Sallé Laurent, Kharche Sanjay, Zhang Henggui, Brette Fabien
Laboratoire de Physiologie Cellulaire, EA3212, Université de Caen, 14032 Caen, France.
Prog Biophys Mol Biol. 2008 Jan-Apr;96(1-3):305-20. doi: 10.1016/j.pbiomolbio.2007.07.008. Epub 2007 Aug 10.
Heart rate is an essential determinant of cardiac performance. In rat ventricular myocytes, a sudden increase in rate yields to a prolongation of the action potential duration (APD). The mechanism underlying this prolongation is controversial: it has been proposed that the longer APD is due to either: (1) a decrease in K+ currents only or (2) an increase in Ca2+ current only. The aim of this study was to quantitatively investigate the contribution of Ca2+ and K+ currents in the adaptation of APD to pacing rate. Simulation using a mathematical model of ventricular rat cardiac cell model [Pandit, S.V., Clark, R.B., Giles, W.R., Demir, S.S., 2001. A mathematical model of action potential heterogeneity in adult rat left ventricular myocytes. Biophys. J. 81, 3029-3051] predicted a role in the prolongation of APD for K+ currents only. In patch clamp experiments, increasing the pacing rate leads to a significant increase in APD in both control and detubulated myocytes, although it was more marked in control than detubulated myocytes. Supporting the model prediction, we observed that increasing stimulation frequency leads to a decrease in K+ currents in voltage clamped rat ventricular myocytes (square and action potential waveforms), and to a similar extent in both cell types. We have also observed that frequency-dependent facilitation of Ca2+ current occurred in control cells but not in detubulated cells (square and action potential waveforms). From these experiments, we calculated that the relative contribution of Ca2+ and K+ currents to the longer APD following an increase in pacing rate is approximately 65% and approximately 35%, respectively. Therefore, in contrast to the model prediction, Ca2+ current has a significant role in the adaptation of APD to pacing rate. Finally, we have introduced a simplistic modification to the Pandit's model to account for the frequency-dependent facilitation of Ca2+ current.
心率是心脏功能的一个重要决定因素。在大鼠心室肌细胞中，心率突然增加会导致动作电位时程（APD）延长。这种延长背后的机制存在争议：有人提出，较长的APD是由于以下两种情况之一：（1）仅K+电流减少；（2）仅Ca2+电流增加。本研究的目的是定量研究Ca2+和K+电流在APD对起搏频率适应中的作用。使用大鼠心室肌细胞数学模型进行的模拟[潘迪特，S.V.，克拉克，R.B.，贾尔斯，W.R.，德米尔，S.S.，2001年。成年大鼠左心室肌细胞动作电位异质性的数学模型。生物物理学杂志。81，3029 - 3051]预测，只有K+电流在APD延长中起作用。在膜片钳实验中，增加起搏频率会导致对照和去管肌细胞的APD显著增加，尽管在对照细胞中比在去管肌细胞中更明显。支持模型预测的是，我们观察到增加刺激频率会导致电压钳制的大鼠心室肌细胞（方波和动作电位波形）中的K+电流减少，并且在两种细胞类型中减少程度相似。我们还观察到，Ca2+电流的频率依赖性易化在对照细胞中出现，但在去管细胞中未出现（方波和动作电位波形）。从这些实验中，我们计算出，起搏频率增加后，Ca2+和K+电流对较长APD的相对贡献分别约为65%和约35%。因此，与模型预测相反，Ca2+电流在APD对起搏频率的适应中起重要作用。最后，我们对潘迪特模型进行了一个简单的修改，以解释Ca2+电流的频率依赖性易化。
