心肌动作电位时程和收缩力的频率依赖性及对TRPC的影响
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摘要
心脏的功能活动是心肌动作电位变化和收缩力变化的统一体,心肌动作电位和收缩力受到心率的影响。心肌的兴奋收缩过程伴随着细胞内外离子浓度的变化,其中钙离子是参与心脏活动最关键的离子。经典瞬时受体电位通道(transient receptor potential canonical channel, TRPC)是TRP的一个亚家族,包括TRPC1-7共七个成员。TRPC广泛分布于心血管系统,是一类对钙通透的非选择性阳离子通道。TRPC的功能及表达异常可见于心肌肥厚、心律失常、心肌缺血等多种心血管疾病。心率的变化会造成细胞内离子的跨膜移动,进而影响心肌动作电位时程(action potential duration, APD)和收缩力,这一过程是否有TRPC参与,值得探讨。
目的：
通过电刺激控制心率,观察各种刺激频率对不同种属动物APD及收缩力的影响；探讨APD-频率依赖性与TRPC的关系,进一步分析TRPC在APD-频率依赖性中的作用；药物的延长APD作用是否有TRPC的参与。
方法：
1.各种刺激频率对不同种属动物心肌APD的影响
采用心外膜接触电极记录不同频率刺激下豚鼠、家兔及大鼠在体心室单相动作电位(monophasic action potential, MAP),标准微电极技术记录大鼠心室乳头肌的动作电位,观察各种刺激频率对不同种属动物APD的影响。
2.心肌APD-频率依赖性与TRPC表达的关系
选用家兔为实验对象,采用心外膜接触电极记录家兔在体心室MAP,在4.5Hz、6Hz、7.5Hz不同频率下给予电刺激控制心率,10min后取心脏,做TRPC的mRNA及蛋白表达分析。
3.甲基莲心碱对家兔心肌APD-频率依赖性及TRPC表达的影响
(1)家兔静脉注射甲基莲心碱(2.5mg/kg)、胺碘酮(5mg/kg),记录并比较给药前后不同刺激频率下(4.5-7Hz)MAP的变化。
(2)家兔静脉注射甲基莲心碱(2.5mg/kg)、胺碘酮(5mg/kg),给药后选取4.5Hz连续电刺激10min,迅速取心脏做TRPC的mRNA及蛋白表达分析。
4.各种刺激频率对不同种属动物心肌收缩力的影响
(1)对大鼠、家兔心室乳头肌标本进行离体组织灌流,依次给予不同频率刺激标本,记录不同刺激频率下心室乳头肌收缩力变化。
(2)给予1Hz基础频率刺激3min,然后停止刺激,记录静息不同时间恢复刺激时心室乳头肌首次收缩力的变化。
结果：
1.各种刺激频率对不同种属动物心肌APD的影响
(1)在体豚鼠心室肌MAP记录,在4.5Hz、5Hz、5.5Hz、6Hz、6.5Hz、7Hz刺激条件下,心肌APD90从对照水平(4.5Hz)的96.84±5.43ms,分别缩短至91.77±3.88ms (5Hz)、87.07±3.78ms (5.5Hz)、81.79±3.92ms (6Hz)、76.84±2.91ms (6.5Hz)、76.52±1.40ms (7Hz);与对照水平(4.5Hz)相比,缩短的百分比分别为5.2±0.9%、10.1±1.1%、15.6±1.5%、20.5±1.3%、20.4±3.0%。表明：在4.5-7Hz范围,随频率的增加APD逐渐缩短,呈现明显的APD-频率依赖性。
(2)在体家兔心室肌MAP记录,在4.5Hz、5Hz、5.5Hz、6Hz、6.5Hz、7Hz、7.5Hz刺激条件下,心肌APD90从对照水平(4.5Hz)的141.53±3.85ms,分别缩短至138.44±3.45ms(5Hz)、131.65±3.23ms(5.5Hz)、125.94±3.11ms(6Hz)、119.77±3.31ms (6.5Hz)、112.64±1.83ms (7Hz)、104.69±1.58ms (7.5Hz);与对照水平(4.5Hz)相比,缩短的百分比分别为2.1±1.5%、6.9±1.3%、10.9±1.7%、15.3±1.8%、20.2±2.1%、25.8±2.0%。提示：在4.5-7.5Hz范围,随频率的增加APD逐渐缩短,呈现明显的APD-频率依赖性。
(3)在体大鼠心室肌MAP记录,频率范围在5-8.5Hz；离体大鼠心室乳头肌跨膜动作电位记录,范围在1-8Hz,随频率的增加APD等无明显变化,未见显著的APD-频率依赖性。
2.心肌APD-频率依赖性与TRPC的关系
在4.5Hz、6Hz和7.5Hz三个刺激频率组中,与4.5Hz组(对照水平)相比,6Hz组、7.5Hz组家兔心肌TRPC3的mRNA表达水平均显著增加(P<0.05)。在同样的刺激条件下,心肌TRPC1～2、TRPC4-7的mRNA表达均无显著影响。
与4.5Hz组(对照水平)相比,6Hz、7.5Hz组增加TRPC3的蛋白表达,后者显著增加TRPC3的蛋白表达水平(P<0.05)。同样条件下,心肌TRPC1和TRPC6的蛋白表达水平无显著影响。
表明：随着刺激频率(4.5-7.5Hz)的增加,家兔心肌TRPC3的mRNA水平和蛋白表达都逐渐增高。
3.甲基莲心碱对家兔心肌APD-频率依赖性及TRPC的影响
(1)静脉注射5mg/kg胺碘酮(AM),刺激频率4.5Hz.5Hz、5.5Hz、6Hz、6.5Hz,与给药前水平相比,APD90延长的百分比分别为11.4±4.1%、10.6±3.4%、6.5±1.6%、7.7±1.8%、8.8±3.0%。静脉注射2.5mg/kg甲基莲心碱(Nef),刺激频率4.5Hz、5Hz、5.5Hz、6Hz.6.5Hz、7Hz,与给药前水平相比,APD90延长的百分比分别为5.8±1.6%、2.0±1.7%、2.4±0.4%、3.1±0.5%、2.5±0.3%、6.2±1.2%。提示：在所给刺激频率范围,胺碘酮(AM)和甲基莲心碱(Nef)均能延长家兔心室肌APD。两药作用性质相似,在各个刺激频率下,延长动作电位的比例(%)均无显著差异,呈非频率依赖性特点。
(2)与对照组(4.5Hz)相比,Nef(2.5mg/kg)明显增加TRPC3的mRNA和蛋白表达水平(P<0.05),而AM(5mg/kg)对TRPC3的mRNA和蛋白表达无明显作用。同样条件下,Nef和AM给药组对TRPC1-2.TRPC4-7的mRNA表达无显著差异,对TRPC1和TRPC6的蛋白表达水平也无显著影响。
4.各种刺激频率对不同种属动物心肌收缩力的影响
(1)在0.4Hz、0.6Hz、0.8Hz、1.0Hz、1.5Hz.2Hz、3Hz刺激条件下,大鼠心室乳头肌收缩力分别从对照水平(以0.2Hz收缩力为100%)降至78.2±3.4%、66.3±4.9%、60.4±5.6%、56.0±6.0%、51.5±6.8%、49.3±6.9%、43.7±5.8%,表明随着刺激频率的增高(0.2-3Hz),收缩力逐渐减弱。同样刺激频率条件下,家兔心室乳头肌收缩力分别从对照水平(以0.2Hz收缩力为100%)升至109.6±3.5%、120.2±5.4%、130.6±7.5%、141.44±10.4%、142.7±12.4%、137.3±13.9%、125.5±14.4%,在0.2-1.5Hz范围,收缩力逐渐增强。
(2)静息15s、30s、60s、120s、180s和240s,大鼠心室乳头肌收缩力分别从对照水平(以静息1s时收缩力为100%)增加至299.8±7.3%、386.7±14.9%、451.3±32.3%、455.7±35.8%、451.1±44.0%、445.9±46.6%,表明随静息时间的延长,收缩力呈逐渐增强。而在同样条件下,家兔心室乳头肌收缩力分别从对照水平(以静息1s时收缩力为100%)降至88.1±2.3%、82.7±1.9%、78.7±2.0%、77.8±2.6%、76.7±3.1%、76.5±3.5%,表明随静息时间的延长,收缩力逐渐减弱。
结论：
1.刺激频率对大鼠、豚鼠和家兔心脏APD的影响不同。在本实验所用频率范围,豚鼠和家兔心肌呈明显的APD-频率依赖性缩短,而对大鼠心肌APD无明显影响。大鼠和家兔心室乳头肌在收缩力-频率相关性方面也存在差别。
2.家兔心肌APD-频率依赖性缩短的作用,可能与频率改变(增加)伴随的TRPC3增加有关。
3.Nef能明显延长家兔心肌APD并呈现非频率依赖性特征(各频率下延长APD的作用无明显差异),提示Nef的这一作用与TRPC3增加有关。
Functional activity of the heart is the integrity of action potential and myocardial contractility, which is affected by heart rate. Myocardial excitation-contraction process is accompanied by changes of intracellular ion concentration, and the calcium ion is the most important inorganic ion involved in cardiac activity. TRPC (transient receptor potential canonical) is one subfamily of TRP, including7isoforms (TRPC1-7). TRPC is widely distributed in the cardiovascular system, which is a non-selective cation channel with permeability for calcium. Abnormal function and expression of TRPC can be seen in various kinds of cardiovascular diseases, such as cardiac hypertrophy, arrhythmia, myocardial ischemia. Heart rate changes can affect the transmembrane movement of intracellular ions, as well as the myocardial action potential duration (APD) and contractile force. Whether TRPC participate in this process, it is worth being investigated further.
Objective:
Controlling heart rate through the electric stimulation, we observe the relationship between myocardial APD or contractile force and stimulation frequency in different kinds of animal, and investigate frequency dependence of APD associated with the expression of TRPC. We further analysis the roles of TRPC in this process, and whether TRPC is involved in the drug effects of APD prolonging.
Methods:
1. The relationship between myocardial APD and stimulation frequency in different species of animal
To observe the relationship between APD and stimulation frequency in different species of animal, monophasic action potentials (MAP) were recorded using contact electrode technique in different programmed stimulus frequencies on rats, guinea pigs, or rabbits ventricular epicardium in vivo. And transmembrane action potentials were recorded using conventional microelectrode techniques on ventricular papillary muscle of rats.
2. Frequency dependence of action potential duration and its influences on TRPC expression of rabbit myocardium
Pacing at the stimulus frequency of4.5Hz、6Hz、7.5Hz, we recorded MAP using contact electrode technique on rabbit ventricular epicardium in vivo. Ten minutes later, hearts were taken out and the expressions of TRPCs were detected using RT-PCR or Western blotting.
3. Effects of neferine on TRPCs expression and frequency dependence of action potential duration of rabbit myocardium
(1) Given intravenous injection of neferine (2.5mg/kg), amiodarone (5mg/kg) in rabbits, the changes of MAP were recorded and compared at different stimulus frequencies (4.5Hz～7Hz) before and after administration.
(2) Given intravenous injection of neferine (2.5mg/kg), amiodarone (2.5mg/kg) in rabbits, a continuous electrical stimulation of10min was applied on rabbit myocardium after administration. Then the hearts were taken out rapidly and the expressions of TRPC were detected.
4. Force-frequency relationship of ventricular papillary muscle in different species of animal
(1) Ventricular papillary muscles were isolated from heart of rats or rabbits and immediately perfused with organ bath. Different frequency electrical stimulations were applied on the preparation in sequence and the contraction force was recorded.
(2) In order to investigate the influences of post-rest twitch, different rest intervals between1and240s were prescribed from a basal stimulation rate of1Hz for3min, and the first contraction amplitude after resume was recorded.
Results:
1. The relationship between myocardial APD and stimulation frequency in different species of animal
(1) At the frequency of4.5Hz,5Hz,5.5Hz,6Hz,6.5Hz,7Hz, myocardial APD gradually shortened with the increase of stimulation frequency in the MAP recording of guinea pigs. The APD90from the control level96.84±5.43ms (4.5Hz), respectively reduced to91.77±3.88ms (5Hz),87.07±3.78ms (5.5Hz),81.79±3.92ms (6Hz),76.84±2.91ms (6.5Hz),76.52±1.40ms (7Hz). Compared with the control (4.5Hz), the shorten percentages correspondingly were5.2±0.9%,10.1±1.1%,15.6±1.5%,20.5±1.3%,20.4±3.0%.
(2) At the frequency of4.5Hz,5Hz,5.5Hz,6Hz,6.5Hz,7Hz,7.5Hz, a clear frequency dependence of APD was showed in the MAP recording of rabbit myocardium in vivo. Myocardial APD90from the control level (4.5Hz)141.53±3.85ms, respectively, reduced to138.44±3.45ms (5Hz),131.65±3.23ms (5.5Hz),125.94±3.11ms(6Hz),119.77±3.31ms (6.5Hz),112.64±1.83ms (7Hz),104.69±1.58ms (7.5Hz). Compared with the control (4.5Hz), the shorten percentages were2.1±1.5%,6.9±1.3%,10.9±1.7%,15.3±1.8%,20.2±2.1%,25.8±2.0%.
(3) There was no obvious frequency dependence of action potential duration in rat MAP in vivo within the range of5-8.5Hz or isolated ventricular papillary muscle TAP (transmembrane action potentials) at the range of1～8Hz.
2. Frequency dependence of action potential duration and its influences on TRPC expression of rabbit myocardium
In the groups of4.5,6and7.5Hz, TRPC3mRNA and protein expression of rabbit myocardial was gradually raised with the increase of stimulus frequency. In contrast with control level (4.5Hz), the mRNA expression of TRPC3remarkably grew in the6Hz and7.5Hz group (P<0.05), while that of myocardial TRPC1-2, TRPC4-7showed no significant change. Compared with4.5Hz group, the protein expression of TRPC3obviously increased in the7.5Hz group (P<0.05). The expression of TRPC1and TRPC6had no significant difference in the three groups.
3. Effects of neferine on frequency dependence of action potential duration and TRPCs expression of rabbit myocardium
(1) At different stimulus frequencies, neferine and amiodarone could prolong APD in rabbit myocardial, and showed characters of rate independence. Compared with that before administration at the frequency of4.5Hz,5Hz,5.5Hz,6Hz,6.5Hz, the prolonging percentage were respectively11.4±4.1%,10.6±3.4%,6.5±1.6%,7.7±1.8%,8.8±3.0%after intravenous injection of amiodarone (5mg/kg) in rabbits. At the frequency of4.5Hz,5Hz,5.5Hz,6Hz,6.5Hz,7Hz, the prolonging percentage of neferine (2.5mg/kg) injection correspondingly were5.8±1.6%,2.0±1.7%,2.4±0.4%,3.1±0.5%,2.5±0.3%,6.2±1.2%compared with that before administration.
(2) Neferine (2.5mg/kg) could significantly increase the expression of TRPC3mRNA and protein in the stimulation of4.5Hz, while amiodarone (5mg/kg) had no such effects. Under the same stimulus conditions, the medication administration groups had no significant difference on the mRNA expression of TRPC1-2and TRPC4-7, and on the protein expression of TRPC1and TRPC6compared with4.5Hz control group.
4. Force-frequency relationship of ventricular papillary muscle in different species of animal
(1)With the increase of frequency (0.2-3Hz), contraction force gradually weakened in papillary muscles of rats, while enhanced in that of rabbits within0.2-1.5Hz range. At the frequency of0.4Hz,0.6Hz,0.8Hz,1.0Hz,1.5Hz,2Hz and3Hz, contraction force percentage of rat papillary muscles from the control level (0.2Hz)100%, respectively reduced to78.2±3.4%,66.3±4.9%,60.4±5.6%,56.0±6.0%,51.5±6.8%,49.3±6.9%and 43.7±5.8%. Under the same stimulus conditions, that of rabbit papillary muscles from the control level (0.2Hz)100%, correspondingly raised to109.6±3.5%,120.2±5.4%,130.6±7.5%,141.4±10.4%,142.7±12.4%,137.3±13.9%and125.5±14.4%.
(2) There was clear rest decay of twitch amplitude in rabbit papillary muscles, while rat ventricular muscles exhibited rest potentiation of twitch force after different rest intervals between1and240s. After rest15s,30s,60s,120s,180s and240s, contraction force percentage of rat papillary muscles from the control level (rest Is)100%, respectively raised to299.8±7.3%,386.7±14.9%,451.3±32.3%,455.7±35.8%,451.1±44.0%and445.9±46.6%. Under the same rest conditions, that of rabbit papillary muscles from the control level (rest Is)100%, correspondingly reduced to88.1±2.3%,82.7±1.9%,78.7±2.0%,77.8±2.6%,76.7±3.1%and76.5±3.5%.
Conclusions:
1. There are species differences in the relationship between myocardial APD and stimulation frequency. An obviously APD shorten with the increase of frequency is showed in guinea pigs and rabbits, while this phenomenon is not observed in rat at the frequency ranges in our experiments. There are also distinctions between rat and rabbit papillary muscles in the force-frequency relationship.
2. Frequency dependent shorten of APD is associated with the increase of TRPC3expression in rabbit myocardium.
3. Neferine could significantly increase the expression of TRPC3rabbit myocardial, and the prolongation of APD showed characters of rate independence.
目的：
通过电刺激控制心率,观察各种刺激频率对不同种属动物APD及收缩力的影响；探讨APD-频率依赖性与TRPC的关系,进一步分析TRPC在APD-频率依赖性中的作用；药物的延长APD作用是否有TRPC的参与。
方法：
1.各种刺激频率对不同种属动物心肌APD的影响
采用心外膜接触电极记录不同频率刺激下豚鼠、家兔及大鼠在体心室单相动作电位(monophasic action potential, MAP),标准微电极技术记录大鼠心室乳头肌的动作电位,观察各种刺激频率对不同种属动物APD的影响。
2.心肌APD-频率依赖性与TRPC表达的关系
选用家兔为实验对象,采用心外膜接触电极记录家兔在体心室MAP,在4.5Hz、6Hz、7.5Hz不同频率下给予电刺激控制心率,10min后取心脏,做TRPC的mRNA及蛋白表达分析。
3.甲基莲心碱对家兔心肌APD-频率依赖性及TRPC表达的影响
(1)家兔静脉注射甲基莲心碱(2.5mg/kg)、胺碘酮(5mg/kg),记录并比较给药前后不同刺激频率下(4.5-7Hz)MAP的变化。
(2)家兔静脉注射甲基莲心碱(2.5mg/kg)、胺碘酮(5mg/kg),给药后选取4.5Hz连续电刺激10min,迅速取心脏做TRPC的mRNA及蛋白表达分析。
4.各种刺激频率对不同种属动物心肌收缩力的影响
(1)对大鼠、家兔心室乳头肌标本进行离体组织灌流,依次给予不同频率刺激标本,记录不同刺激频率下心室乳头肌收缩力变化。
(2)给予1Hz基础频率刺激3min,然后停止刺激,记录静息不同时间恢复刺激时心室乳头肌首次收缩力的变化。
结果：
1.各种刺激频率对不同种属动物心肌APD的影响
(1)在体豚鼠心室肌MAP记录,在4.5Hz、5Hz、5.5Hz、6Hz、6.5Hz、7Hz刺激条件下,心肌APD90从对照水平(4.5Hz)的96.84±5.43ms,分别缩短至91.77±3.88ms (5Hz)、87.07±3.78ms (5.5Hz)、81.79±3.92ms (6Hz)、76.84±2.91ms (6.5Hz)、76.52±1.40ms (7Hz);与对照水平(4.5Hz)相比,缩短的百分比分别为5.2±0.9%、10.1±1.1%、15.6±1.5%、20.5±1.3%、20.4±3.0%。表明：在4.5-7Hz范围,随频率的增加APD逐渐缩短,呈现明显的APD-频率依赖性。
(2)在体家兔心室肌MAP记录,在4.5Hz、5Hz、5.5Hz、6Hz、6.5Hz、7Hz、7.5Hz刺激条件下,心肌APD90从对照水平(4.5Hz)的141.53±3.85ms,分别缩短至138.44±3.45ms(5Hz)、131.65±3.23ms(5.5Hz)、125.94±3.11ms(6Hz)、119.77±3.31ms (6.5Hz)、112.64±1.83ms (7Hz)、104.69±1.58ms (7.5Hz);与对照水平(4.5Hz)相比,缩短的百分比分别为2.1±1.5%、6.9±1.3%、10.9±1.7%、15.3±1.8%、20.2±2.1%、25.8±2.0%。提示：在4.5-7.5Hz范围,随频率的增加APD逐渐缩短,呈现明显的APD-频率依赖性。
(3)在体大鼠心室肌MAP记录,频率范围在5-8.5Hz；离体大鼠心室乳头肌跨膜动作电位记录,范围在1-8Hz,随频率的增加APD等无明显变化,未见显著的APD-频率依赖性。
2.心肌APD-频率依赖性与TRPC的关系
在4.5Hz、6Hz和7.5Hz三个刺激频率组中,与4.5Hz组(对照水平)相比,6Hz组、7.5Hz组家兔心肌TRPC3的mRNA表达水平均显著增加(P<0.05)。在同样的刺激条件下,心肌TRPC1～2、TRPC4-7的mRNA表达均无显著影响。
与4.5Hz组(对照水平)相比,6Hz、7.5Hz组增加TRPC3的蛋白表达,后者显著增加TRPC3的蛋白表达水平(P<0.05)。同样条件下,心肌TRPC1和TRPC6的蛋白表达水平无显著影响。
表明：随着刺激频率(4.5-7.5Hz)的增加,家兔心肌TRPC3的mRNA水平和蛋白表达都逐渐增高。
3.甲基莲心碱对家兔心肌APD-频率依赖性及TRPC的影响
(1)静脉注射5mg/kg胺碘酮(AM),刺激频率4.5Hz.5Hz、5.5Hz、6Hz、6.5Hz,与给药前水平相比,APD90延长的百分比分别为11.4±4.1%、10.6±3.4%、6.5±1.6%、7.7±1.8%、8.8±3.0%。静脉注射2.5mg/kg甲基莲心碱(Nef),刺激频率4.5Hz、5Hz、5.5Hz、6Hz.6.5Hz、7Hz,与给药前水平相比,APD90延长的百分比分别为5.8±1.6%、2.0±1.7%、2.4±0.4%、3.1±0.5%、2.5±0.3%、6.2±1.2%。提示：在所给刺激频率范围,胺碘酮(AM)和甲基莲心碱(Nef)均能延长家兔心室肌APD。两药作用性质相似,在各个刺激频率下,延长动作电位的比例(%)均无显著差异,呈非频率依赖性特点。
(2)与对照组(4.5Hz)相比,Nef(2.5mg/kg)明显增加TRPC3的mRNA和蛋白表达水平(P<0.05),而AM(5mg/kg)对TRPC3的mRNA和蛋白表达无明显作用。同样条件下,Nef和AM给药组对TRPC1-2.TRPC4-7的mRNA表达无显著差异,对TRPC1和TRPC6的蛋白表达水平也无显著影响。
4.各种刺激频率对不同种属动物心肌收缩力的影响
(1)在0.4Hz、0.6Hz、0.8Hz、1.0Hz、1.5Hz.2Hz、3Hz刺激条件下,大鼠心室乳头肌收缩力分别从对照水平(以0.2Hz收缩力为100%)降至78.2±3.4%、66.3±4.9%、60.4±5.6%、56.0±6.0%、51.5±6.8%、49.3±6.9%、43.7±5.8%,表明随着刺激频率的增高(0.2-3Hz),收缩力逐渐减弱。同样刺激频率条件下,家兔心室乳头肌收缩力分别从对照水平(以0.2Hz收缩力为100%)升至109.6±3.5%、120.2±5.4%、130.6±7.5%、141.44±10.4%、142.7±12.4%、137.3±13.9%、125.5±14.4%,在0.2-1.5Hz范围,收缩力逐渐增强。
(2)静息15s、30s、60s、120s、180s和240s,大鼠心室乳头肌收缩力分别从对照水平(以静息1s时收缩力为100%)增加至299.8±7.3%、386.7±14.9%、451.3±32.3%、455.7±35.8%、451.1±44.0%、445.9±46.6%,表明随静息时间的延长,收缩力呈逐渐增强。而在同样条件下,家兔心室乳头肌收缩力分别从对照水平(以静息1s时收缩力为100%)降至88.1±2.3%、82.7±1.9%、78.7±2.0%、77.8±2.6%、76.7±3.1%、76.5±3.5%,表明随静息时间的延长,收缩力逐渐减弱。
结论：
1.刺激频率对大鼠、豚鼠和家兔心脏APD的影响不同。在本实验所用频率范围,豚鼠和家兔心肌呈明显的APD-频率依赖性缩短,而对大鼠心肌APD无明显影响。大鼠和家兔心室乳头肌在收缩力-频率相关性方面也存在差别。
2.家兔心肌APD-频率依赖性缩短的作用,可能与频率改变(增加)伴随的TRPC3增加有关。
3.Nef能明显延长家兔心肌APD并呈现非频率依赖性特征(各频率下延长APD的作用无明显差异),提示Nef的这一作用与TRPC3增加有关。
Functional activity of the heart is the integrity of action potential and myocardial contractility, which is affected by heart rate. Myocardial excitation-contraction process is accompanied by changes of intracellular ion concentration, and the calcium ion is the most important inorganic ion involved in cardiac activity. TRPC (transient receptor potential canonical) is one subfamily of TRP, including7isoforms (TRPC1-7). TRPC is widely distributed in the cardiovascular system, which is a non-selective cation channel with permeability for calcium. Abnormal function and expression of TRPC can be seen in various kinds of cardiovascular diseases, such as cardiac hypertrophy, arrhythmia, myocardial ischemia. Heart rate changes can affect the transmembrane movement of intracellular ions, as well as the myocardial action potential duration (APD) and contractile force. Whether TRPC participate in this process, it is worth being investigated further.
Objective:
Controlling heart rate through the electric stimulation, we observe the relationship between myocardial APD or contractile force and stimulation frequency in different kinds of animal, and investigate frequency dependence of APD associated with the expression of TRPC. We further analysis the roles of TRPC in this process, and whether TRPC is involved in the drug effects of APD prolonging.
Methods:
1. The relationship between myocardial APD and stimulation frequency in different species of animal
To observe the relationship between APD and stimulation frequency in different species of animal, monophasic action potentials (MAP) were recorded using contact electrode technique in different programmed stimulus frequencies on rats, guinea pigs, or rabbits ventricular epicardium in vivo. And transmembrane action potentials were recorded using conventional microelectrode techniques on ventricular papillary muscle of rats.
2. Frequency dependence of action potential duration and its influences on TRPC expression of rabbit myocardium
Pacing at the stimulus frequency of4.5Hz、6Hz、7.5Hz, we recorded MAP using contact electrode technique on rabbit ventricular epicardium in vivo. Ten minutes later, hearts were taken out and the expressions of TRPCs were detected using RT-PCR or Western blotting.
3. Effects of neferine on TRPCs expression and frequency dependence of action potential duration of rabbit myocardium
(1) Given intravenous injection of neferine (2.5mg/kg), amiodarone (5mg/kg) in rabbits, the changes of MAP were recorded and compared at different stimulus frequencies (4.5Hz～7Hz) before and after administration.
(2) Given intravenous injection of neferine (2.5mg/kg), amiodarone (2.5mg/kg) in rabbits, a continuous electrical stimulation of10min was applied on rabbit myocardium after administration. Then the hearts were taken out rapidly and the expressions of TRPC were detected.
4. Force-frequency relationship of ventricular papillary muscle in different species of animal
(1) Ventricular papillary muscles were isolated from heart of rats or rabbits and immediately perfused with organ bath. Different frequency electrical stimulations were applied on the preparation in sequence and the contraction force was recorded.
(2) In order to investigate the influences of post-rest twitch, different rest intervals between1and240s were prescribed from a basal stimulation rate of1Hz for3min, and the first contraction amplitude after resume was recorded.
Results:
1. The relationship between myocardial APD and stimulation frequency in different species of animal
(1) At the frequency of4.5Hz,5Hz,5.5Hz,6Hz,6.5Hz,7Hz, myocardial APD gradually shortened with the increase of stimulation frequency in the MAP recording of guinea pigs. The APD90from the control level96.84±5.43ms (4.5Hz), respectively reduced to91.77±3.88ms (5Hz),87.07±3.78ms (5.5Hz),81.79±3.92ms (6Hz),76.84±2.91ms (6.5Hz),76.52±1.40ms (7Hz). Compared with the control (4.5Hz), the shorten percentages correspondingly were5.2±0.9%,10.1±1.1%,15.6±1.5%,20.5±1.3%,20.4±3.0%.
(2) At the frequency of4.5Hz,5Hz,5.5Hz,6Hz,6.5Hz,7Hz,7.5Hz, a clear frequency dependence of APD was showed in the MAP recording of rabbit myocardium in vivo. Myocardial APD90from the control level (4.5Hz)141.53±3.85ms, respectively, reduced to138.44±3.45ms (5Hz),131.65±3.23ms (5.5Hz),125.94±3.11ms(6Hz),119.77±3.31ms (6.5Hz),112.64±1.83ms (7Hz),104.69±1.58ms (7.5Hz). Compared with the control (4.5Hz), the shorten percentages were2.1±1.5%,6.9±1.3%,10.9±1.7%,15.3±1.8%,20.2±2.1%,25.8±2.0%.
(3) There was no obvious frequency dependence of action potential duration in rat MAP in vivo within the range of5-8.5Hz or isolated ventricular papillary muscle TAP (transmembrane action potentials) at the range of1～8Hz.
2. Frequency dependence of action potential duration and its influences on TRPC expression of rabbit myocardium
In the groups of4.5,6and7.5Hz, TRPC3mRNA and protein expression of rabbit myocardial was gradually raised with the increase of stimulus frequency. In contrast with control level (4.5Hz), the mRNA expression of TRPC3remarkably grew in the6Hz and7.5Hz group (P<0.05), while that of myocardial TRPC1-2, TRPC4-7showed no significant change. Compared with4.5Hz group, the protein expression of TRPC3obviously increased in the7.5Hz group (P<0.05). The expression of TRPC1and TRPC6had no significant difference in the three groups.
3. Effects of neferine on frequency dependence of action potential duration and TRPCs expression of rabbit myocardium
(1) At different stimulus frequencies, neferine and amiodarone could prolong APD in rabbit myocardial, and showed characters of rate independence. Compared with that before administration at the frequency of4.5Hz,5Hz,5.5Hz,6Hz,6.5Hz, the prolonging percentage were respectively11.4±4.1%,10.6±3.4%,6.5±1.6%,7.7±1.8%,8.8±3.0%after intravenous injection of amiodarone (5mg/kg) in rabbits. At the frequency of4.5Hz,5Hz,5.5Hz,6Hz,6.5Hz,7Hz, the prolonging percentage of neferine (2.5mg/kg) injection correspondingly were5.8±1.6%,2.0±1.7%,2.4±0.4%,3.1±0.5%,2.5±0.3%,6.2±1.2%compared with that before administration.
(2) Neferine (2.5mg/kg) could significantly increase the expression of TRPC3mRNA and protein in the stimulation of4.5Hz, while amiodarone (5mg/kg) had no such effects. Under the same stimulus conditions, the medication administration groups had no significant difference on the mRNA expression of TRPC1-2and TRPC4-7, and on the protein expression of TRPC1and TRPC6compared with4.5Hz control group.
4. Force-frequency relationship of ventricular papillary muscle in different species of animal
(1)With the increase of frequency (0.2-3Hz), contraction force gradually weakened in papillary muscles of rats, while enhanced in that of rabbits within0.2-1.5Hz range. At the frequency of0.4Hz,0.6Hz,0.8Hz,1.0Hz,1.5Hz,2Hz and3Hz, contraction force percentage of rat papillary muscles from the control level (0.2Hz)100%, respectively reduced to78.2±3.4%,66.3±4.9%,60.4±5.6%,56.0±6.0%,51.5±6.8%,49.3±6.9%and 43.7±5.8%. Under the same stimulus conditions, that of rabbit papillary muscles from the control level (0.2Hz)100%, correspondingly raised to109.6±3.5%,120.2±5.4%,130.6±7.5%,141.4±10.4%,142.7±12.4%,137.3±13.9%and125.5±14.4%.
(2) There was clear rest decay of twitch amplitude in rabbit papillary muscles, while rat ventricular muscles exhibited rest potentiation of twitch force after different rest intervals between1and240s. After rest15s,30s,60s,120s,180s and240s, contraction force percentage of rat papillary muscles from the control level (rest Is)100%, respectively raised to299.8±7.3%,386.7±14.9%,451.3±32.3%,455.7±35.8%,451.1±44.0%and445.9±46.6%. Under the same rest conditions, that of rabbit papillary muscles from the control level (rest Is)100%, correspondingly reduced to88.1±2.3%,82.7±1.9%,78.7±2.0%,77.8±2.6%,76.7±3.1%and76.5±3.5%.
Conclusions:
1. There are species differences in the relationship between myocardial APD and stimulation frequency. An obviously APD shorten with the increase of frequency is showed in guinea pigs and rabbits, while this phenomenon is not observed in rat at the frequency ranges in our experiments. There are also distinctions between rat and rabbit papillary muscles in the force-frequency relationship.
2. Frequency dependent shorten of APD is associated with the increase of TRPC3expression in rabbit myocardium.
3. Neferine could significantly increase the expression of TRPC3rabbit myocardial, and the prolongation of APD showed characters of rate independence.
引文
[1]Dorian P, Newman D. Rate dependence of the effect of antiarrhythmic drugs delaying cardiac repolarization:an overview. Europace,2000,2(4):277-285.
[2]Boyett M R, Fedida D. Changes in the electrical activity of dog cardiac Purkinje fibres at high heart rates. J Physiol,1984,350:361-391.
[3]Stengl M, Volders P G, Thomsen M B, et al. Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes. J Physiol, 2003,551(Pt3):777-786.
[4]Janvier N C, Boyett M R. The role of Na-Ca exchange current in the cardiac action potential. Cardiovasc Res,1996,32(1):69-84.
[5]Spencer C I, Sham J S. Effects of Na+/Ca2+ exchange induced by SR Ca2+ release on action potentials and afterdepolarizations in guinea pig ventricular myocytes. Am J Physiol Heart Circ Physiol,2003,285(6):H2552-H2562.
[6]Williams B A, Dickenson D R, Beatch G N. Kinetics of rate-dependent shortening of action potential duration in guinea-pig ventricle; effects of IK1 and IKr blockade. Br J Pharmacol,1999,126(6):1426-1436.
[7]Li G R, Yang B, Feng J, et al. Transmembrane ICa contributes to rate-dependent changes of action potentials in human ventricular myocytes. Am J Physiol, 1999,276(1 Pt2):H98-H106.
[8]Endoh M. Force-frequency relationship in intact mammalian ventricular myocardium:physiological and pathophysiological relevance. Eur J Pharmacol, 2004,500(1-3):73-86.
[9]Wu L J, Sweet T B, Clapham D E. International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family. Pharmacol Rev,2010,62(3):381-404.
[10]Nilius B, Owsianik G. The transient receptor potential family of ion channels. Genome Biol,2011,12(3):218.
[11]Moran M M, Mcalexander M A, Biro T, et al. Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov,2011,10(8):601-620.
[12]Venkatachalam K, Montell C. TRP channels. Annu Rev Biochem,2007,76: 387-417.
[13]Clapham D E. TRP channels as cellular sensors. Nature,2003,426(6966):517-524.
[14]Vannier B, Peyton M, Boulay G, et al. Mouse trp2, the homologue of the human trpc2 pseudogene, encodes mTrp2, a store depletion-activated capacitative Ca2+ entry channel. Proc Natl Acad Sci U S A,1999,96(5):2060-2064.
[15]Minke B, Cook B. TRP channel proteins and signal transduction. Physiol Rev, 2002,82(2):429-472.
[16]Venkatachalam K, van Rossum D B, Patterson R L, et al. The cellular and molecular basis of store-operated calcium entry. Nat Cell Biol,2002,4(11): E263-E272.
[17]Harteneck C, Gollasch M. Pharmacological modulation of diacylglycerol-sensitive TRPC3/6/7 channels. Curr Pharm Biotechnol,2011,12(1):35-41.
[18]Maroto R, Raso A, Wood T G, et al. TRPC1 forms the stretch-activated cation channel in vertebrate cells. Nat Cell Biol,2005,7(2):179-185.
[19]Seth M, Zhang Z S, Mao L, et al. TRPC1 channels are critical for hypertrophic signaling in the heart. Circ Res,2009,105(10):1023-1030.
[20]Spassova M A, Hewavitharana T, Xu W, et al. A common mechanism underlies stretch activation and receptor activation of TRPC6 channels. Proc Natl Acad Sci USA,2006,103(44):16586-16591.
[21]Kinoshita H, Kuwahara K, Nishida M, et al. Inhibition of TRPC6 channel activity contributes to the antihypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart. Circ Res,2010,106(12):1849-1860.
[22]Eder P, Molkentin J D. TRPC channels as effectors of cardiac hypertrophy. Circ Res,2011,108(2):265-272.
[23]Harada M, Luo X, Qi X Y, et al. Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation, 2012,126(17):2051-2064.
[24]Sabourin J, Antigny F, Robin E, et al. Activation of transient receptor potential canonical 3 (TRPC3)-mediated Ca2+ entry by A1 adenosine receptor in cardiomyocytes disturbs atrioventricular conduction. J Biol Chem,2012,287(32): 26688-26701.
[25]Williams I A, Allen D G. Intracellular calcium handling in ventricular myocytes from mdx mice. Am J Physiol Heart Circ Physiol,2007,292(2):H846-H855.
[26]Ingueneau C, Huynh U D, Marcheix B, et al. TRPC1 is regulated by caveolin-1 and is involved in oxidized LDL-induced apoptosis of vascular smooth muscle cells. J Cell Mol Med,2009,13(8B):1620-1631.
[27]Ward M L, Williams I A, Chu Y, et al. Stretch-activated channels in the heart: contributions to length-dependence and to cardiomyopathy. Prog Biophys Mol Biol, 2008,97(2-3):232-249.
[28]Qian J Q. Cardiovascular pharmacological effects of bisbenzylisoquinoline alkaloid derivatives. Acta Pharmacol Sin,2002,23(12):1086-1092.
[29]Dong Z X, Zhao X, Gu D F, et al. Comparative effects of liensinine and neferine on the human ether-a-go-go-related gene potassium channel and pharmacological activity analysis. Cell Physiol Biochem,2012,29(3-4):431-442.
[1]Nilius B, Owsianik G. The transient receptor potential family of ion channels. Genome Biol,2011,12(3):218.
[2]Vennekens R. Emerging concepts for the role of TRP channels in the cardiovascular system. J Physiol,2011,589(Pt 7):1527-1534.
[3]Watanabe H, Murakami M, Ohba T, et al. TRP channel and cardiovascular disease. Pharmacol Ther,2008,118(3):337-351.
[4]Dong Z X, Zhao X, Gu D F, et al. Comparative effects of liensinine and neferine on the human ether-a-go-go-related gene potassium channel and pharmacological activity analysis. Cell Physiol Biochem,2012,29(3-4):431-442.
[5]Qian J Q. Cardiovascular pharmacological effects of bisbenzylisoquinoline alkaloid derivatives. Acta Pharmacol Sin,2002,23(12):1086-1092.
[6]Franz M R, Flaherty J T, Platia E V, et al. Localization of regional myocardial ischemia by recording of monophasic action potentials. Circulation, 1984,69(3):593-604.
[7]Franz M R. Long-term recording of monophasic action potentials from human endocardium. Am J Cardiol,1983,51(10):1629-1634.
[8]Franz M, Schottler M, Schaefer J, et al. Simultaneous recording of monophasic action potentials and contractile force from the human heart. Klin Wochenschr, 1980,58(24):1357-1359.
[9]Franz M R, Chin M C, Sharkey H R, et al. A new single catheter technique for simultaneous measurement of action potential duration and refractory period in vivo. J Am Coll Cardiol,1990,16(4):878-886.
[10]Patel S P, Campbell D L. Transient outward potassium current,'Ito', phenotypes in the mammalian left ventricle:underlying molecular, cellular and biophysical mechanisms. J Physiol,2005,569(Pt 1):7-39.
[11]Oudit G Y, Kassiri Z, Sah R, et al. The molecular physiology of the cardiac transient outward potassium current (I(to)) in normal and diseased myocardium. J Mol Cell Cardiol,2001,33(5):851-872.
[12]Nerbonne J M. Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium. J Physiol,2000,525 Pt 2:285-298.
[13]Shimoni Y, Severson D, Giles W. Thyroid status and diabetes modulate regional differences in potassium currents in rat ventricle. J Physiol,1995,488 (Pt 3):673-688.
[14]Salle L, Kharche S, Zhang H, et al. Mechanisms underlying adaptation of action potential duration by pacing rate in rat myocytes. Prog Biophys Mol Biol, 2008,96(1-3):305-320.
[15]Shigematsu S, Kiyosue T, Sato T, et al. Rate-dependent prolongation of action potential duration in isolated rat ventricular myocytes. Basic Res Cardiol, 1997,92(3):123-128.
[16]Zicha S, Moss I, Allen B, et al. Molecular basis of species-specific expression of repolarizing K+ currents in the heart. Am J Physiol Heart Circ Physiol, 2003,285(4):H1641-H1649.
[17]Lu Z, Kamiya K, Opthof T, et al. Density and kinetics of I(Kr) and I(Ks) in guinea pig and rabbit ventricular myocytes explain different efficacy of I(Ks) blockade at high heart rate in guinea pig and rabbit:implications for arrhythmogenesis in humans. Circulation,2001,104(8):951-956.
[18]Stengl M, Volders P G, Thomsen M B, et al. Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes. J Physiol, 2003,551(Pt 3):777-786.
[19]Janvier N C, Boyett M R. The role of Na-Ca exchange current in the cardiac action potential. Cardiovasc Res,1996,32(1):69-84.
[20]Williams B A, Dickenson D R, Beatch G N. Kinetics of rate-dependent shortening of action potential duration in guinea-pig ventricle; effects of IK1 and IKr blockade. Br J Pharmacol,1999,126(6):1426-1436.
[21]Li G R, Yang B, Feng J, et al. Transmembrane ICa contributes to rate-dependent changes of action potentials in human ventricular myocytes. Am J Physiol, 1999,276(1 Pt2):H98-H106.
[22]Bril A, Forest M C, Cheval B, et al. Combined potassium and calcium channel antagonistic activities as a basis for neutral frequency dependent increase in action potential duration:comparison between BRL-32872 and azimilide. Cardiovasc Res, 1998,37(1):130-140.
[23]Michael G, Xiao L, Qi X Y, et al. Remodelling of cardiac repolarization:how homeostatic responses can lead to arrhythmogenesis. Cardiovasc Res,2009,81(3): 491-499.
[24]Carmeliet E. Intracellular Ca(2+) concentration and rate adaptation of the cardiac action potential. Cell Calcium,2004,35(6):557-573.
[25]Xiao L, Coutu P, Villeneuve L R, et al. Mechanisms underlying rate-dependent remodeling of transient outward potassium current in canine ventricular myocytes. Circ Res,2008,103(7):733-742.
[26]Harada M, Luo X, Qi X Y, et al. Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation,2012,126(17): 2051-2064.
[27]Dominguez-Rodriguez A, Ruiz-Hurtado G, Benitah J P, et al. The other side of cardiac Ca(2+) signaling:transcriptional control. Front Physiol,2012,3:452.
[28]Sager P T, Uppal P, Follmer C, et al. Frequency-dependent electrophysiologic effects of amiodarone in humans. Circulation,1993,88(3):1063-1071.
[1]Janssen P M, Periasamy M. Determinants of frequency-dependent contraction and relaxation of mammalian myocardium. J Mol Cell Cardiol,2007,43(5):523-531.
[2]Endoh M. Frequency-dependent inhibition of the intracellular calcium transients by calmodulin antagonists in the aequorin-injected rabbit papillary muscle. Adv Exp Med Biol,1989,255:461-470.
[3]Maier L S, Bers D M, Pieske B. Differences in Ca(2+)-handling and sarcoplasmic reticulum Ca(2+)-content in isolated rat and rabbit myocardium. J Mol Cell Cardiol, 2000,32(12):2249-2258.
[4]Bers D M. Cardiac excitation-contraction coupling. Nature,2002,415(6868): 198-205.
[5]Hove-Madsen L, Bers D M. Sarcoplasmic reticulum Ca2+ uptake and thapsigargin sensitivity in permeabilized rabbit and rat ventricular myocytes. Circ Res, 1993,73(5):820-828.
[6]Bers D M. Calcium fluxes involved in control of cardiac myocyte contraction. Circ Res,2000,87(4):275-281.
[7]Bers D M, Bassani R A, Bassani J W, et al. Paradoxical twitch potentiation after rest in cardiac muscle:increased fractional release of SR calcium. J Mol Cell Cardiol,1993,25(9):1047-1057.
[8]Bassani R A, Bers D M. Na-Ca exchange is required for rest-decay but not for rest-potentiation of twitches in rabbit and rat ventricular myocytes. J Mol Cell Cardiol,1994,26(10):1335-1347.
[9]Endoh M. Force-frequency relationship in intact mammalian ventricular myocardium:physiological and pathophysiological relevance. Eur J Pharmacol, 2004,500(1-3):73-86.
[10]Redel A, Baumgartner W, Golenhofen K, et al. Mechanical activity and force-frequency relationship of isolated mouse papillary muscle:effects of extracellular calcium concentration, temperature and contraction type. Pflugers Arch,2002,445(2):297-304.
[11]Schouten V J, ter Keurs H E. The force-frequency relationship in rat myocardium. The influence of muscle dimensions. Pflugers Arch,1986,407(1):14-17.
[1]Chen X, Wilson R M, Kubo H, et al. Adolescent feline heart contains a population of small, proliferative ventricular myocytes with immature physiological properties. Circ Res,2007,100(4):536-544.
[2]Xu X, Colecraft H M. Engineering proteins for custom inhibition of Ca(V) channels. Physiology (Bethesda),2009,24:210-218.
[3]Dzhura I, Wu Y, Zhang R, et al. C terminus L-type Ca2+ channel calmodulin-binding domains are'auto-agonist' ligands in rabbit ventricular myocytes. J Physiol,2003,550(Pt 3):731-738.
[4]Dick I E, Tadross M R, Liang H, et al. A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels. Nature, 2008,451(7180):830-834.
[5]Xiong L, Kleerekoper Q K, He R, et al. Sites on calmodulin that interact with the C-terminal tail of Cavl.2 channel. J Biol Chem,2005,280(8):7070-7079.
[6]Josephson I R, Guia A, Lakatta E G, et al. Ca2+-dependent components of inactivation of unitary cardiac L-type Ca2+ channels. J Physiol,2010,588(Pt 1):213-223.
[7]Matthes J, Herzig S. Less is more, or enough is enough? Ca2+-dependent inactivation revisited. J Physiol,2010,588(Pt 1):15-16.
[8]Sham J S, Song L S, Chen Y, et al. Termination of Ca2+ release by a local inactivation of ryanodine receptors in cardiac myocytes. Proc Natl Acad Sci U S A, 1998,95(25):15096-15101.
[9]Fowler M R, Smith G L. The cardiac contraction cycle:Is Ca2+ going local? J Appl Physiol,2009.
[10]Puglisi J L, Yuan W, Bassani J W, et al. Ca2+ influx through Ca2+ channels in rabbit ventricular myocytes during action potential clamp:influence of temperature. Circ Res,1999,85(6):e7-e16.
[11]Dzhura I, Wu Y, Colbran R J, et al. Calmodulin kinase determines calcium-dependent facilitation of L-type calcium channels. Nat Cell Biol, 2000,2(3):173-177.
[12]Hashambhoy Y L, Winslow R L, Greenstein J L. CaMKII-induced shift in modal gating explains L-type Ca2+ current facilitation:a modeling study. Biophys J,2009,96(5):1770-1785.
[13]Bassani J W, Bassani R A, Bers D M. Relaxation in rabbit and rat cardiac cells: species-dependent differences in cellular mechanisms. J Physiol, 1994,476(2):279-293.
[14]Bers D M. Cardiac excitation-contraction coupling. Nature, 2002,415(6868):198-205.
[15]Hove-Madsen L, Bers D M. Sarcoplasmic reticulum Ca2+ uptake and thapsigargin sensitivity in permeabilized rabbit and rat ventricular myocytes. Circ Res,1993,73(5):820-828.
[16]Li L, Chu G, Kranias E G, et al. Cardiac myocyte calcium transport in phospholamban knockout mouse:relaxation and endogenous CaMKII effects. Am J Physiol,1998,274(4 Pt 2):H1335-H1347.
[17]Hasenfuss G. Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res,1998,37(2):279-289.
[18]Flesch M, Schwinger R H, Schiffer F, et al. Evidence for functional relevance of an enhanced expression of the Na+-Ca2+ exchanger in failing human myocardium. Circulation,1996,94(5):992-1002.
[19]Elliott E B, Kelly A, Smith G L, et al. Isolated rabbit working heart function during progressive inhibition of myocardial SERCA activity. Circ Res, 2012,110(12):1618-1627.
[20]Lu Y M, Huang J, Shioda N, et al. CaMKIIdeltaB mediates aberrant NCX1 expression and the imbalance of NCX1/SERCA in transverse aortic constriction-induced failing heart. PLoS One,2011,6(9):e24724.
[21]Cutler M J, Wan X, Plummer B N, et al. Targeted sarcoplasmic reticulum Ca2+ATPase 2a gene delivery to restore electrical stability in the failing heart. Circulation,2012,126(17):2095-2104.
[22]Delbridge L M, Bassani J W, Bers D M. Steady-state twitch Ca2+ fluxes and cytosolic Ca2+ buffering in rabbit ventricular myocytes. Am J Physiol,1996,270(1 Pt 1):C192-C199.
[23]Bassani J W, Yuan W, Bers D M. Fractional SR Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes. Am J Physiol,1995,268(5 Pt 1):C1313-C1319.
[24]Delbridge L M, Satoh H, Yuan W, et al. Cardiac myocyte volume, Ca2+ fluxes, and sarcoplasmic reticulum loading in pressure-overload hypertrophy. Am J Physiol,1997,272(5 Pt 2):H2425-H2435.
[25]Yuan W, Ginsburg K S, Bers D M. Comparison of sarcolemmal calcium channel current in rabbit and rat ventricular myocytes. J Physiol,1996,493 (Pt 3):733-746.
[26]Philipson K D, Nicoll D A. Sodium-calcium exchange:a molecular perspective. Annu Rev Physiol,2000,62:111-133.
[27]Reuter H, Pott C, Goldhaber J I, et al. Na+-Ca2+ exchange in the regulation of cardiac excitation-contraction coupling. Cardiovasc Res,2005,67(2):198-207.
[28]Sher A A, Noble P J, Hinch R, et al. The role of the Na+/Ca2+ exchangers in Ca2+ dynamics in ventricular myocytes. Prog Biophys Mol Biol, 2008,96(1-3):377-398.
[29]Egger M, Niggli E. Paradoxical block of the Na+-Ca2+ exchanger by extracellular protons in guinea-pig ventricular myocytes. J Physiol,2000,523 Pt 2:353-366.
[30]Kang T M, Hilgemann D W. Multiple transport modes of the cardiac Na+/Ca2+ exchanger. Nature,2004,427(6974):544-548.
[31]Weber C R, Piacentino V R, Ginsburg K S, et al. Na+-Ca2+ exchange current and submembrane [Ca2+] during the cardiac action potential. Circ Res, 2002,90(2):182-189.
[32]Luo C H, Rudy Y. A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. Circ Res, 1994,74(6):1071-1096.
[33]Gaughan J P, Furukawa S, Jeevanandam V, et al. Sodium/calcium exchange contributes to contraction and relaxation in failed human ventricular myocytes. Am J Physiol,1999,277(2 Pt 2):H714-H724.
[34]Leblanc N, Hume J R. Sodium current-induced release of calcium from cardiac sarcoplasmic reticulum. Science,1990,248(4953):372-376.
[35]Levi A J, Spitzer K W, Kohmoto O, et al. Depolarization-induced Ca entry via Na-Ca exchange triggers SR release in guinea pig cardiac myocytes. Am J Physiol,1994,266(4 Pt 2):H1422-H1433.
[36]Wasserstrom J A, Vites A M. The role of Na+-Ca2+ exchange in activation of excitation-contraction coupling in rat ventricular myocytes. J Physiol,1996,493 (Pt2):529-542.
[37]Litwin S E, Li J, Bridge J H. Na-Ca exchange and the trigger for sarcoplasmic reticulum Ca release:studies in adult rabbit ventricular myocytes. Biophys J, 1998,75(1):359-371.
[38]Sham J S, Cleemann L, Morad M. Gating of the cardiac Ca2+release channel: the role of Na+ current and Na+-Ca2+ exchange. Science, 1992,255(5046):850-853.
[39]Sipido K R, Maes M, Van de Werf F. Low efficiency of Ca2+entry through the Na+-Ca2+ exchanger as trigger for Ca2+ release from the sarcoplasmic reticulum. A comparison between L-type Ca2+ current and reverse-mode Na+-Ca2+ exchange. Circ Res,1997,81 (6):1034-1044.
[40]Weber C R, Piacentino V R, Houser S R, et al. Dynamic regulation of sodium/calcium exchange function in human heart failure. Circulation, 2003,108(18):2224-2229.
[41]Li Y, Kranias E G, Mignery G A, et al. Protein kinase A phosphorylation of the ryanodine receptor does not affect calcium sparks in mouse ventricular myocytes. Circ Res,2002,90(3):309-316.
[42]Ginsburg K S, Bers D M. Modulation of excitation-contraction coupling by isoproterenol in cardiomyocytes with controlled SR Ca2+ load and Ca2+ current trigger. J Physiol,2004,556(Pt 2):463-480.
[43]Guo T, Zhang T, Mestril R, et al. Ca2+/Calmodulin-dependent protein kinase II phosphorylation of ryanodine receptor does affect calcium sparks in mouse ventricular myocytes. Circ Res,2006,99(4):398-406.
[44]Yang D, Zhu W Z, Xiao B, et al. Ca2+/calmodulin kinase II-dependent phosphorylation of ryanodine receptors suppresses Ca2+ sparks and Ca2+ waves in cardiac myocytes. Circ Res,2007,100(3):399-407.
[45]Huke S, Bers D M. Temporal dissociation of frequency-dependent acceleration of relaxation and protein phosphorylation by CaMKII. J Mol Cell Cardiol, 2007,42(3):590-599.
[46]Sitsapesan R, Williams A J. Regulation of the gating of the sheep cardiac sarcoplasmic reticulum Ca2+-release channel by luminal Ca2+. J Membr Biol, 1994,137(3):215-226.
[47]Stevens S C, Terentyev D, Kalyanasundaram A, et al. Intra-sarcoplasmic reticulum Ca2+ oscillations are driven by dynamic regulation of ryanodine receptor function by luminal Ca2+ in cardiomyocytes. J Physiol,2009,587(Pt 20):4863-4872.
[48]Lukyanenko V, Gyorke I, Gyorke S. Regulation of calcium release by calcium inside the sarcoplasmic reticulum in ventricular myocytes. Pflugers Arch, 1996,432(6):1047-1054
[49]Shannon T R, Ginsburg K S, Bers D M. Potentiation of fractional sarcoplasmic reticulum calcium release by total and free intra-sarcoplasmic reticulum calcium concentration. Biophys J,2000,78(1):334-343.
[50]Koss K L, Kranias E G. Phospholamban:a prominent regulator of myocardial contractility. Cire Res,1996,79(6):1059-1063.
[51]Lindner M, Erdmann E, Beuckelmann D J. Calcium content of the sarcoplasmic reticulum in isolated ventricular myocytes from patients with terminal heart failure. J Mol Cell Cardiol,1998,30(4):743-749.
[52]Pogwizd S M, Qi M, Yuan W, et al. Upregulation of Na+/Ca2+ exchanger expression and function in an arrhythmogenic rabbit model of heart failure. Circ Res,1999,85(11):1009-1019.
[53]Bogeholz N, Muszynski A, Pott C. The physiology of cardiac calcium handling. Wien Med Wochenschr,2012,162(13-14):278-282.
[54]Eisner D A, Dibb K M, Trafford A W. The mechanism and significance of the slow changes of ventricular action potential duration following a change of heart rate. Exp Physiol,2009,94(5):520-528.
[55]Franz M R, Swerdlow C D, Liem L B, et al. Cycle length dependence of human action potential duration in vivo. Effects of single extrastimuli, sudden sustained rate acceleration and deceleration, and different steady-state frequencies. J Clin Invest,1988,82(3):972-979.
[56]Barandi L, Harmati G, Horvath B, et al. Drug-induced changes in action potential duration are proportional to action potential duration in rat ventricular myocardium. Gen Physiol Biophys,2010,29(3):309-313.
[57]Barandi L, Virag L, Jost N, et al. Reverse rate-dependent changes are determined by baseline action potential duration in mammalian and human ventricular preparations. Basic Res Cardiol,2010,105(3):315-323.
[58]Antzelevitch C, Sicouri S, Litovsky S H, et al. Heterogeneity within the ventricular wall. Electrophysiology and pharmacology of epicardial, endocardial, and M cells. Circ Res,1991,69(6):1427-1449.
[59]Antzelevitch C, Fish J. Electrical heterogeneity within the ventricular wall. Basic Res Cardiol,2001,96(6):517-527.
[60]Sicouri S, Antzelevitch C. A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle. The M cell. Circ Res,1991,68(6):1729-1741.
[61]Sicouri S, Quist M, Antzelevitch C. Evidence for the presence of M cells in the guinea pig ventricle. J Cardiovasc Electrophysiol,1996,7(6):503-511.
[62]Marschang H, Brachmann J, Karolyi L, et al. Isoproterenol specifically modulates reverse rate-dependent effects of d,l-sotalol, d-sotalol, and dofetilide. J Cardiovasc Pharmacol,2000,35(3):443-450.
[63]Kovacs A, Magyar J, Banyasz T, et al. Beta-adrenoceptor activation plays a role in the reverse rate-dependency of effective refractory period lengthening by dofetilide in the guinea-pig atrium, in vitro. Br J Pharmacol, 2003,139(8):1555-1563.
[64]Lu Z, Kamiya K, Opthof T, et al. Density and kinetics of I(Kr) and I(Ks) in guinea pig and rabbit ventricular myocytes explain different efficacy of I(Ks) blockade at high heart rate in guinea pig and rabbit:implications for arrhythmogenesis in humans. Circulation,2001,104(8):951-956.
[65]Rudy Y. Molecular basis of cardiac action potential repolarization. Ann N Y Acad Sci,2008,1123:113-118.
[66]Cheng J H, Kodama I. Two components of delayed rectifier K+ current in heart:molecular basis, functional diversity, and contribution to repolarization. Acta Pharmacol Sin,2004,25(2):137-145.
[67]Stengl M, Volders P G, Thomsen M B, et al. Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes. J Physiol,2003,551(Pt 3):777-786.
[68]Janvier N C, Boyett M R. The role of Na-Ca exchange current in the cardiac action potential. Cardiovasc Res,1996,32(1):69-84.
[69]Williams B A, Dickenson D R, Beatch G N. Kinetics of rate-dependent shortening of action potential duration in guinea-pig ventricle; effects of IK1 and IKr blockade. Br J Pharmacol,1999,126(6):1426-1436.
[70]Li G R, Yang B, Feng J, et al. Transmembrane ICa contributes to rate-dependent changes of action potentials in human ventricular myocytes. Am J Physiol,1999,276(1 Pt2):H98-H106.
[71]Bril A, Forest M C, Cheval B, et al. Combined potassium and calcium channel antagonistic activities as a basis for neutral frequency dependent increase in action potential duration:comparison between BRL-32872 and azimilide. Cardiovasc Res, 1998,37(1):130-140.
[72]Spencer C I, Sham J S. Effects of Na+/Ca2+ exchange induced by SR Ca2+ release on action potentials and afterdepolarizations in guinea pig ventricular myocytes. Am J Physiol Heart Circ Physiol,2003,285(6):H2552-H2562.
[73]Workman A J, Marshall G E, Rankin A C, et al. Transient outward K+ current (ITO) reduction prolongs action potentials and promotes afterdepolarisations:a dynamic-clamp study in human and rabbit cardiac atrial myocytes. J Physiol, 2012.
[74]Shigematsu S, Kiyosue T, Sato T, et al. Rate-dependent prolongation of action potential duration in isolated rat ventricular myocytes. Basic Res Cardiol, 1997,92(3):123-128.
[75]Shimoni Y, Firek L, Severson D, et al. Short-term diabetes alters K+currents in rat ventricular myocytes. Circ Res,1994,74(4):620-628.
[76]Dorian P, Newman D. Rate dependence of the effect of antiarrhythmic drugs delaying cardiac repolarization:an overview. Europace,2000,2(4):277-285.
[77]Banyasz T, Barandi L, Harmati G, et al. Mechanism of reverse rate-dependent action of cardioactive agents. Curr Med Chem,2011,18(24):3597-3606.
[78]Virag L, Acsai K, Hala O, et al. Self-augmentation of the lengthening of repolarization is related to the shape of the cardiac action potential:implications for reverse rate dependency. Br J Pharmacol,2009,156(7):1076-1084.
[79]Hondeghem L M, Matsubara T. Quinidine blocks cardiac sodium channels during opening and slow inactivation in guinea-pig papillary muscle. Br J Pharmacol,1988,93(2):311-318.
[80]Ragsdale D S, Mcphee J C, Scheuer T, et al. Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels. Proc Natl Acad Sci U S A,1996,93(17):9270-9275.
[81]Sunami A, Fan Z, Sawanobori T, et al. Use-dependent block of Na+currents by mexiletine at the single channel level in guinea-pig ventricular myocytes. Br J Pharmacol,1993,110(1):183-192.
[82]Bauer A, Becker R, Freigang K D, et al. Rate- and site-dependent effects of propafenone, dofetilide, and the new I(Ks)-blocking agent chromanol 293b on individual muscle layers of the intact canine heart. Circulation, 1999,100(21):2184-2190.
[83]Baskin E P, Lynch J J. Differential atrial versus ventricular activities of class III potassium channel blockers. J Pharmacol Exp Ther,1998,285(1):135-142.
[84]Jurkiewicz N K, Sanguinetti M C. Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class Ⅲ antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide. Circ Res, 1993,72(1):75-83.
[85]Nalos L, Varkevisser R, Jonsson M K, et al. Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes. Br J Pharmacol, 2012,165(2):467-478.
[86]Varro A, Balati B, lost N, et al. The role of the delayed rectifier component IKs in dog ventricular muscle and Purkinje fibre repolarization. J Physiol, 2000,523 Pt 1:67-81.
[87]Bosch R F, Gaspo R, Busch A E, et al. Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes. Cardiovasc Res, 1998,38(2):441-450.
[88]So P P, Hu X D, Backx P H, et al. Blockade of IKs by HMR 1556 increases the reverse rate-dependence of refractoriness prolongation by dofetilide in isolated rabbit ventricles. Br J Pharmacol,2006,148(3):255-263.
[89]Sager P T, Uppal P, Follmer C, et al. Frequency-dependent electrophysiologic effects of amiodarone in humans. Circulation,1993,88(3):1063-1071.
[90]Karam R, Marcello S, Brooks R R, et al. Azimilide dihydrochloride, a novel antiarrhythmic agent. Am J Cardiol,1998,81(6A):40D-46D.
[91]Abrol R, Page R L. Azimilide dihydrochloride:a new class III anti-arrhythmic agent. Expert Opin Investig Drugs,2000,9(11):2705-2715.
[92]Karle C A, Thomas D, Kiehn J. The antiarrhythmic drug BRL-32872. Cardiovasc Drug Rev,2002,20(2):111-120.
[93]Varro A, Biliczki P, lost N, et al. Theoretical possibilities for the development of novel antiarrhythmic drugs. Curr Med Chem,2004,11(1):1-11.
[94]Endoh M. Frequency-dependent inhibition of the intracellular calcium transients by calmodulin antagonists in the aequorin-injected rabbit papillary muscle. Adv Exp Med Biol,1989,255:461-470.
[95]Endoh M. Force-frequency relationship in intact mammalian ventricular myocardium:physiological and pathophysiological relevance. Eur J Pharmacol, 2004,500(1-3):73-86.
[96]Maier L S, Bers D M, Pieske B. Differences in Ca(2+)-handling and sarcoplasmic reticulum Ca(2+)-content in isolated rat and rabbit myocardium. J Mol Cell Cardiol,2000,32(12):2249-2258.
[97]Orchard C H, Lakatta E G. Intracellular calcium transients and developed tension in rat heart muscle. A mechanism for the negative interval-strength relationship. J Gen Physiol,1985,86(5):637-651.
[98]Mubagwa K, Lin W, Sipido K, et al. Monensin-induced reversal of positive force-frequency relationship in cardiac muscle:role of intracellular sodium in rest-dependent potentiation of contraction. J Mol Cell Cardiol,1997,29(3):977-989.
[99]Schouten V J, ter Keurs H E. Role of Ica and Na+/Ca2+ exchange in the force-frequency relationship of rat heart muscle. J Mol Cell Cardiol, 1991,23(9):1039-1050.
[100]Vornanen M. Force-frequency relationship, contraction duration and recirculating fraction of calcium in postnatally developing rat heart ventricles: correlation with heart rate. Acta Physiol Scand,1992,145(4):311-321.
[101]Redel A, Baumgartner W, Golenhofen K, et al. Mechanical activity and force-frequency relationship of isolated mouse papillary muscle:effects of extracellular calcium concentration, temperature and contraction type. Pflugers Arch,2002,445(2):297-304.
[102]Bers D M. Calcium fluxes involved in control of cardiac myocyte contraction. Circ Res,2000,87(4):275-281.
[103]Finkel M S, Oddis C V, Mayer O H, et al. Nitric oxide synthase inhibitor alters papillary muscle force-frequency relationship. J Pharmacol Exp Ther, 1995,272(2):945-952.
[104]Cotton J M, Kearney M T, Maccarthy P A, et al. Effects of nitric oxide synthase inhibition on Basal function and the force-frequency relationship in the normal and failing human heart in vivo. Circulation,2001,104(19):2318-2323.
[105]Prabhu S D, Azimi A, Frosto T. Nitric oxide effects on myocardial function and force-interval relations:regulation of twitch duration. J Mol Cell Cardiol, 1999,31(12):2077-2085.
[106]Rossman E I, Petre R E, Chaudhary K W, et al. Abnormal frequency-dependent responses represent the pathophysiologic signature of contractile failure in human myocardium. J Mol Cell Cardiol,2004,36(1):33-42.
[107]Janssen P M, Periasamy M. Determinants of frequency-dependent contraction and relaxation of mammalian myocardium. J Mol Cell Cardiol, 2007,43(5):523-531.
[108]Schouten V J, ter Keurs H E. The force-frequency relationship in rat myocardium. The influence of muscle dimensions.Pflugers Arch, 1986,407(1):14-17.
[109]Raman S,Kelley M A, Janssen P M.Effect of muscle dimensions on trabecular contractile performance under physiological conditions. Pflugers Arch, 2006,451(5):625-630.
[110]Schmidt U, Hajjar R J, Helm P A, et al. Contribution of abnormal sarcoplasmic reticulum ATPase activity to systolic and diastolic dysfunction in human heart failure. J Mol Cell Cardiol,1998,30(10):1929-1937.
[111]Hashimoto K, Perez N G, Kusuoka H, et al. Frequency-dependent changes in calcium cycling and contractile activation in SERCA2a transgenic mice. Basic Res Cardiol,2000,95(2):144-151.
[112]Reuter H, Zobel C, Brixius K, et al. The force-frequency relationship is dependent on Ca(2+)-influx via L-type-and SR-Ca(2+)-channels in human heart. Basic Res Cardiol,1999,94(3):159-170.
[113]Li L, Satoh H, Ginsburg K S, et al. The effect of Ca(2+)-calmodulin-dependent protein kinase II on cardiac excitation-contraction coupling in ferret ventricular myocytes. J Physiol,1997,501 (Pt 1):17-31.
[114]Suematsu N, Satoh S, Ueda Y, et al. Effects of calmodulin and okadaic acid on myofibrillar Ca2+ sensitivity in cardiac myocytes. Basic Res Cardiol, 2002,97(2):137-144.
[115]Shimoni Y, Severson D, Giles W. Thyroid status and diabetes modulate regional differences in potassium currents in rat ventricle. J Physiol,1995,488 (Pt 3):673-688.
[116]Fauconnier J, Bedut S, Le Guennec J Y, et al. Ca2+ current-mediated regulation of action potential by pacing rate in rat ventricular myocytes. Cardiovasc Res,2003,57(3):670-680.
[117]Salle L, Kharche S, Zhang H, et al. Mechanisms underlying adaptation of action potential duration by pacing rate in rat myocytes. Prog Biophys Mol Biol, 2008,96(l-3):305-320.
[118]Carmeliet E. Intracellular Ca(2+) concentration and rate adaptation of the cardiac action potential. Cell Calcium,2004,35(6):557-573.
[119]Ravens U, Wettwer E. Electrophysiological aspects of changes in heart rate. Basic Res Cardiol,1998,93 Suppl 1:60-65.
[2]Boyett M R, Fedida D. Changes in the electrical activity of dog cardiac Purkinje fibres at high heart rates. J Physiol,1984,350:361-391.
[3]Stengl M, Volders P G, Thomsen M B, et al. Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes. J Physiol, 2003,551(Pt3):777-786.
[4]Janvier N C, Boyett M R. The role of Na-Ca exchange current in the cardiac action potential. Cardiovasc Res,1996,32(1):69-84.
[5]Spencer C I, Sham J S. Effects of Na+/Ca2+ exchange induced by SR Ca2+ release on action potentials and afterdepolarizations in guinea pig ventricular myocytes. Am J Physiol Heart Circ Physiol,2003,285(6):H2552-H2562.
[6]Williams B A, Dickenson D R, Beatch G N. Kinetics of rate-dependent shortening of action potential duration in guinea-pig ventricle; effects of IK1 and IKr blockade. Br J Pharmacol,1999,126(6):1426-1436.
[7]Li G R, Yang B, Feng J, et al. Transmembrane ICa contributes to rate-dependent changes of action potentials in human ventricular myocytes. Am J Physiol, 1999,276(1 Pt2):H98-H106.
[8]Endoh M. Force-frequency relationship in intact mammalian ventricular myocardium:physiological and pathophysiological relevance. Eur J Pharmacol, 2004,500(1-3):73-86.
[9]Wu L J, Sweet T B, Clapham D E. International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family. Pharmacol Rev,2010,62(3):381-404.
[10]Nilius B, Owsianik G. The transient receptor potential family of ion channels. Genome Biol,2011,12(3):218.
[11]Moran M M, Mcalexander M A, Biro T, et al. Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov,2011,10(8):601-620.
[12]Venkatachalam K, Montell C. TRP channels. Annu Rev Biochem,2007,76: 387-417.
[13]Clapham D E. TRP channels as cellular sensors. Nature,2003,426(6966):517-524.
[14]Vannier B, Peyton M, Boulay G, et al. Mouse trp2, the homologue of the human trpc2 pseudogene, encodes mTrp2, a store depletion-activated capacitative Ca2+ entry channel. Proc Natl Acad Sci U S A,1999,96(5):2060-2064.
[15]Minke B, Cook B. TRP channel proteins and signal transduction. Physiol Rev, 2002,82(2):429-472.
[16]Venkatachalam K, van Rossum D B, Patterson R L, et al. The cellular and molecular basis of store-operated calcium entry. Nat Cell Biol,2002,4(11): E263-E272.
[17]Harteneck C, Gollasch M. Pharmacological modulation of diacylglycerol-sensitive TRPC3/6/7 channels. Curr Pharm Biotechnol,2011,12(1):35-41.
[18]Maroto R, Raso A, Wood T G, et al. TRPC1 forms the stretch-activated cation channel in vertebrate cells. Nat Cell Biol,2005,7(2):179-185.
[19]Seth M, Zhang Z S, Mao L, et al. TRPC1 channels are critical for hypertrophic signaling in the heart. Circ Res,2009,105(10):1023-1030.
[20]Spassova M A, Hewavitharana T, Xu W, et al. A common mechanism underlies stretch activation and receptor activation of TRPC6 channels. Proc Natl Acad Sci USA,2006,103(44):16586-16591.
[21]Kinoshita H, Kuwahara K, Nishida M, et al. Inhibition of TRPC6 channel activity contributes to the antihypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart. Circ Res,2010,106(12):1849-1860.
[22]Eder P, Molkentin J D. TRPC channels as effectors of cardiac hypertrophy. Circ Res,2011,108(2):265-272.
[23]Harada M, Luo X, Qi X Y, et al. Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation, 2012,126(17):2051-2064.
[24]Sabourin J, Antigny F, Robin E, et al. Activation of transient receptor potential canonical 3 (TRPC3)-mediated Ca2+ entry by A1 adenosine receptor in cardiomyocytes disturbs atrioventricular conduction. J Biol Chem,2012,287(32): 26688-26701.
[25]Williams I A, Allen D G. Intracellular calcium handling in ventricular myocytes from mdx mice. Am J Physiol Heart Circ Physiol,2007,292(2):H846-H855.
[26]Ingueneau C, Huynh U D, Marcheix B, et al. TRPC1 is regulated by caveolin-1 and is involved in oxidized LDL-induced apoptosis of vascular smooth muscle cells. J Cell Mol Med,2009,13(8B):1620-1631.
[27]Ward M L, Williams I A, Chu Y, et al. Stretch-activated channels in the heart: contributions to length-dependence and to cardiomyopathy. Prog Biophys Mol Biol, 2008,97(2-3):232-249.
[28]Qian J Q. Cardiovascular pharmacological effects of bisbenzylisoquinoline alkaloid derivatives. Acta Pharmacol Sin,2002,23(12):1086-1092.
[29]Dong Z X, Zhao X, Gu D F, et al. Comparative effects of liensinine and neferine on the human ether-a-go-go-related gene potassium channel and pharmacological activity analysis. Cell Physiol Biochem,2012,29(3-4):431-442.
[1]Nilius B, Owsianik G. The transient receptor potential family of ion channels. Genome Biol,2011,12(3):218.
[2]Vennekens R. Emerging concepts for the role of TRP channels in the cardiovascular system. J Physiol,2011,589(Pt 7):1527-1534.
[3]Watanabe H, Murakami M, Ohba T, et al. TRP channel and cardiovascular disease. Pharmacol Ther,2008,118(3):337-351.
[4]Dong Z X, Zhao X, Gu D F, et al. Comparative effects of liensinine and neferine on the human ether-a-go-go-related gene potassium channel and pharmacological activity analysis. Cell Physiol Biochem,2012,29(3-4):431-442.
[5]Qian J Q. Cardiovascular pharmacological effects of bisbenzylisoquinoline alkaloid derivatives. Acta Pharmacol Sin,2002,23(12):1086-1092.
[6]Franz M R, Flaherty J T, Platia E V, et al. Localization of regional myocardial ischemia by recording of monophasic action potentials. Circulation, 1984,69(3):593-604.
[7]Franz M R. Long-term recording of monophasic action potentials from human endocardium. Am J Cardiol,1983,51(10):1629-1634.
[8]Franz M, Schottler M, Schaefer J, et al. Simultaneous recording of monophasic action potentials and contractile force from the human heart. Klin Wochenschr, 1980,58(24):1357-1359.
[9]Franz M R, Chin M C, Sharkey H R, et al. A new single catheter technique for simultaneous measurement of action potential duration and refractory period in vivo. J Am Coll Cardiol,1990,16(4):878-886.
[10]Patel S P, Campbell D L. Transient outward potassium current,'Ito', phenotypes in the mammalian left ventricle:underlying molecular, cellular and biophysical mechanisms. J Physiol,2005,569(Pt 1):7-39.
[11]Oudit G Y, Kassiri Z, Sah R, et al. The molecular physiology of the cardiac transient outward potassium current (I(to)) in normal and diseased myocardium. J Mol Cell Cardiol,2001,33(5):851-872.
[12]Nerbonne J M. Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium. J Physiol,2000,525 Pt 2:285-298.
[13]Shimoni Y, Severson D, Giles W. Thyroid status and diabetes modulate regional differences in potassium currents in rat ventricle. J Physiol,1995,488 (Pt 3):673-688.
[14]Salle L, Kharche S, Zhang H, et al. Mechanisms underlying adaptation of action potential duration by pacing rate in rat myocytes. Prog Biophys Mol Biol, 2008,96(1-3):305-320.
[15]Shigematsu S, Kiyosue T, Sato T, et al. Rate-dependent prolongation of action potential duration in isolated rat ventricular myocytes. Basic Res Cardiol, 1997,92(3):123-128.
[16]Zicha S, Moss I, Allen B, et al. Molecular basis of species-specific expression of repolarizing K+ currents in the heart. Am J Physiol Heart Circ Physiol, 2003,285(4):H1641-H1649.
[17]Lu Z, Kamiya K, Opthof T, et al. Density and kinetics of I(Kr) and I(Ks) in guinea pig and rabbit ventricular myocytes explain different efficacy of I(Ks) blockade at high heart rate in guinea pig and rabbit:implications for arrhythmogenesis in humans. Circulation,2001,104(8):951-956.
[18]Stengl M, Volders P G, Thomsen M B, et al. Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes. J Physiol, 2003,551(Pt 3):777-786.
[19]Janvier N C, Boyett M R. The role of Na-Ca exchange current in the cardiac action potential. Cardiovasc Res,1996,32(1):69-84.
[20]Williams B A, Dickenson D R, Beatch G N. Kinetics of rate-dependent shortening of action potential duration in guinea-pig ventricle; effects of IK1 and IKr blockade. Br J Pharmacol,1999,126(6):1426-1436.
[21]Li G R, Yang B, Feng J, et al. Transmembrane ICa contributes to rate-dependent changes of action potentials in human ventricular myocytes. Am J Physiol, 1999,276(1 Pt2):H98-H106.
[22]Bril A, Forest M C, Cheval B, et al. Combined potassium and calcium channel antagonistic activities as a basis for neutral frequency dependent increase in action potential duration:comparison between BRL-32872 and azimilide. Cardiovasc Res, 1998,37(1):130-140.
[23]Michael G, Xiao L, Qi X Y, et al. Remodelling of cardiac repolarization:how homeostatic responses can lead to arrhythmogenesis. Cardiovasc Res,2009,81(3): 491-499.
[24]Carmeliet E. Intracellular Ca(2+) concentration and rate adaptation of the cardiac action potential. Cell Calcium,2004,35(6):557-573.
[25]Xiao L, Coutu P, Villeneuve L R, et al. Mechanisms underlying rate-dependent remodeling of transient outward potassium current in canine ventricular myocytes. Circ Res,2008,103(7):733-742.
[26]Harada M, Luo X, Qi X Y, et al. Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation,2012,126(17): 2051-2064.
[27]Dominguez-Rodriguez A, Ruiz-Hurtado G, Benitah J P, et al. The other side of cardiac Ca(2+) signaling:transcriptional control. Front Physiol,2012,3:452.
[28]Sager P T, Uppal P, Follmer C, et al. Frequency-dependent electrophysiologic effects of amiodarone in humans. Circulation,1993,88(3):1063-1071.
[1]Janssen P M, Periasamy M. Determinants of frequency-dependent contraction and relaxation of mammalian myocardium. J Mol Cell Cardiol,2007,43(5):523-531.
[2]Endoh M. Frequency-dependent inhibition of the intracellular calcium transients by calmodulin antagonists in the aequorin-injected rabbit papillary muscle. Adv Exp Med Biol,1989,255:461-470.
[3]Maier L S, Bers D M, Pieske B. Differences in Ca(2+)-handling and sarcoplasmic reticulum Ca(2+)-content in isolated rat and rabbit myocardium. J Mol Cell Cardiol, 2000,32(12):2249-2258.
[4]Bers D M. Cardiac excitation-contraction coupling. Nature,2002,415(6868): 198-205.
[5]Hove-Madsen L, Bers D M. Sarcoplasmic reticulum Ca2+ uptake and thapsigargin sensitivity in permeabilized rabbit and rat ventricular myocytes. Circ Res, 1993,73(5):820-828.
[6]Bers D M. Calcium fluxes involved in control of cardiac myocyte contraction. Circ Res,2000,87(4):275-281.
[7]Bers D M, Bassani R A, Bassani J W, et al. Paradoxical twitch potentiation after rest in cardiac muscle:increased fractional release of SR calcium. J Mol Cell Cardiol,1993,25(9):1047-1057.
[8]Bassani R A, Bers D M. Na-Ca exchange is required for rest-decay but not for rest-potentiation of twitches in rabbit and rat ventricular myocytes. J Mol Cell Cardiol,1994,26(10):1335-1347.
[9]Endoh M. Force-frequency relationship in intact mammalian ventricular myocardium:physiological and pathophysiological relevance. Eur J Pharmacol, 2004,500(1-3):73-86.
[10]Redel A, Baumgartner W, Golenhofen K, et al. Mechanical activity and force-frequency relationship of isolated mouse papillary muscle:effects of extracellular calcium concentration, temperature and contraction type. Pflugers Arch,2002,445(2):297-304.
[11]Schouten V J, ter Keurs H E. The force-frequency relationship in rat myocardium. The influence of muscle dimensions. Pflugers Arch,1986,407(1):14-17.
[1]Chen X, Wilson R M, Kubo H, et al. Adolescent feline heart contains a population of small, proliferative ventricular myocytes with immature physiological properties. Circ Res,2007,100(4):536-544.
[2]Xu X, Colecraft H M. Engineering proteins for custom inhibition of Ca(V) channels. Physiology (Bethesda),2009,24:210-218.
[3]Dzhura I, Wu Y, Zhang R, et al. C terminus L-type Ca2+ channel calmodulin-binding domains are'auto-agonist' ligands in rabbit ventricular myocytes. J Physiol,2003,550(Pt 3):731-738.
[4]Dick I E, Tadross M R, Liang H, et al. A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels. Nature, 2008,451(7180):830-834.
[5]Xiong L, Kleerekoper Q K, He R, et al. Sites on calmodulin that interact with the C-terminal tail of Cavl.2 channel. J Biol Chem,2005,280(8):7070-7079.
[6]Josephson I R, Guia A, Lakatta E G, et al. Ca2+-dependent components of inactivation of unitary cardiac L-type Ca2+ channels. J Physiol,2010,588(Pt 1):213-223.
[7]Matthes J, Herzig S. Less is more, or enough is enough? Ca2+-dependent inactivation revisited. J Physiol,2010,588(Pt 1):15-16.
[8]Sham J S, Song L S, Chen Y, et al. Termination of Ca2+ release by a local inactivation of ryanodine receptors in cardiac myocytes. Proc Natl Acad Sci U S A, 1998,95(25):15096-15101.
[9]Fowler M R, Smith G L. The cardiac contraction cycle:Is Ca2+ going local? J Appl Physiol,2009.
[10]Puglisi J L, Yuan W, Bassani J W, et al. Ca2+ influx through Ca2+ channels in rabbit ventricular myocytes during action potential clamp:influence of temperature. Circ Res,1999,85(6):e7-e16.
[11]Dzhura I, Wu Y, Colbran R J, et al. Calmodulin kinase determines calcium-dependent facilitation of L-type calcium channels. Nat Cell Biol, 2000,2(3):173-177.
[12]Hashambhoy Y L, Winslow R L, Greenstein J L. CaMKII-induced shift in modal gating explains L-type Ca2+ current facilitation:a modeling study. Biophys J,2009,96(5):1770-1785.
[13]Bassani J W, Bassani R A, Bers D M. Relaxation in rabbit and rat cardiac cells: species-dependent differences in cellular mechanisms. J Physiol, 1994,476(2):279-293.
[14]Bers D M. Cardiac excitation-contraction coupling. Nature, 2002,415(6868):198-205.
[15]Hove-Madsen L, Bers D M. Sarcoplasmic reticulum Ca2+ uptake and thapsigargin sensitivity in permeabilized rabbit and rat ventricular myocytes. Circ Res,1993,73(5):820-828.
[16]Li L, Chu G, Kranias E G, et al. Cardiac myocyte calcium transport in phospholamban knockout mouse:relaxation and endogenous CaMKII effects. Am J Physiol,1998,274(4 Pt 2):H1335-H1347.
[17]Hasenfuss G. Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res,1998,37(2):279-289.
[18]Flesch M, Schwinger R H, Schiffer F, et al. Evidence for functional relevance of an enhanced expression of the Na+-Ca2+ exchanger in failing human myocardium. Circulation,1996,94(5):992-1002.
[19]Elliott E B, Kelly A, Smith G L, et al. Isolated rabbit working heart function during progressive inhibition of myocardial SERCA activity. Circ Res, 2012,110(12):1618-1627.
[20]Lu Y M, Huang J, Shioda N, et al. CaMKIIdeltaB mediates aberrant NCX1 expression and the imbalance of NCX1/SERCA in transverse aortic constriction-induced failing heart. PLoS One,2011,6(9):e24724.
[21]Cutler M J, Wan X, Plummer B N, et al. Targeted sarcoplasmic reticulum Ca2+ATPase 2a gene delivery to restore electrical stability in the failing heart. Circulation,2012,126(17):2095-2104.
[22]Delbridge L M, Bassani J W, Bers D M. Steady-state twitch Ca2+ fluxes and cytosolic Ca2+ buffering in rabbit ventricular myocytes. Am J Physiol,1996,270(1 Pt 1):C192-C199.
[23]Bassani J W, Yuan W, Bers D M. Fractional SR Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes. Am J Physiol,1995,268(5 Pt 1):C1313-C1319.
[24]Delbridge L M, Satoh H, Yuan W, et al. Cardiac myocyte volume, Ca2+ fluxes, and sarcoplasmic reticulum loading in pressure-overload hypertrophy. Am J Physiol,1997,272(5 Pt 2):H2425-H2435.
[25]Yuan W, Ginsburg K S, Bers D M. Comparison of sarcolemmal calcium channel current in rabbit and rat ventricular myocytes. J Physiol,1996,493 (Pt 3):733-746.
[26]Philipson K D, Nicoll D A. Sodium-calcium exchange:a molecular perspective. Annu Rev Physiol,2000,62:111-133.
[27]Reuter H, Pott C, Goldhaber J I, et al. Na+-Ca2+ exchange in the regulation of cardiac excitation-contraction coupling. Cardiovasc Res,2005,67(2):198-207.
[28]Sher A A, Noble P J, Hinch R, et al. The role of the Na+/Ca2+ exchangers in Ca2+ dynamics in ventricular myocytes. Prog Biophys Mol Biol, 2008,96(1-3):377-398.
[29]Egger M, Niggli E. Paradoxical block of the Na+-Ca2+ exchanger by extracellular protons in guinea-pig ventricular myocytes. J Physiol,2000,523 Pt 2:353-366.
[30]Kang T M, Hilgemann D W. Multiple transport modes of the cardiac Na+/Ca2+ exchanger. Nature,2004,427(6974):544-548.
[31]Weber C R, Piacentino V R, Ginsburg K S, et al. Na+-Ca2+ exchange current and submembrane [Ca2+] during the cardiac action potential. Circ Res, 2002,90(2):182-189.
[32]Luo C H, Rudy Y. A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. Circ Res, 1994,74(6):1071-1096.
[33]Gaughan J P, Furukawa S, Jeevanandam V, et al. Sodium/calcium exchange contributes to contraction and relaxation in failed human ventricular myocytes. Am J Physiol,1999,277(2 Pt 2):H714-H724.
[34]Leblanc N, Hume J R. Sodium current-induced release of calcium from cardiac sarcoplasmic reticulum. Science,1990,248(4953):372-376.
[35]Levi A J, Spitzer K W, Kohmoto O, et al. Depolarization-induced Ca entry via Na-Ca exchange triggers SR release in guinea pig cardiac myocytes. Am J Physiol,1994,266(4 Pt 2):H1422-H1433.
[36]Wasserstrom J A, Vites A M. The role of Na+-Ca2+ exchange in activation of excitation-contraction coupling in rat ventricular myocytes. J Physiol,1996,493 (Pt2):529-542.
[37]Litwin S E, Li J, Bridge J H. Na-Ca exchange and the trigger for sarcoplasmic reticulum Ca release:studies in adult rabbit ventricular myocytes. Biophys J, 1998,75(1):359-371.
[38]Sham J S, Cleemann L, Morad M. Gating of the cardiac Ca2+release channel: the role of Na+ current and Na+-Ca2+ exchange. Science, 1992,255(5046):850-853.
[39]Sipido K R, Maes M, Van de Werf F. Low efficiency of Ca2+entry through the Na+-Ca2+ exchanger as trigger for Ca2+ release from the sarcoplasmic reticulum. A comparison between L-type Ca2+ current and reverse-mode Na+-Ca2+ exchange. Circ Res,1997,81 (6):1034-1044.
[40]Weber C R, Piacentino V R, Houser S R, et al. Dynamic regulation of sodium/calcium exchange function in human heart failure. Circulation, 2003,108(18):2224-2229.
[41]Li Y, Kranias E G, Mignery G A, et al. Protein kinase A phosphorylation of the ryanodine receptor does not affect calcium sparks in mouse ventricular myocytes. Circ Res,2002,90(3):309-316.
[42]Ginsburg K S, Bers D M. Modulation of excitation-contraction coupling by isoproterenol in cardiomyocytes with controlled SR Ca2+ load and Ca2+ current trigger. J Physiol,2004,556(Pt 2):463-480.
[43]Guo T, Zhang T, Mestril R, et al. Ca2+/Calmodulin-dependent protein kinase II phosphorylation of ryanodine receptor does affect calcium sparks in mouse ventricular myocytes. Circ Res,2006,99(4):398-406.
[44]Yang D, Zhu W Z, Xiao B, et al. Ca2+/calmodulin kinase II-dependent phosphorylation of ryanodine receptors suppresses Ca2+ sparks and Ca2+ waves in cardiac myocytes. Circ Res,2007,100(3):399-407.
[45]Huke S, Bers D M. Temporal dissociation of frequency-dependent acceleration of relaxation and protein phosphorylation by CaMKII. J Mol Cell Cardiol, 2007,42(3):590-599.
[46]Sitsapesan R, Williams A J. Regulation of the gating of the sheep cardiac sarcoplasmic reticulum Ca2+-release channel by luminal Ca2+. J Membr Biol, 1994,137(3):215-226.
[47]Stevens S C, Terentyev D, Kalyanasundaram A, et al. Intra-sarcoplasmic reticulum Ca2+ oscillations are driven by dynamic regulation of ryanodine receptor function by luminal Ca2+ in cardiomyocytes. J Physiol,2009,587(Pt 20):4863-4872.
[48]Lukyanenko V, Gyorke I, Gyorke S. Regulation of calcium release by calcium inside the sarcoplasmic reticulum in ventricular myocytes. Pflugers Arch, 1996,432(6):1047-1054
[49]Shannon T R, Ginsburg K S, Bers D M. Potentiation of fractional sarcoplasmic reticulum calcium release by total and free intra-sarcoplasmic reticulum calcium concentration. Biophys J,2000,78(1):334-343.
[50]Koss K L, Kranias E G. Phospholamban:a prominent regulator of myocardial contractility. Cire Res,1996,79(6):1059-1063.
[51]Lindner M, Erdmann E, Beuckelmann D J. Calcium content of the sarcoplasmic reticulum in isolated ventricular myocytes from patients with terminal heart failure. J Mol Cell Cardiol,1998,30(4):743-749.
[52]Pogwizd S M, Qi M, Yuan W, et al. Upregulation of Na+/Ca2+ exchanger expression and function in an arrhythmogenic rabbit model of heart failure. Circ Res,1999,85(11):1009-1019.
[53]Bogeholz N, Muszynski A, Pott C. The physiology of cardiac calcium handling. Wien Med Wochenschr,2012,162(13-14):278-282.
[54]Eisner D A, Dibb K M, Trafford A W. The mechanism and significance of the slow changes of ventricular action potential duration following a change of heart rate. Exp Physiol,2009,94(5):520-528.
[55]Franz M R, Swerdlow C D, Liem L B, et al. Cycle length dependence of human action potential duration in vivo. Effects of single extrastimuli, sudden sustained rate acceleration and deceleration, and different steady-state frequencies. J Clin Invest,1988,82(3):972-979.
[56]Barandi L, Harmati G, Horvath B, et al. Drug-induced changes in action potential duration are proportional to action potential duration in rat ventricular myocardium. Gen Physiol Biophys,2010,29(3):309-313.
[57]Barandi L, Virag L, Jost N, et al. Reverse rate-dependent changes are determined by baseline action potential duration in mammalian and human ventricular preparations. Basic Res Cardiol,2010,105(3):315-323.
[58]Antzelevitch C, Sicouri S, Litovsky S H, et al. Heterogeneity within the ventricular wall. Electrophysiology and pharmacology of epicardial, endocardial, and M cells. Circ Res,1991,69(6):1427-1449.
[59]Antzelevitch C, Fish J. Electrical heterogeneity within the ventricular wall. Basic Res Cardiol,2001,96(6):517-527.
[60]Sicouri S, Antzelevitch C. A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle. The M cell. Circ Res,1991,68(6):1729-1741.
[61]Sicouri S, Quist M, Antzelevitch C. Evidence for the presence of M cells in the guinea pig ventricle. J Cardiovasc Electrophysiol,1996,7(6):503-511.
[62]Marschang H, Brachmann J, Karolyi L, et al. Isoproterenol specifically modulates reverse rate-dependent effects of d,l-sotalol, d-sotalol, and dofetilide. J Cardiovasc Pharmacol,2000,35(3):443-450.
[63]Kovacs A, Magyar J, Banyasz T, et al. Beta-adrenoceptor activation plays a role in the reverse rate-dependency of effective refractory period lengthening by dofetilide in the guinea-pig atrium, in vitro. Br J Pharmacol, 2003,139(8):1555-1563.
[64]Lu Z, Kamiya K, Opthof T, et al. Density and kinetics of I(Kr) and I(Ks) in guinea pig and rabbit ventricular myocytes explain different efficacy of I(Ks) blockade at high heart rate in guinea pig and rabbit:implications for arrhythmogenesis in humans. Circulation,2001,104(8):951-956.
[65]Rudy Y. Molecular basis of cardiac action potential repolarization. Ann N Y Acad Sci,2008,1123:113-118.
[66]Cheng J H, Kodama I. Two components of delayed rectifier K+ current in heart:molecular basis, functional diversity, and contribution to repolarization. Acta Pharmacol Sin,2004,25(2):137-145.
[67]Stengl M, Volders P G, Thomsen M B, et al. Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes. J Physiol,2003,551(Pt 3):777-786.
[68]Janvier N C, Boyett M R. The role of Na-Ca exchange current in the cardiac action potential. Cardiovasc Res,1996,32(1):69-84.
[69]Williams B A, Dickenson D R, Beatch G N. Kinetics of rate-dependent shortening of action potential duration in guinea-pig ventricle; effects of IK1 and IKr blockade. Br J Pharmacol,1999,126(6):1426-1436.
[70]Li G R, Yang B, Feng J, et al. Transmembrane ICa contributes to rate-dependent changes of action potentials in human ventricular myocytes. Am J Physiol,1999,276(1 Pt2):H98-H106.
[71]Bril A, Forest M C, Cheval B, et al. Combined potassium and calcium channel antagonistic activities as a basis for neutral frequency dependent increase in action potential duration:comparison between BRL-32872 and azimilide. Cardiovasc Res, 1998,37(1):130-140.
[72]Spencer C I, Sham J S. Effects of Na+/Ca2+ exchange induced by SR Ca2+ release on action potentials and afterdepolarizations in guinea pig ventricular myocytes. Am J Physiol Heart Circ Physiol,2003,285(6):H2552-H2562.
[73]Workman A J, Marshall G E, Rankin A C, et al. Transient outward K+ current (ITO) reduction prolongs action potentials and promotes afterdepolarisations:a dynamic-clamp study in human and rabbit cardiac atrial myocytes. J Physiol, 2012.
[74]Shigematsu S, Kiyosue T, Sato T, et al. Rate-dependent prolongation of action potential duration in isolated rat ventricular myocytes. Basic Res Cardiol, 1997,92(3):123-128.
[75]Shimoni Y, Firek L, Severson D, et al. Short-term diabetes alters K+currents in rat ventricular myocytes. Circ Res,1994,74(4):620-628.
[76]Dorian P, Newman D. Rate dependence of the effect of antiarrhythmic drugs delaying cardiac repolarization:an overview. Europace,2000,2(4):277-285.
[77]Banyasz T, Barandi L, Harmati G, et al. Mechanism of reverse rate-dependent action of cardioactive agents. Curr Med Chem,2011,18(24):3597-3606.
[78]Virag L, Acsai K, Hala O, et al. Self-augmentation of the lengthening of repolarization is related to the shape of the cardiac action potential:implications for reverse rate dependency. Br J Pharmacol,2009,156(7):1076-1084.
[79]Hondeghem L M, Matsubara T. Quinidine blocks cardiac sodium channels during opening and slow inactivation in guinea-pig papillary muscle. Br J Pharmacol,1988,93(2):311-318.
[80]Ragsdale D S, Mcphee J C, Scheuer T, et al. Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels. Proc Natl Acad Sci U S A,1996,93(17):9270-9275.
[81]Sunami A, Fan Z, Sawanobori T, et al. Use-dependent block of Na+currents by mexiletine at the single channel level in guinea-pig ventricular myocytes. Br J Pharmacol,1993,110(1):183-192.
[82]Bauer A, Becker R, Freigang K D, et al. Rate- and site-dependent effects of propafenone, dofetilide, and the new I(Ks)-blocking agent chromanol 293b on individual muscle layers of the intact canine heart. Circulation, 1999,100(21):2184-2190.
[83]Baskin E P, Lynch J J. Differential atrial versus ventricular activities of class III potassium channel blockers. J Pharmacol Exp Ther,1998,285(1):135-142.
[84]Jurkiewicz N K, Sanguinetti M C. Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class Ⅲ antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide. Circ Res, 1993,72(1):75-83.
[85]Nalos L, Varkevisser R, Jonsson M K, et al. Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes. Br J Pharmacol, 2012,165(2):467-478.
[86]Varro A, Balati B, lost N, et al. The role of the delayed rectifier component IKs in dog ventricular muscle and Purkinje fibre repolarization. J Physiol, 2000,523 Pt 1:67-81.
[87]Bosch R F, Gaspo R, Busch A E, et al. Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes. Cardiovasc Res, 1998,38(2):441-450.
[88]So P P, Hu X D, Backx P H, et al. Blockade of IKs by HMR 1556 increases the reverse rate-dependence of refractoriness prolongation by dofetilide in isolated rabbit ventricles. Br J Pharmacol,2006,148(3):255-263.
[89]Sager P T, Uppal P, Follmer C, et al. Frequency-dependent electrophysiologic effects of amiodarone in humans. Circulation,1993,88(3):1063-1071.
[90]Karam R, Marcello S, Brooks R R, et al. Azimilide dihydrochloride, a novel antiarrhythmic agent. Am J Cardiol,1998,81(6A):40D-46D.
[91]Abrol R, Page R L. Azimilide dihydrochloride:a new class III anti-arrhythmic agent. Expert Opin Investig Drugs,2000,9(11):2705-2715.
[92]Karle C A, Thomas D, Kiehn J. The antiarrhythmic drug BRL-32872. Cardiovasc Drug Rev,2002,20(2):111-120.
[93]Varro A, Biliczki P, lost N, et al. Theoretical possibilities for the development of novel antiarrhythmic drugs. Curr Med Chem,2004,11(1):1-11.
[94]Endoh M. Frequency-dependent inhibition of the intracellular calcium transients by calmodulin antagonists in the aequorin-injected rabbit papillary muscle. Adv Exp Med Biol,1989,255:461-470.
[95]Endoh M. Force-frequency relationship in intact mammalian ventricular myocardium:physiological and pathophysiological relevance. Eur J Pharmacol, 2004,500(1-3):73-86.
[96]Maier L S, Bers D M, Pieske B. Differences in Ca(2+)-handling and sarcoplasmic reticulum Ca(2+)-content in isolated rat and rabbit myocardium. J Mol Cell Cardiol,2000,32(12):2249-2258.
[97]Orchard C H, Lakatta E G. Intracellular calcium transients and developed tension in rat heart muscle. A mechanism for the negative interval-strength relationship. J Gen Physiol,1985,86(5):637-651.
[98]Mubagwa K, Lin W, Sipido K, et al. Monensin-induced reversal of positive force-frequency relationship in cardiac muscle:role of intracellular sodium in rest-dependent potentiation of contraction. J Mol Cell Cardiol,1997,29(3):977-989.
[99]Schouten V J, ter Keurs H E. Role of Ica and Na+/Ca2+ exchange in the force-frequency relationship of rat heart muscle. J Mol Cell Cardiol, 1991,23(9):1039-1050.
[100]Vornanen M. Force-frequency relationship, contraction duration and recirculating fraction of calcium in postnatally developing rat heart ventricles: correlation with heart rate. Acta Physiol Scand,1992,145(4):311-321.
[101]Redel A, Baumgartner W, Golenhofen K, et al. Mechanical activity and force-frequency relationship of isolated mouse papillary muscle:effects of extracellular calcium concentration, temperature and contraction type. Pflugers Arch,2002,445(2):297-304.
[102]Bers D M. Calcium fluxes involved in control of cardiac myocyte contraction. Circ Res,2000,87(4):275-281.
[103]Finkel M S, Oddis C V, Mayer O H, et al. Nitric oxide synthase inhibitor alters papillary muscle force-frequency relationship. J Pharmacol Exp Ther, 1995,272(2):945-952.
[104]Cotton J M, Kearney M T, Maccarthy P A, et al. Effects of nitric oxide synthase inhibition on Basal function and the force-frequency relationship in the normal and failing human heart in vivo. Circulation,2001,104(19):2318-2323.
[105]Prabhu S D, Azimi A, Frosto T. Nitric oxide effects on myocardial function and force-interval relations:regulation of twitch duration. J Mol Cell Cardiol, 1999,31(12):2077-2085.
[106]Rossman E I, Petre R E, Chaudhary K W, et al. Abnormal frequency-dependent responses represent the pathophysiologic signature of contractile failure in human myocardium. J Mol Cell Cardiol,2004,36(1):33-42.
[107]Janssen P M, Periasamy M. Determinants of frequency-dependent contraction and relaxation of mammalian myocardium. J Mol Cell Cardiol, 2007,43(5):523-531.
[108]Schouten V J, ter Keurs H E. The force-frequency relationship in rat myocardium. The influence of muscle dimensions.Pflugers Arch, 1986,407(1):14-17.
[109]Raman S,Kelley M A, Janssen P M.Effect of muscle dimensions on trabecular contractile performance under physiological conditions. Pflugers Arch, 2006,451(5):625-630.
[110]Schmidt U, Hajjar R J, Helm P A, et al. Contribution of abnormal sarcoplasmic reticulum ATPase activity to systolic and diastolic dysfunction in human heart failure. J Mol Cell Cardiol,1998,30(10):1929-1937.
[111]Hashimoto K, Perez N G, Kusuoka H, et al. Frequency-dependent changes in calcium cycling and contractile activation in SERCA2a transgenic mice. Basic Res Cardiol,2000,95(2):144-151.
[112]Reuter H, Zobel C, Brixius K, et al. The force-frequency relationship is dependent on Ca(2+)-influx via L-type-and SR-Ca(2+)-channels in human heart. Basic Res Cardiol,1999,94(3):159-170.
[113]Li L, Satoh H, Ginsburg K S, et al. The effect of Ca(2+)-calmodulin-dependent protein kinase II on cardiac excitation-contraction coupling in ferret ventricular myocytes. J Physiol,1997,501 (Pt 1):17-31.
[114]Suematsu N, Satoh S, Ueda Y, et al. Effects of calmodulin and okadaic acid on myofibrillar Ca2+ sensitivity in cardiac myocytes. Basic Res Cardiol, 2002,97(2):137-144.
[115]Shimoni Y, Severson D, Giles W. Thyroid status and diabetes modulate regional differences in potassium currents in rat ventricle. J Physiol,1995,488 (Pt 3):673-688.
[116]Fauconnier J, Bedut S, Le Guennec J Y, et al. Ca2+ current-mediated regulation of action potential by pacing rate in rat ventricular myocytes. Cardiovasc Res,2003,57(3):670-680.
[117]Salle L, Kharche S, Zhang H, et al. Mechanisms underlying adaptation of action potential duration by pacing rate in rat myocytes. Prog Biophys Mol Biol, 2008,96(l-3):305-320.
[118]Carmeliet E. Intracellular Ca(2+) concentration and rate adaptation of the cardiac action potential. Cell Calcium,2004,35(6):557-573.
[119]Ravens U, Wettwer E. Electrophysiological aspects of changes in heart rate. Basic Res Cardiol,1998,93 Suppl 1:60-65.