. Calcium-calcineurin signaling in the regulation of cardiac hypertrophy[J]. Biochem Biophys Res Commun ,2004,322, 1178?1191.
[101]Bers DM, Guo T. Calcium signaling in cardiac ventricular myocytes[J]. Ann N YAcad Sci,2005, 1047, 86?98.
[102]Dorn GW, Force T. Protein kinase cascades in the regulation of cardiac hypertrophy[J]. J Clin Invest ,2005,115(3), 527?537.
[103]Bache RJ, Vrobel TR, Arentzen CE, et al. Effect of maximal coronary vasodilation on transmural myocardial perfusion during tachycardia in dogs with left ventricular hypertrophy[J]. Circ Res ,1981,49(3), 742?750.
[104]Nador F, Beria G, De Ferrari GM, et al. Unsuspected echocardiographic abnormality in the long Q–T syndrome:diagnostic, prognostic and pathogenetic implications[J]. Circulation ,1991,84(4), 1530?1542.
[105]Maack C, Cortassa S, Aon MA, et al. Elevated cytosolic Na+ decreases mitochondrial Ca2+ uptake during excitation–contraction coupling and impairs energetic adaptation in cardiacmyocytes[J]. Circ Res ,2006,99(2),172?182.
[106]Fredj S, Lindegger N, Sampson KJ, et al.Altered Na+channels promote pause-induced spontaneous diastolic activity in long QT syndrome type 3 myocytes[J]. Circ Res,2006, 99(11), 1225?1232.
[107]Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young[J]. J Am Coll Cardiol ,2007,49(2), 240?246.
[108]Martin RL, McDermott JS, Salmen HJ, et al.The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization: influence of multi-channel block[J]. J Cardiovasc Pharmacol ,2004,43,369?379.
[109]Song Y, Shryock JC, Wu L, et al. Antagonism by ranolazine of the pro-arrhythmic effects of increasing late INa in guinea pig ventricularmyocytes[J]. J Cardiovasc Pharmacol , 2004,44(2), 192?199.
[110]Fedida D, Orth PM, Hesketh JC, et al. The role of late I and antiarrhythmic drugs inEADformation and termination in Purkinje fibers[J]. J Cardiovasc Electrophysiol , 2006, 17(Suppl 1), S71?S78.
[111]Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associated proarrhythmic effects. A review with special reference to torsade de pointes tachycardia[J]. Ann Intern Med ,1994,121(7), 529?535.
[112]Benhorin J, Taub R, Goldmit M, et al. Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? [J]. Circulation,2000, 101 (14), 1698?1706.
[113]Epstein AE, Hallstrom AP, Rogers WJ, et al. Mortality following ventricular arrhythmia suppression by encainide,flecainide, and moricizine after myocardial infarction. The original design concept of the Cardiac Arrhythmia Suppression Trial (CAST) [J]. JAMA ,1993,270(20), 2451?2455.
[114]Allessie MA, Bonke FIM, Schopman FJG. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. The“leading circle”concept: a new model of circus move- ment in cardiac tissue without the involvement of an anatomical obstacle[J]. Circ Res, 1977, 41(1), 9?18.
[115]Morrow DA., Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial[J]. JAMA,2007, 297(16), 1775?1783.
[116]Scirica BM, Morrow DA, Hod H, et al. Effect of ranolazine, an antianginal agent with novel electrophysiologicalproperties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial[J]. Circulation ,2007,116(15), 1647?1652.
[117]Sossalla S, Wagner S, Rasenack EC, et al. Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts—role of late sodium current and intracellular ion accumulation[J]. J Moll Cell Cardiol ,2007,45(1), 32?43.
[118]Shannon TR, Ginsburg KS, Bers DM. Quantitative assessment of the SR Ca2+ leak-load relationship. Circ Res,2002, 91(3), 594?600.
[119]Tamareille S, Le Grand B, John GW, et al. Antiischemic compound KC 12291 prevents diastolic contracture in isolated atria by blockade of voltage-gated sodium channels[J]. J Cardiovasc Pharmacol ,2002,40,346?355.
[120]Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions[J]. Circulation ,2006,113(20), 2462?2472.
[121]Cheng JW. Ranolazine for the management of coronary artery disease[J]. ClinTher ,2006,28(12), 1996?2007.
[122]Rousseau MF, Pouleur H, Cocco G, et al. Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris[J]. Am J Cardiol ,2005,95(3), 311?316.
[123]Cocco G, Rousseau MF, Bouvy T, et al. Effects of a new metabolic modulator, ranolazine, on exercise tolerance in angina pectoris patients treated with beta-blocker or diltiazem[J]. J Cardiovasc Pharmacol,1992,20(1), 131?138.
[124]Stone PH, Gratsiansky NA, Blokhin A, et al.Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial[J]. J Am Coll Cardiol ,2006,48(3), 566?575
[125]Libby P. Current concepts of the pathogenesis of the acute coronary syndromes [J]. Circulation,2001, 104(3), 365?372.
[126]Akhtar M, Breithardt G, Camm AJ, et al.Task Force of the Working Group on Arrhythmias of the European Society of Cardiology CAST and beyond. Implications of the Cardiac Arrhythmia Suppression Trial[J]. Circulation ,1990,81(3), 1123?1127.
[127]The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction[J]. N Engl J Med ,1989,321(6), 406?412.
[128]Walker MJA,Eustis MJ,Hearse DJ etal.The lambeth convention: Guide- lines for the study of arrhythmias in ischemia,infarction and reperfusion [J]. Ca- driovas Res, 1988,22:447-455.
[129]Steaer SE,Yellow DM.The protective effect of heart stress against reper- fusion arrhymias in the rat[J].J Mol cell cardiol,1993,25:1471.
[130]Ruiz-Gines JA,Lopez-Ongil S,Gonzalez-Rubio M,et al.Reactive oxygen species induce proliferation of bovine aortic endothelial cells[J].Jcardiovasc Pharmacol, 2000, 35 (1):109-113.
[131]Granger DN,Rutili G,McCord JM.Superoxide radicals in feline intestinal ischemia [J]Gastroenterology,1981,81(1):22-29.
[132].孙涛,苏全生.自由基与心肌缺血/再灌注损伤[J].实用医院临床志,2006,3(4):94-96.
[133]Kim JK,Pedram A,Razandi M,et al.Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase is forms[J].J Biol Chem,2006,281(10):6760-6767.
[134]Bhakuni D,ChandraM,MisraMK.Oxidative stress Parameters in erythro- cytes of post-reperfused patients with myocardial infarvction[J].J Enzyme Inhib Med Chem., 2005,20(4):377-381.
[135]Cheng H,Liu W,Ai X.Protective effect of cureumin on myocardial Iso- cheimal reperfusion injury in rats[J]ZhongYaoCai,2005,28(10):920-922.
[136]Paradies G Petrosillo G Pistolese M et al.Deerease in mitoehondrial complex activity in ischemic/reperfused rat heart:involvement of reactive oxygen species and cardiolipin [J].Circ Res,2004,94(l):53-59.
[137]Zima AV;Blatter LA.Redox regulation of cardiac calcium channels and transporters [J].Cardiovasc Res,2006,71(2):310-321.
[138]Wagner S,Seidler T,Pieht E,etal.Na+-Ca2+ exehanger overexpression Predisposes to reactive oxygen species-induced injury[J].Cardiovase Res,2003,60(2):404-412.
[139]Paradies G,Petrosillo G,Pistolese M,etal.Devcrease in mitoehondrial complex I activity in isehemic/reperfused rat heart: involvement of reactive ox- ygen species and cardiologic[J].Circ Res,2004,94(l):53-59.
[140]Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions[ J ]. Circulation, 2006, 113: 2462-2472.
[141]Wang P,Fraser H,Lloyd SG,et al.A Comparison between ranolazine and CVT-4325,a novel inhibitor of fatty acid oxidation, on cardiac metabolism and left ventricular function in rat isolated perfused heart during ischemia and reperfusion[J].J Pharmacol Exp Ther,2007,321(1):213-220.
[142]Mason RP. Mechanisms of plaque stabilization for the dihydropyridine calcium channel blocker amlodip ine: review of the evidence [J].Atherosclerosis, 2002,165: 191-199.
[143]Ide T,Tsutsui H,Kinugawa S,et al.Direct evidence for increased hydro xyl Radicals originating from superoxide in the failing myocardium[J].Circ Res,2000,86(2):152-157.
[144]Matsumura H,Hara A,Hashizume H,etal.Protective effeets of rano- lazine,a Novel anti-ischemic drug,on the hydrogen peroxide-induced deran- gements in isolated,Perfused rat heart:comparsion with dichloroacetate [J].Jpn J Pharmacol,1998,77(l):31-39.
[145]Song Y,ShryocJC,Wagner S,etal.Blocking Late Sodium Current Red- uces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dys- function[J]. JPET, 2006,318(l):214-222.
[146]Song Y,Sllryoek JC,Wu L,etal.Antagonism by ranolazine of the Pro- arrhythmic effects of increasing late INA in guinea pig ventricula rmyocytes[J].J Cardiovasc Pharmacol,2004,44(2):192-199.
[147]Antzelevitch C,Belardinelli L,Zygmunt AC,etal.Electrophysiological effects of ranolazine,a novel antianginal agent with antiarrhythmic properties [J].Circulation,2004, 110(8):904-910.
[148]ThomPson Da,Waldron CB,Jnul SM,etal.Analysis of veniricular Pre- ssure during isovolumic relaxation in coronary artery disease[J].Circulation,1982,65(4):690-697.
[149]Okda Y.Volume exPansion-sensing outward-rectifier Cl- cannels:fresh start to The molecular identity and volume sensor[J].AmJ physiol,1997,273(Cell physil 42):C755- C789.
[150]Shen AC,Jennings RB.Kinctics of caleium accumulation in acute myo- cardial Ischemic injury[J].AmJ Pathol,1972,67(3):441-452.
[151]Anderson JR,Nawarskas JJ.Ranolazine.A metabolic modulator for the Treatment of chronic stable angina[J].Cardiol Rev,2005,13(4):202-210.
[152]Chaitman BR,Skettino SL,Parker JO,etal.Anti-ischemic effects and lo-ng-term survival during ranolazine monotherapy in patients with chronic severe angina[J].J Am Coll Cardiol,2004,43(8):1375-1382.
[153]Seiriea BM,Morrow DA.Ranolazine in patients with Angina and Coro- nary Artery Disease [J].Curr Cardiol Rep,2007,9(4):272-278.
[154]Hale SL, Kloner RA.Ranolazine,an Inhibitor of the Late Sodium Channel Current, Reduces postischemic Myocardial Dysfunetion in the Rabbit [J]. J Cardiovasc PhannacolTher,2006,11(4):249-255.
[155]Ju YK,Saint DA,Gage PW.Hypoxia increases persistent sodium current in rat ventricular myocytes[J].J Physiol,1996,497(Pt 2):337-347.
[156]Gralinski MR,Black SC,Kilgore KS,etal,Cardioprotective effects of ranolazine(RS-43285)in the isolated perfused rabbit heart[J]. Cardiovasc Res,1994,28 (8): 1231-1237.
[157]Williams IA,Xiao XH,Ju YK,etal.The rise of [Na(+)](i)during ischemia and reperfusion in the rat heart-underlying mechanisms [J].Pfiugers Arch,2007,454(6):903-912.
[158]Ramasamy R,Payne JA,Whang J,etal.Protection of ischemic myoc- ardium in Diabeties by inhibition of electroneutral Na+-K+-2Cl- cotransporter [J].Am J Physiol Heart Circ Physiol,2001,281(2):H515-522.
[159]Takeo S,Tanonaka K.Na+ overload-induecd mitochondrial damage in the Ischemic heart[J].Can J Physiol Phannacol,2004,82(12):1033-1043.
[160]Barry WH.Na“Fuzzy space”:does it exist,and is it important in ischemic injury? [J].J Cardiovase Electrophysiol,2006,17(l):543-546.
[161]Zhao W,Choi JH,Hong GR,etal.Left ventricular relaxation [J].Heart Fail Clin, 2008,4(l):37-46.
[162]Baartseheer A,Sehumaeher CA,Belterman CN,etal.[Na+]I and the driving force of the Na+/Ca2+-exchanger in heart failure[J].Cardiovasc Res,2003,57(15):986-995.
[163]An RH,He RR.Electrophysiological effects of m-nisoldipine and nisodipine on papillary muscles of guinea pig.Acta Pharmacol Sin,1990,11:310-314.
[164]Dangman KH,Dresdner KP J r,Michler RE.Transmembrane action potentials and intracellular potassium activity of baboon cardiac tissues[J].Cardiovasc Res, 1988,22 (3):204-212.
[165]Nazir SA,Lab MJ.Mechanoelectric feedback in the atrium of the isolated guinea-pig heart.Cardiovasc Res, 1996, 32:11.
[166]Yejia Song, John C. Shryock, Stefan Wagner, Lars S. Maier, and Luiz Belardinelli Blocking Late Sodium Current Reduces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dysfunction THE JOURNAL OF PHARMACOLOGY AND EXPEIMEN TAL THERAPEUTICS 2006;318[1]:214-222.
[167]贾宏钧.细胞膜离子通道[A].见:贾宏钧,王钟林,杨期东,主编.离子通道与心脑血管疾病—基础与临床[M].北京:人民卫生出版社,2001.24-71.
[168]苏静怡,李澈,苏哲坦,主编.心脏:从基础到临床[M].北京:北京医科大学中国协和医科大学联合出版社,1999.45-87.
[169]吴博威.心肌细胞电生理.见:贾宏钧,王钟林,杨期东主编.离子通道与心脑血管疾病(第一版) [M].人民卫生出版社,2001;153-178.
[170]Josephson IR,Sanchez-Chapula J,Brown AM. Early outward current in rat single ventricular cells[J].Circ Res,1984,54:157.
[171]Carmeliet E,Biermans G Callewaert G etal.potassium currents in cardiac cells [J]. Experientia,1987,43(11-12):1175-1184.
[172]Nerbonne JM.Molecular basis of functional voltage-gated K+ chnnael diversity in the mammalian myocardium [J].J Physiol,2000,525Pt2:285-298.
[173]张琼,王晓良.比较奎尼丁、E-4031对大鼠和豚鼠药物诱发心律失常模型的作用[J].中国药理学与毒理学杂志,1998,12(3):181-183·
[174]Varro A,Nanasi PP Lathrop DA.Potassiumu currents in isolated human atrial and ventricular cardiocytes[J].Acta physiol Scand,1993,149(2):133-142.
[175]SongY,Sllryoek JC,Wu L,etal.Antagonism by ranolazine of the Pro-arrhytmic effects of increasing late INA in guinea Pig ventricular myoeytes[J].J Cardiovase Pharinacol, 2004, 44(2):192-199.
[176]Belardinelli L,Shryoek JC,Fraser H.Inhibition of the late sodium current as a potential cardioprotective prineiple:effects of the late sodium current inhibiton ranolazine [J].Heart,2006,92(4):iv6-ivl4.
[177]Bers DM. Exitation-contraction coupling and cardiac contractile force [M]. Dordrecht, Germany: Kluwer Academic Publishers, 2001.
[178]Huang B, Sherif T, Gidh-Jain M, et al. Alterations of sodium channel kinetics and gene expression in the postinfarction remodeled myocardium [ J ]. J Cardiovasc Electrophysiol, 2001, 12: 218-225.
[179]Maier LS, Hasenfuss G. Role of [Na ] i and the emerging involvement of the late sodium current in the pathophysiology of cardiovascular disease [J].Eur Heart J,2006, 8:A6-A9.
[180]Song Y, Shryock JC,Wu L. Antagnism by ranolazine of the pro-arrhythmic effects ofincreasing late /Na in guinea pig ventricularmyocytes[J].J Cardiovasc Pharmacol, 2004,44: 192-199.
[181]Antzelevitch C,BelardinelliL, ZygmuntAC, et al. Electrophysiological effects of ranolazine, a novel antianginal agentwith antiarrhythmic p roperties[J].Circulation, 2004, 110: 904-910.
[182]Areles Molleman. Patch Clamping.( University of Hertfordshire, UK.) John Wiley & Sons, Ltd. 2003.
[183]刘振伟.实用膜片钳技术[M].北京:军事医学科学出版社,2006,115.
[184]Hamill OP,Marty A,Necher E,et al.improved patch clamp techniques for high resolution current recording from cells free membrane patches.Pflugers Arch,1981;39(1):85-100.
[185]周亮,曾晓荣.豚鼠心肌细胞急性酶分离的方法[J] .四川生理科学杂志,2000,22(2):35-36.
[186]张培华,马季骅.豚鼠心室肌细胞急性分离法中的要则[J] .中国病理生理杂志,2005,21(4):742、771.
[187]Razawa K.Kaibara M,Chara M etal.An improved method for isolating cardiac myocytes useful for Patchclamp studies[J]. Jap J Physiol 1990,40:157-163.
[188]陈军.膜片钳实验技术[M].北京:科学出版社,2001:1-7
[189]Yoshizumi Habuchi,Taiji Furukawa ,etal. Ethanol inhibition of Ca2十and Na+ currents in the guinea-ig heart.Eur J pharmacol,1995,292(2):143-149.
[190]Nobukuni O and Yoshiaki O . Molecular Diversity of Structure and Function of the Voltage-Gated Na+ Channels. Jpn. J. Pharmacol,2002;8(8):365-377.
[191]Kirsch GE. Na+ channels: structure,function,and classification. Drug DevelopRes, 1994: 3(3):26-35.
[192]罗自强,余承高.心脏的生物电活动.见:姚泰,罗自强主编.生理学(7年制规划教材) [M].北京:人民卫生出版社,2001;105.
[193]Song Y,Shryock JC,Wu L,etal.Antagonism by ranolazine of the Pro- arrhythmic effects of increasing late Ina in guinea pig ventrieular myocytes [J].J Cardiovase Phamacol, 2004,44(2):192-199.
[194]Baartscheer A,Schumacher CA,Belterman CN,etal.[Na+]i and the dri- ving force of the Na+/Ca2+-exehanger in heart failure [J].Cardiovase Res,2003,57(15):986-995.
[195]张自东,关新民,涂宗苹.神经元生物电的产生.见:关新民主编.医学神经生物学[M].北京:人民卫生出版社,2002;39-40.
[196]杨宝峰主编.药理学(第六版) [M].北京:人民卫生出版社,2003;209-214.
[197]Working Group on Arrhythmias of the European Society of Cardiology,The Sicillian gambit a New Approach to the Classification of Antiarrhythmic Drugs Based on Their Action on Arrhythmogenic Mechanisms. Circulation,1991;84(7):1831-1839.
[198]Juan Tamargo, Ricardo Caballero,Carmen Valenzuela, et al.Pharmacology of cardiac potassium channels.Cardiovascular Research 2004;62:9-33.
[199]Heidbuchel H,Vereecke J,Carmeliet E. Different K+ channes in human artial cells. Pflugers Arch,1989,414(Suppl l)S171-S172.
[200]Zicha S,Moss I,Allen B·Molecular basis of species-specific expression of repolarizing K+ currents in the heart. .Am J Physiol Heart Circ Physiol,2003;285(4):H1641-1649.
[201]Shibataa E,Drury T, Refsum H, etal. Contribution of transient outward current to repolarization in human atrium [J] Am J Physiol,989,257:H1773.
[202]Colatsky TJ ,Argentieri TM. Potassium channel blockers as antiarrhythmic drugs[J ]. Drug Dev Res ,1994 ,33 :235-249.
[203]Roden DM. Ionic mechanisms for prolongation of refractoriness and their proar2 rhythmic and antiarrhythmic correlates[J ]. Am J Cardiol , 1996 ,72 :12-16.
[204]Tamargo J,Caballero R,Gomez R. Pharmacology of cardiac Potassium channels, Cardiovasc Res,2004;62(1):9-33.
[205]Nakaya H. Electropharmacological assessment of the risk of dru-induced long-QT syndrome cusing native cardiac cells and cultured cells expressing HERG channels. Nippon Yakurigaku Zasshi,2003;121(6):384-392.
[206]Schram G,Zhang L,Derakhehan K,etal.Ranolazine: ion- channelbloc- king actions and in vivo electroPhysiological effects [J].Br J Pharrnacol,2004,142(8):1300-1308.
[207]Tamargo J,Caballero R,Gomez R. Pharmacology of cardiac potassium channels, Cardiovase Res,2004;62(1):9-33.
[208]Bean BP.Two kind of calcium channels in canine atrial cell:Differeces in kineties, Selectivity,and Pharmacology.J Gen physiol,1985;86:1-30.
[209]Xu X,Best PM.Increase in T-type currents in artrial myocytes from adultray with groghhormon secreting tumors.Proc Natl Acad Sci USA,1990;87:4655-4659.
[210]EliAsbeeta Cerbai,Alberto Giotti,AlesAsndro Mugelli.Charateristics of L-type calcium channel blockade by lacidipine in guinea-pig ventricular myocytes.British Journal of Pharmacology,1997,120:667-715
[212]Kenneth B.Walsh,Graham E.Parks.Changes in cardiac myocyte morphology alter the properties of voltage-gated ion channels [J].Cardiovascular Research,2002, 45(3):457-461
[213]Chu L,Takahashi R,Norota I,et al.Signal transduction and Ca2+ signaling in contractile regulation induced by crosstalk between endothein-1 and norepinephrine in dog ventricular myocardium[J]. Circ Res,2003,92(9):1024 -1032.
[214]Piacentino V , Dipla K, Gaughan JP, et al. Voltage-dependent Ca2+ release from the SR of feline ventricular myocytes is ex-plained by Ca2+ -induced Ca2+ release [J].J Physiol, 2000,523: 533-548.
[215]Maltsev VA, Sabbah UN, Higgins RSD, et al. Novel ultraslow inac- tivating sodium current in human ventricular cardiomyocytes [J].Circulation, 1998, 98: 2545-2552.
[216]吴立玲.心血管病理生理学[M].北京:北京医科大学出版社.2000;24-29.
[217] Wang W, Martindale J, Metzger JM. Parvalbumin isoforms for enhancing cardiac diastolic function[J], Cell Biochem Biophys.2008; 51(1):1-8.
[218]李小鹰.肌浆网钙ATP酶2a基因转导治疗心衰的研究[J].中华心血管病杂志,2005,33(6): 576-578.
[2]Zeng J, Rudy Y. Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence [J]. J Biophys ,1995,68(3), 949?964.
[3]Maltsev VA, Sabbah H N, Higgins RS, et al. Novel, ultraslow inactivating sodium current in human ventricularcardiomyocytes[J]. Circulation ,1998,98(23), 2545?2552.
[4]Wagner S, Dybkova N, Rasenack E C, et al. Ca/calmodulin-dependent protein kinase II regulates cardiac Na channels[J]. J Clin Invest, 2006,116(12), 3127?3138.
[5]Attwell D, Cohen IS, Eisner DA, et al. The steady state TTXsensitive (“window”) sodium current in cardiac Purkinje fibres[J]. Pflugers Arch ,1979,379,137?142.
[6]Colatsky TJ. Mechanism of action of lidocaine and quinidine on action potential duration in rabbit cardiac Purkinje fibers. Effects on steady state Na+ currents? [J]. Circ Res ,1982,50(1), 17?27.
[7]Wang DW, Kiyosue T, Sato T, et al. Comparison of the effects of class I antiarrhythmic drugs, cibenzoline, mexiletine and flecainide on the delayed rectifier K+ current of guinea-pig ventricular myocytes[J]. J Mol Cell Cardiol ,1996,28(5), 893?903.
[8]Patlak JB, Ortiz M. Slow currents through single sodium channels of the adult rat heart[J]. J Gen Physiol ,1985,86(1), 89?104.
[9]Berecki G, Zegers JG, Bhuiyan ZA, et al. Long-QT syndrome-related sodium channel mutations probed by the dynamic action potential clamp technique[J]. J Physiol, 2006,570(2), 237?250.
[10]Maltsev VA, Undrovinas AI. A multi-modal composition of the late Na+current in human ventricular cardiomyocytes[J]. Cardiovasc Res ,2006,69(1), 116?127.
[11]Zilberter Y, Starmer CF, Starobin J, et al. Late Na channels in cardiac cells: the physiological role of background Na channels[J]. Biophys J ,1994,67(1), 153?160.
[12]Maltsev VA, Sabbah HN, Undrovinas AI. Late sodium current is a novel target for amiodarone: studies in failing human myocardium[J]. J Mol Cell Cardiol ,2001,33,923?932.
[13]Zygmunt AC, Eddlestone GT, Thomas GP, et al. Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle[J]. Am J Physiol Heart Circ Physiol, 2001,281(2), H689?H697.
[14]Gintant GA, Datyner NB, Cohen IS. Slow inactivation of a tetrodotoxinsensitive current in canine cardiac Purkinje fibers[J]. Biophys J ,1984,45(3), 509?512.
[15]Vassalle M, Bocchi L, Du F. A slowly inactivating sodium current (INa2) in the plateau range in canine cardiac Purkinje single cells[J]. Exp Physiol, 2007,92(1), 161?173.
[16]Sakmann BF, Spindler AJ, Bryant SM, et al. Distribution of a persistent sodium current across the ventricular wall in guinea pigs[J]. Circ Res ,2000,87(10),910?914.
[17]Saint DA. The role of the persistent Na(+) current during cardiac ischemia and hypoxia[J]. J Cardiovasc Electrophysiol ,2006, 17(Suppl 1), S96?S103.
[18]Undrovinas AI, Maltsev VA, Kyle JW, et al.Gating of the late Na+ channel in normal and failing human myocardium[J]. J Mol Cell Cardiol,2002,34(11), 1477?1489.
[19]Maltsev VA, Sabbah HN, Tanimura M, et al.Relationship between action potential, contraction–relaxation pattern, and intracellular Ca2+ transient in cardiomyocytes of dogs with chronic heart failure[J].Cell Mol Life Sci ,1998,54(6), 597?605.
[20]Maltsev VA., Silverman N, Sabbah HN, et al. Chronic heart failure slows late sodium current in human and canine ventricular myocytes: implications for repolarization variability[J]. Eur J Heart Fail,2007,9(3),219?227.
[21]Bennett PB, Yazawa K, Makita N, et al. Molecular mechanism for an inherited cardiac arrhythmia[J]. Nature ,1995,376, 683?685.
[22]Wang DW, Yazawa K, George AL, et al. Characterization of human cardiac Na+ channel mutations in the congenital long QT syndrome[J]. Proc Natl Acad Sci U S A,1996,93, 13200?13205.
[23]Clancy CE, Tateyama M, Liu H, et al. Non-equilibrium gating in cardiac Na+ channels: an original mechanism of arrhythmia[J]. Circulation ,2003,107(17), 2233?2237.
[24]Abriel H, Kass RS. Regulation of the voltage-gated cardiac sodium channel Nav1.5 by interacting proteins. Trends Cardiovasc Med ,2005,15(1), 35?40.
[25]Meadows LS, Isom LL. Sodium channels as macromolecular complexes:implications for inherited arrhythmia syndromes[J]. Cardiovasc Res ,2005, 67(3), 448?458.
[26]Mohler PJ, Schott JJ, Gramolini AO, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death[J]. Nature ,2003, 421(6923), 634?639.
[27]Vatta M, Ackerman MJ, Ye B, et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome[J]. Circulation ,2006,114(2006), 2104?2112.
[28]Priori SG, Corr PB. Mechanisms underlying early and delayed afterdepolarizations induced by catecholamines[J]. Am J Physiol ,1990,258(1990), H1796?H1805.
[29]Burashnikov A, Antzelevitch C. Late-phase 3 EAD. A unique mechanism contributing to initiation of atrial fibrillation[J]. Pacing Clin Electrophysiol ,2006,29(3), 290?295.
[30]Undrovinas AI, Belardinelli L, Undrovinas NA, et al. Ranolazine improves abnormal repolarization and contraction in left ventricular myocytes of dogs with heart failure by inhibiting late sodium current[J]. J Cardiovasc Electrophysiol ,2006,17(Suppl 1), S169?S177.
[31]Chauhan VS, Tuvia S, Buhusi M, et al.Abnormal cardiac Na(+) channel properties and QT heart rate adaptation in neonatal ankyrin(B) knockout mice[J]. Circ Res, 2000,86(4), 441?447.
[32]Chen C, Bharucha V, Chen Y, et al.Reduced sodium channel density, altered voltage dependence of inactivation,and increased susceptibility to seizures in mice lacking sodium channel beta 2-subunits[J]. Proc Natl Acad Sci U S A ,2002, 99(26), 17072?17077.
[33]Waxman SG. Neurobiology: a channel sets the gain on pain[J].Nature ,2006,444, 831?832.
[34]Lehmann-Horn F, Jurkat-Rott K. Voltage-gated ion channels and hereditarydisease[J]. Physiol Rev, 1999,79(4), 1317?1372.
[35]Macianskiene R, Bito V, Raeymaekers L, et al.Action potential changes associated with a slowed inactivation of cardiac voltage-gated sodium channels by KB130015[J]. Br J Pharmacol , 2003,139(8), 1469?1479.
[36]Undrovinas AI, Maltsev VA, Sabbah HN. Repolarization abnormalities in cardiomyocytes of dogs with chronic heart failure: role of sustained inward current[J]. Cell Mol Life Sci, 1999,55(3), 494?505.
[37]Valdivia CR, Chu WW, Pu J, et al. Increased late sodium current in myocytes from a canine heart failure model and from failing human heart[J]. J Mol Cell Cardiol ,2005,38(3),475?483.
[38]Ward CA, Giles WR. Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes[J]. J Physiol, 1997,500(Pt 3), 631?642.
[39]Ma JH, Luo AT, Zhang PH. Effect of hydrogen peroxide on persistent sodium current in guinea pig ventricular myocytes[J]. Acta Pharmacol Sin ,2005,26,828?834.
[40]Song Y, Shryock JC, Wagner S, et al. Blocking late sodium current reduces hydrogen peroxide-induced arrhythmogenic activity and contractile dysfunction[J]. J Pharmacol Exp Ther ,2006,318(1), 214?222.
[41]Ahern GP,Hsu SF, Klyachko VA, et al. Induction ofpersistent sodium current by exogenous and endogenous nitric oxide[J]. J Biol Chem ,2000,275, 28810?28815.
[42]Tateyama M, Liu H, Yang AS, et al. Structural effects of an LQT-3 mutation on heart Na+ channel gating[J]. Biophys J,2004, 86(3), 1843?1851.
[43]Hammarstrom AK, Gage PW. Hypoxia and persistent sodium current[J]. Eur Biophys J, 2002,31(5), 323?330.
[44]Ferrari R. Oxygen-free radicals at myocardial level: effects of ischaemia and reperfusion[J]. Adv Exp Med Biol,1994, 366, 99?111.
[45]Pacher P, Schulz R, Liaudet L, et al.Nitrosative stress and pharmacological modulation of heart failure[J]. Trends Pharmacol Sci ,2005,26(6), 302?310.
[46]Wu J, Corr PB. Palmitoyl carnitine modifies sodium currents and induces transient inward current in ventricular myocytes[J]. Am J Physiol ,1994, 266(3,Pt2), H1034?H1046.
[47]Gautier M, Zhang H, Fearon IM.Peroxynitrite formation mediates LPCinduced augmentation of cardiac late sodium currents[J]. J Mol Cell Cardiol ,2008,44(2), 241?251.
[48]Kohlhardt M, Fichtner H, Frobe U. Metabolites of the glycolytic pathway modulate the activity of single cardiac Na+ channels[J]. FASEB,1989, J 3(8), 1963?1967.
[49]Tan HL, Kupershmidt S, Zhang R, et al. A calcium sensor in the sodium channel modulates cardiac excitability[J]. Nature,2002, 415, 442?447.
[50]Bezzina C, Veldkamp M.W, van Den Berg MP, et al. A single Na(+) channel mutation causing both long-QT and Brugada syndromes[J]. Circ Res ,1999,85(12), 1206?1213.
[51]Zong XG, Dugas M, Honerjager P. Relation between veratridine reaction dynamics and macroscopic Na current in single cardiac cells[J]. J Gen Physiol ,1992,99(5), 683?697.
[52]Wang SY, Wang GK. Voltage-gated sodium channels as primary targets of diverse lipid-soluble neurotoxins[J]. Cell Signal ,2003,15(2), 151?159.
[53]Spencer CI, Yuill KH, Borg JJ, et al. Actions of pyrethroid insecticides on sodium currents, action potentials, and contractile rhythm in isolatedmammalian ventricularmyocytes and perfused hearts[J]. J Pharmacol Exp Ther ,2001,298(3), 1067?1082.
[54]Soderlund DM, Clark JM, Sheets LP, et al. Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment[J]. Toxicology ,2002,171(1), 3?59.
[55]Spencer CI., Sham JS. Mechanisms underlying the effects of the pyrethroid tefluthrin on action potential duration in isolated rat ventricular myocytes[J].J Pharmacol Exp Ther ,2005,315(1), 16?23.
[56]Honerjager P. Cardioactive substances that prolong the open state of sodium channels[J]. Rev Physiol Biochem Pharmacol ,1982,92, 1?74.
[57]Hoey A, Amos GJ, Ravens U. Comparison of the action potential prolonging and positive inotropic activity of DPI 201-106 and BDF 9148 in human ventricular myocardium[J]. J Mol Cell Cardiol ,1994,26, 985?994.
[58]Yuill KH, Convery MK, Dooley PC, et al. Effects of BDF 9198 on action potentials and ionic currents from guinea-pig isolated ventricular myocytes[J]. Br J Pharmacol ,2000,130, 1753?1766.
[59]Fu LY, Li Y, Cheng L, Zhou HY, et al. Effect of sea anemone toxin anthopleurin-Q on sodium current in guinea pig ventricular myocytes[J]. Acta Pharmacol Sin,2001, 22(12), 1107?1112.
[60]Schreibmayer W, Kazerani H,Tritthart HA. A mechanistic interpretation of the action of toxin II from Anemonia sulcata on the cardiac sodium channel[J]. Biochim Biophys Acta ,1987,901(2), 273?282.
[61]Chahine M, Plante E, Kallen RG. Sea anemone toxin (ATX II) modulation of heart and skeletal muscle sodium channel alpha-subunits expressed in tsA201cells[J]. J Membr Biol, 1996,152(1), 39?48.
[62]Mantegazza M, Franceschetti S, Avanzini G. Anemone toxin (ATX II)-induced increase in persistent sodium current: effects on the firing properties of rat neocortical pyramidal75
[63]Sicouri S, Antzelevitch D, Heilmann C, et al. Effects of sodium channel block with mexiletine to reverse action potential prolongation in in vitro models of the long term QT syndrome[J]. J Cardiovasc Electrophysiol ,1997,8(11), 1280?1290.
[64]Nagatomo T, January CT, Makielski JC. Preferential block of late sodium current in the LQT3 DeltaKPQ mutant by the class I(C) antiarrhythmic flecainide[J]. Mol Pharmacol,2000, 57(1), 101?107.
[65]Fredj S, Sampson KJ, Liu H, et al. Molecular basis of ranolazine block of LQT-3 mutant sodium channels: evidence for site of action[J]. Br J Pharmacol ,2006,148(1),16?24.
[66]Sicouri S, Glass A, Belardinelli L, et al. Antiarrhythmic effects of ranolazine in canine pulmonary vein sleeve preparations[J]. Heart Rhythm ,2008,5(7), 1019?1026.
[67]、Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties[J]. Circulation , 2004,110(8), 904?910.
[68]Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine[J]. Heart ,2006,92(Suppl 4), iv6?iv14.
[69]Tian XL, Yong SL,Wan X, et al. Mechanisms by which SCN5A mutation N1325S causes cardiac arrhythmias and sudden death in vivo[J]. Cardiovasc Res ,2004,61(2), 256?267.
[70]Wu L, Shryock JC, Song Y, et al. An increase in late sodium current potentiates the proarrhythmic activities of low-risk QT-prolonging drugs in female rabbit hearts[J]. J Pharmacol Exp Ther,2006, 316(2), 718?726.
[71] Wu L, Rajamani S, Shryock JC, et al. Augmentation of late sodium current unmasks the proarrhythmic effects of amiodarone[J]. Cardiovasc Res,2007, 77(3), 481?488.
[72]Lathrop DA, Varro A. The combined electrophysiological effects of lignocaine and sotalol in canine isolated cardiac Purkinje fibres are rate-dependent[J].Br J Pharmacol,1990, 99(1), 124?130.
[73]Thomsen MB, Verduyn SC, Stengl M, et al. Increased short-term variability of repolarization predicts d-sotalolinduced torsades de pointes in dogs[J]. Circulation ,2004,110(16), 2453?2459.
[74]Hondeghem LM, Carlsson L, Duker G. Instability and triangulation of the action potentialpredict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic[J]. Circulation ,2001,103(15), 2004?2013.
[75]Lu HR, Vlaminckx E, Van Ammel K, et al. Drug-induced long QT in isolated rabbit Purkinje fibers: importance of action potential duration, triangulation and early afterdepolarizations[J]. Eur J Pharmacol ,2002,452(2), 183?192.
[76]Shimizu W, Antzelevitch C. Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsade despointes in LQT2 and LQT3 models of the long-QT syndrome[J]. Circulation ,1997,96(6),2038?2047.
[77]Studenik CR, Zhou Z, January CT. Differences in action potential and early afterdepolarization properties in LQT2 and LQT3 models of long QT syndrome[J]. Br J Pharmacol ,2001,132(1), 85?92.
[78]Abrahamsson C, Carlsson L, Duker G. Lidocaine and nisoldipine attenuate almokalant- induced dispersion of repolarization and early afterdepolarizations in vitro[J]. J Cardiovasc Electrophysiol 1996,7(11),1074?1081.
[79]Belardinelli L, Antzelevitch C, Vos MA. Assessing predictors of druginduced torsade de pointes[J]. Trends Pharmacol Sci ,2003,24(12), 619?625.
[80]Tomaselli GF, Beuckelmann DJ, Calkins HG, et al. Sudden cardiac death in heart failure[J]. The role of abnormal repolarization. Circulation ,1994,90(5), 2534?2539.
[81]Roden DM. Long QT syndrome: reduced repolarization reserve and the genetic link[J]. J Intern Med ,2006,259(1), 59?69.
[82]Ueda N, Zipes DP, Wu J.Prior ischemia enhances arrhythmogenicity in isolated canine ventricular wedge model of long QT3[J]. Cardiovasc Res,2004, 63(1), 69?76.
[83]Kaprielian R, Wickenden AD, Kassiri Z, et al. Relationship between K+ channel down- regulation and [Ca2+]i in rat ventricular myocytes following myocardial infarction[J]. J Physiol ,1999,517(Pt 1), 229?245.
[84]Lei M, Zhang H, Grace AA, Huang CL. SCN5A and sinoatrial node pacemaker function[J]. Cardiovasc Res ,2007,74(3), 356?365.
[85]Veldkamp MW, Wilders R, Baartscheer A, et al. Contribution of sodium channel mutations to bradycardia and sinus node dysfunction in LQT3 families[J]. Circ Res,2003, 92(9), 976?983.
[86]Levi AJ, Dalton GR, Hancox JC, et al. Role of intracellular sodium overload in the genesis of cardiac arrhythmias[J].J Cardiovasc Electrophysiol ,1997,8(6), 700?721.
[87]Makielski JC, Farley AL. Na(+) current in human ventricle: implications for sodium loading and homeostasis[J]. J Cardiovasc Electrophysiol,2006, 17(Suppl 1), S15?S20.
[88]Pieske B, Houser SR. [Na+]i handling in the failing human heart[J]. Cardiovasc Res ,2003,57(4), 874?886.
[89]Li L, DeSantiago J, Chu G, et al.Phosphorylation of phospholamban and troponin I in beta-adrenergic-induced acceleration of cardiac relaxation[J]. Am J Physiol Heart Circ Physiol ,2000,278(3), H769?H779.
[90]Bers DM. Cardiac inotropy and Ca mismanagement. In D. M. Bers ,Editor, Excitation–contraction coupling and cardiac contractile force (2nd ed). [M] Boston:Kluwer Academic Publishers. 2002,273?331.
[91]Vassalle M, Lin CI. Calcium overload and cardiac function[J]. J Biomed Sci ,2004,11(5), 542?565.
[92]Sipido KR. Calcium overload, spontaneous calcium release, and ventricular arrhythmias[J]. Heart Rhythm ,2006,3(8), 977?979.
[93]Gyorke S, Gyorke I, Lukyanenko V, et al. Regulation of sarcoplasmic reticulum calcium release by luminal calcium in cardiac muscle[J]. Front Biosci ,2002, 7, d1454?d1463.
[94]Zaza A, Rocchetti M, Brioschi A, et al. Dynamic Ca2+- induced inward rectification of K+ current during the ventricular action potential[J]. Circ Res ,1998,82(9), 947?956.
[95]Choi BR, Burton F, Salama G. Cytosolic Ca2+ triggers early afterdepolarizations and Torsade de Pointes in rabbit hearts with type 2 long QTsyndrome[J]. J Physiol,2002, 543(2), 615?631.
[96]Wan X, Laurita KR, Pruvot EJ, et al. Molecular correlates of repolarization alternans in cardiac myocytes[J]. J Mol Cell Cardiol,2005, 39(3), 419?428.
[97]Maier LS, Zhang T, Chen L, et al. Transgenic CaMKIIdeltaC overexpression uniquely alters cardiac myocyte Ca2+handling: reduced SR Ca2+ load and activated SR Ca2+ release[J]. Circ Res ,2003,92(8), 904?911.
[98]Kranias EG. Regulation of Ca2+ transport by cyclic 3′,5′-AMP-dependent and calcium-calmodulin-dependent phosphorylation of cardiac sarcoplasmic reticulum[J].Biochim Biophys Acta,1985, 844(2), 193?199.
[99]Wagner S, Dybkova N, Rasenack EC, et al. Ca/calmodulin-dependent protein kinase II regulates cardiac Na channels[J]. J Clin Invest 2006,116,3127-3138.
[100]Wilkins BJ, Molkentin JD. Calcium-calcineurin signaling in the regulation of cardiac hypertrophy[J]. Biochem Biophys Res Commun ,2004,322, 1178?1191.
[101]Bers DM, Guo T. Calcium signaling in cardiac ventricular myocytes[J]. Ann N YAcad Sci,2005, 1047, 86?98.
[102]Dorn GW, Force T. Protein kinase cascades in the regulation of cardiac hypertrophy[J]. J Clin Invest ,2005,115(3), 527?537.
[103]Bache RJ, Vrobel TR, Arentzen CE, et al. Effect of maximal coronary vasodilation on transmural myocardial perfusion during tachycardia in dogs with left ventricular hypertrophy[J]. Circ Res ,1981,49(3), 742?750.
[104]Nador F, Beria G, De Ferrari GM, et al. Unsuspected echocardiographic abnormality in the long Q–T syndrome:diagnostic, prognostic and pathogenetic implications[J]. Circulation ,1991,84(4), 1530?1542.
[105]Maack C, Cortassa S, Aon MA, et al. Elevated cytosolic Na+ decreases mitochondrial Ca2+ uptake during excitation–contraction coupling and impairs energetic adaptation in cardiacmyocytes[J]. Circ Res ,2006,99(2),172?182.
[106]Fredj S, Lindegger N, Sampson KJ, et al.Altered Na+channels promote pause-induced spontaneous diastolic activity in long QT syndrome type 3 myocytes[J]. Circ Res,2006, 99(11), 1225?1232.
[107]Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young[J]. J Am Coll Cardiol ,2007,49(2), 240?246.
[108]Martin RL, McDermott JS, Salmen HJ, et al.The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization: influence of multi-channel block[J]. J Cardiovasc Pharmacol ,2004,43,369?379.
[109]Song Y, Shryock JC, Wu L, et al. Antagonism by ranolazine of the pro-arrhythmic effects of increasing late INa in guinea pig ventricularmyocytes[J]. J Cardiovasc Pharmacol , 2004,44(2), 192?199.
[110]Fedida D, Orth PM, Hesketh JC, et al. The role of late I and antiarrhythmic drugs inEADformation and termination in Purkinje fibers[J]. J Cardiovasc Electrophysiol , 2006, 17(Suppl 1), S71?S78.
[111]Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associated proarrhythmic effects. A review with special reference to torsade de pointes tachycardia[J]. Ann Intern Med ,1994,121(7), 529?535.
[112]Benhorin J, Taub R, Goldmit M, et al. Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? [J]. Circulation,2000, 101 (14), 1698?1706.
[113]Epstein AE, Hallstrom AP, Rogers WJ, et al. Mortality following ventricular arrhythmia suppression by encainide,flecainide, and moricizine after myocardial infarction. The original design concept of the Cardiac Arrhythmia Suppression Trial (CAST) [J]. JAMA ,1993,270(20), 2451?2455.
[114]Allessie MA, Bonke FIM, Schopman FJG. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. The“leading circle”concept: a new model of circus move- ment in cardiac tissue without the involvement of an anatomical obstacle[J]. Circ Res, 1977, 41(1), 9?18.
[115]Morrow DA., Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial[J]. JAMA,2007, 297(16), 1775?1783.
[116]Scirica BM, Morrow DA, Hod H, et al. Effect of ranolazine, an antianginal agent with novel electrophysiologicalproperties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial[J]. Circulation ,2007,116(15), 1647?1652.
[117]Sossalla S, Wagner S, Rasenack EC, et al. Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts—role of late sodium current and intracellular ion accumulation[J]. J Moll Cell Cardiol ,2007,45(1), 32?43.
[118]Shannon TR, Ginsburg KS, Bers DM. Quantitative assessment of the SR Ca2+ leak-load relationship. Circ Res,2002, 91(3), 594?600.
[119]Tamareille S, Le Grand B, John GW, et al. Antiischemic compound KC 12291 prevents diastolic contracture in isolated atria by blockade of voltage-gated sodium channels[J]. J Cardiovasc Pharmacol ,2002,40,346?355.
[120]Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions[J]. Circulation ,2006,113(20), 2462?2472.
[121]Cheng JW. Ranolazine for the management of coronary artery disease[J]. ClinTher ,2006,28(12), 1996?2007.
[122]Rousseau MF, Pouleur H, Cocco G, et al. Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris[J]. Am J Cardiol ,2005,95(3), 311?316.
[123]Cocco G, Rousseau MF, Bouvy T, et al. Effects of a new metabolic modulator, ranolazine, on exercise tolerance in angina pectoris patients treated with beta-blocker or diltiazem[J]. J Cardiovasc Pharmacol,1992,20(1), 131?138.
[124]Stone PH, Gratsiansky NA, Blokhin A, et al.Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial[J]. J Am Coll Cardiol ,2006,48(3), 566?575
[125]Libby P. Current concepts of the pathogenesis of the acute coronary syndromes [J]. Circulation,2001, 104(3), 365?372.
[126]Akhtar M, Breithardt G, Camm AJ, et al.Task Force of the Working Group on Arrhythmias of the European Society of Cardiology CAST and beyond. Implications of the Cardiac Arrhythmia Suppression Trial[J]. Circulation ,1990,81(3), 1123?1127.
[127]The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction[J]. N Engl J Med ,1989,321(6), 406?412.
[128]Walker MJA,Eustis MJ,Hearse DJ etal.The lambeth convention: Guide- lines for the study of arrhythmias in ischemia,infarction and reperfusion [J]. Ca- driovas Res, 1988,22:447-455.
[129]Steaer SE,Yellow DM.The protective effect of heart stress against reper- fusion arrhymias in the rat[J].J Mol cell cardiol,1993,25:1471.
[130]Ruiz-Gines JA,Lopez-Ongil S,Gonzalez-Rubio M,et al.Reactive oxygen species induce proliferation of bovine aortic endothelial cells[J].Jcardiovasc Pharmacol, 2000, 35 (1):109-113.
[131]Granger DN,Rutili G,McCord JM.Superoxide radicals in feline intestinal ischemia [J]Gastroenterology,1981,81(1):22-29.
[132].孙涛,苏全生.自由基与心肌缺血/再灌注损伤[J].实用医院临床志,2006,3(4):94-96.
[133]Kim JK,Pedram A,Razandi M,et al.Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase is forms[J].J Biol Chem,2006,281(10):6760-6767.
[134]Bhakuni D,ChandraM,MisraMK.Oxidative stress Parameters in erythro- cytes of post-reperfused patients with myocardial infarvction[J].J Enzyme Inhib Med Chem., 2005,20(4):377-381.
[135]Cheng H,Liu W,Ai X.Protective effect of cureumin on myocardial Iso- cheimal reperfusion injury in rats[J]ZhongYaoCai,2005,28(10):920-922.
[136]Paradies G Petrosillo G Pistolese M et al.Deerease in mitoehondrial complex activity in ischemic/reperfused rat heart:involvement of reactive oxygen species and cardiolipin [J].Circ Res,2004,94(l):53-59.
[137]Zima AV;Blatter LA.Redox regulation of cardiac calcium channels and transporters [J].Cardiovasc Res,2006,71(2):310-321.
[138]Wagner S,Seidler T,Pieht E,etal.Na+-Ca2+ exehanger overexpression Predisposes to reactive oxygen species-induced injury[J].Cardiovase Res,2003,60(2):404-412.
[139]Paradies G,Petrosillo G,Pistolese M,etal.Devcrease in mitoehondrial complex I activity in isehemic/reperfused rat heart: involvement of reactive ox- ygen species and cardiologic[J].Circ Res,2004,94(l):53-59.
[140]Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions[ J ]. Circulation, 2006, 113: 2462-2472.
[141]Wang P,Fraser H,Lloyd SG,et al.A Comparison between ranolazine and CVT-4325,a novel inhibitor of fatty acid oxidation, on cardiac metabolism and left ventricular function in rat isolated perfused heart during ischemia and reperfusion[J].J Pharmacol Exp Ther,2007,321(1):213-220.
[142]Mason RP. Mechanisms of plaque stabilization for the dihydropyridine calcium channel blocker amlodip ine: review of the evidence [J].Atherosclerosis, 2002,165: 191-199.
[143]Ide T,Tsutsui H,Kinugawa S,et al.Direct evidence for increased hydro xyl Radicals originating from superoxide in the failing myocardium[J].Circ Res,2000,86(2):152-157.
[144]Matsumura H,Hara A,Hashizume H,etal.Protective effeets of rano- lazine,a Novel anti-ischemic drug,on the hydrogen peroxide-induced deran- gements in isolated,Perfused rat heart:comparsion with dichloroacetate [J].Jpn J Pharmacol,1998,77(l):31-39.
[145]Song Y,ShryocJC,Wagner S,etal.Blocking Late Sodium Current Red- uces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dys- function[J]. JPET, 2006,318(l):214-222.
[146]Song Y,Sllryoek JC,Wu L,etal.Antagonism by ranolazine of the Pro- arrhythmic effects of increasing late INA in guinea pig ventricula rmyocytes[J].J Cardiovasc Pharmacol,2004,44(2):192-199.
[147]Antzelevitch C,Belardinelli L,Zygmunt AC,etal.Electrophysiological effects of ranolazine,a novel antianginal agent with antiarrhythmic properties [J].Circulation,2004, 110(8):904-910.
[148]ThomPson Da,Waldron CB,Jnul SM,etal.Analysis of veniricular Pre- ssure during isovolumic relaxation in coronary artery disease[J].Circulation,1982,65(4):690-697.
[149]Okda Y.Volume exPansion-sensing outward-rectifier Cl- cannels:fresh start to The molecular identity and volume sensor[J].AmJ physiol,1997,273(Cell physil 42):C755- C789.
[150]Shen AC,Jennings RB.Kinctics of caleium accumulation in acute myo- cardial Ischemic injury[J].AmJ Pathol,1972,67(3):441-452.
[151]Anderson JR,Nawarskas JJ.Ranolazine.A metabolic modulator for the Treatment of chronic stable angina[J].Cardiol Rev,2005,13(4):202-210.
[152]Chaitman BR,Skettino SL,Parker JO,etal.Anti-ischemic effects and lo-ng-term survival during ranolazine monotherapy in patients with chronic severe angina[J].J Am Coll Cardiol,2004,43(8):1375-1382.
[153]Seiriea BM,Morrow DA.Ranolazine in patients with Angina and Coro- nary Artery Disease [J].Curr Cardiol Rep,2007,9(4):272-278.
[154]Hale SL, Kloner RA.Ranolazine,an Inhibitor of the Late Sodium Channel Current, Reduces postischemic Myocardial Dysfunetion in the Rabbit [J]. J Cardiovasc PhannacolTher,2006,11(4):249-255.
[155]Ju YK,Saint DA,Gage PW.Hypoxia increases persistent sodium current in rat ventricular myocytes[J].J Physiol,1996,497(Pt 2):337-347.
[156]Gralinski MR,Black SC,Kilgore KS,etal,Cardioprotective effects of ranolazine(RS-43285)in the isolated perfused rabbit heart[J]. Cardiovasc Res,1994,28 (8): 1231-1237.
[157]Williams IA,Xiao XH,Ju YK,etal.The rise of [Na(+)](i)during ischemia and reperfusion in the rat heart-underlying mechanisms [J].Pfiugers Arch,2007,454(6):903-912.
[158]Ramasamy R,Payne JA,Whang J,etal.Protection of ischemic myoc- ardium in Diabeties by inhibition of electroneutral Na+-K+-2Cl- cotransporter [J].Am J Physiol Heart Circ Physiol,2001,281(2):H515-522.
[159]Takeo S,Tanonaka K.Na+ overload-induecd mitochondrial damage in the Ischemic heart[J].Can J Physiol Phannacol,2004,82(12):1033-1043.
[160]Barry WH.Na“Fuzzy space”:does it exist,and is it important in ischemic injury? [J].J Cardiovase Electrophysiol,2006,17(l):543-546.
[161]Zhao W,Choi JH,Hong GR,etal.Left ventricular relaxation [J].Heart Fail Clin, 2008,4(l):37-46.
[162]Baartseheer A,Sehumaeher CA,Belterman CN,etal.[Na+]I and the driving force of the Na+/Ca2+-exchanger in heart failure[J].Cardiovasc Res,2003,57(15):986-995.
[163]An RH,He RR.Electrophysiological effects of m-nisoldipine and nisodipine on papillary muscles of guinea pig.Acta Pharmacol Sin,1990,11:310-314.
[164]Dangman KH,Dresdner KP J r,Michler RE.Transmembrane action potentials and intracellular potassium activity of baboon cardiac tissues[J].Cardiovasc Res, 1988,22 (3):204-212.
[165]Nazir SA,Lab MJ.Mechanoelectric feedback in the atrium of the isolated guinea-pig heart.Cardiovasc Res, 1996, 32:11.
[166]Yejia Song, John C. Shryock, Stefan Wagner, Lars S. Maier, and Luiz Belardinelli Blocking Late Sodium Current Reduces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dysfunction THE JOURNAL OF PHARMACOLOGY AND EXPEIMEN TAL THERAPEUTICS 2006;318[1]:214-222.
[167]贾宏钧.细胞膜离子通道[A].见:贾宏钧,王钟林,杨期东,主编.离子通道与心脑血管疾病—基础与临床[M].北京:人民卫生出版社,2001.24-71.
[168]苏静怡,李澈,苏哲坦,主编.心脏:从基础到临床[M].北京:北京医科大学中国协和医科大学联合出版社,1999.45-87.
[169]吴博威.心肌细胞电生理.见:贾宏钧,王钟林,杨期东主编.离子通道与心脑血管疾病(第一版) [M].人民卫生出版社,2001;153-178.
[170]Josephson IR,Sanchez-Chapula J,Brown AM. Early outward current in rat single ventricular cells[J].Circ Res,1984,54:157.
[171]Carmeliet E,Biermans G Callewaert G etal.potassium currents in cardiac cells [J]. Experientia,1987,43(11-12):1175-1184.
[172]Nerbonne JM.Molecular basis of functional voltage-gated K+ chnnael diversity in the mammalian myocardium [J].J Physiol,2000,525Pt2:285-298.
[173]张琼,王晓良.比较奎尼丁、E-4031对大鼠和豚鼠药物诱发心律失常模型的作用[J].中国药理学与毒理学杂志,1998,12(3):181-183·
[174]Varro A,Nanasi PP Lathrop DA.Potassiumu currents in isolated human atrial and ventricular cardiocytes[J].Acta physiol Scand,1993,149(2):133-142.
[175]SongY,Sllryoek JC,Wu L,etal.Antagonism by ranolazine of the Pro-arrhytmic effects of increasing late INA in guinea Pig ventricular myoeytes[J].J Cardiovase Pharinacol, 2004, 44(2):192-199.
[176]Belardinelli L,Shryoek JC,Fraser H.Inhibition of the late sodium current as a potential cardioprotective prineiple:effects of the late sodium current inhibiton ranolazine [J].Heart,2006,92(4):iv6-ivl4.
[177]Bers DM. Exitation-contraction coupling and cardiac contractile force [M]. Dordrecht, Germany: Kluwer Academic Publishers, 2001.
[178]Huang B, Sherif T, Gidh-Jain M, et al. Alterations of sodium channel kinetics and gene expression in the postinfarction remodeled myocardium [ J ]. J Cardiovasc Electrophysiol, 2001, 12: 218-225.
[179]Maier LS, Hasenfuss G. Role of [Na ] i and the emerging involvement of the late sodium current in the pathophysiology of cardiovascular disease [J].Eur Heart J,2006, 8:A6-A9.
[180]Song Y, Shryock JC,Wu L. Antagnism by ranolazine of the pro-arrhythmic effects ofincreasing late /Na in guinea pig ventricularmyocytes[J].J Cardiovasc Pharmacol, 2004,44: 192-199.
[181]Antzelevitch C,BelardinelliL, ZygmuntAC, et al. Electrophysiological effects of ranolazine, a novel antianginal agentwith antiarrhythmic p roperties[J].Circulation, 2004, 110: 904-910.
[182]Areles Molleman. Patch Clamping.( University of Hertfordshire, UK.) John Wiley & Sons, Ltd. 2003.
[183]刘振伟.实用膜片钳技术[M].北京:军事医学科学出版社,2006,115.
[184]Hamill OP,Marty A,Necher E,et al.improved patch clamp techniques for high resolution current recording from cells free membrane patches.Pflugers Arch,1981;39(1):85-100.
[185]周亮,曾晓荣.豚鼠心肌细胞急性酶分离的方法[J] .四川生理科学杂志,2000,22(2):35-36.
[186]张培华,马季骅.豚鼠心室肌细胞急性分离法中的要则[J] .中国病理生理杂志,2005,21(4):742、771.
[187]Razawa K.Kaibara M,Chara M etal.An improved method for isolating cardiac myocytes useful for Patchclamp studies[J]. Jap J Physiol 1990,40:157-163.
[188]陈军.膜片钳实验技术[M].北京:科学出版社,2001:1-7
[189]Yoshizumi Habuchi,Taiji Furukawa ,etal. Ethanol inhibition of Ca2十and Na+ currents in the guinea-ig heart.Eur J pharmacol,1995,292(2):143-149.
[190]Nobukuni O and Yoshiaki O . Molecular Diversity of Structure and Function of the Voltage-Gated Na+ Channels. Jpn. J. Pharmacol,2002;8(8):365-377.
[191]Kirsch GE. Na+ channels: structure,function,and classification. Drug DevelopRes, 1994: 3(3):26-35.
[192]罗自强,余承高.心脏的生物电活动.见:姚泰,罗自强主编.生理学(7年制规划教材) [M].北京:人民卫生出版社,2001;105.
[193]Song Y,Shryock JC,Wu L,etal.Antagonism by ranolazine of the Pro- arrhythmic effects of increasing late Ina in guinea pig ventrieular myocytes [J].J Cardiovase Phamacol, 2004,44(2):192-199.
[194]Baartscheer A,Schumacher CA,Belterman CN,etal.[Na+]i and the dri- ving force of the Na+/Ca2+-exehanger in heart failure [J].Cardiovase Res,2003,57(15):986-995.
[195]张自东,关新民,涂宗苹.神经元生物电的产生.见:关新民主编.医学神经生物学[M].北京:人民卫生出版社,2002;39-40.
[196]杨宝峰主编.药理学(第六版) [M].北京:人民卫生出版社,2003;209-214.
[197]Working Group on Arrhythmias of the European Society of Cardiology,The Sicillian gambit a New Approach to the Classification of Antiarrhythmic Drugs Based on Their Action on Arrhythmogenic Mechanisms. Circulation,1991;84(7):1831-1839.
[198]Juan Tamargo, Ricardo Caballero,Carmen Valenzuela, et al.Pharmacology of cardiac potassium channels.Cardiovascular Research 2004;62:9-33.
[199]Heidbuchel H,Vereecke J,Carmeliet E. Different K+ channes in human artial cells. Pflugers Arch,1989,414(Suppl l)S171-S172.
[200]Zicha S,Moss I,Allen B·Molecular basis of species-specific expression of repolarizing K+ currents in the heart. .Am J Physiol Heart Circ Physiol,2003;285(4):H1641-1649.
[201]Shibataa E,Drury T, Refsum H, etal. Contribution of transient outward current to repolarization in human atrium [J] Am J Physiol,989,257:H1773.
[202]Colatsky TJ ,Argentieri TM. Potassium channel blockers as antiarrhythmic drugs[J ]. Drug Dev Res ,1994 ,33 :235-249.
[203]Roden DM. Ionic mechanisms for prolongation of refractoriness and their proar2 rhythmic and antiarrhythmic correlates[J ]. Am J Cardiol , 1996 ,72 :12-16.
[204]Tamargo J,Caballero R,Gomez R. Pharmacology of cardiac Potassium channels, Cardiovasc Res,2004;62(1):9-33.
[205]Nakaya H. Electropharmacological assessment of the risk of dru-induced long-QT syndrome cusing native cardiac cells and cultured cells expressing HERG channels. Nippon Yakurigaku Zasshi,2003;121(6):384-392.
[206]Schram G,Zhang L,Derakhehan K,etal.Ranolazine: ion- channelbloc- king actions and in vivo electroPhysiological effects [J].Br J Pharrnacol,2004,142(8):1300-1308.
[207]Tamargo J,Caballero R,Gomez R. Pharmacology of cardiac potassium channels, Cardiovase Res,2004;62(1):9-33.
[208]Bean BP.Two kind of calcium channels in canine atrial cell:Differeces in kineties, Selectivity,and Pharmacology.J Gen physiol,1985;86:1-30.
[209]Xu X,Best PM.Increase in T-type currents in artrial myocytes from adultray with groghhormon secreting tumors.Proc Natl Acad Sci USA,1990;87:4655-4659.
[210]EliAsbeeta Cerbai,Alberto Giotti,AlesAsndro Mugelli.Charateristics of L-type calcium channel blockade by lacidipine in guinea-pig ventricular myocytes.British Journal of Pharmacology,1997,120:667-715
[212]Kenneth B.Walsh,Graham E.Parks.Changes in cardiac myocyte morphology alter the properties of voltage-gated ion channels [J].Cardiovascular Research,2002, 45(3):457-461
[213]Chu L,Takahashi R,Norota I,et al.Signal transduction and Ca2+ signaling in contractile regulation induced by crosstalk between endothein-1 and norepinephrine in dog ventricular myocardium[J]. Circ Res,2003,92(9):1024 -1032.
[214]Piacentino V , Dipla K, Gaughan JP, et al. Voltage-dependent Ca2+ release from the SR of feline ventricular myocytes is ex-plained by Ca2+ -induced Ca2+ release [J].J Physiol, 2000,523: 533-548.
[215]Maltsev VA, Sabbah UN, Higgins RSD, et al. Novel ultraslow inac- tivating sodium current in human ventricular cardiomyocytes [J].Circulation, 1998, 98: 2545-2552.
[216]吴立玲.心血管病理生理学[M].北京:北京医科大学出版社.2000;24-29.
[217] Wang W, Martindale J, Metzger JM. Parvalbumin isoforms for enhancing cardiac diastolic function[J], Cell Biochem Biophys.2008; 51(1):1-8.
[218]李小鹰.肌浆网钙ATP酶2a基因转导治疗心衰的研究[J].中华心血管病杂志,2005,33(6): 576-578.