The calcium-frequency response in the rat ventricular myocyte: an experimental and modelling study
The calcium-frequency response in the rat ventricular myocyte: an experimental and modelling study
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DOI：
10.1113/jp272011
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发表时间：
2016-08-01
影响因子：
5.5
通讯作者：
Smith, Nicolas P.
中科院分区：
文献类型：
--
作者：
Gattoni, Sara;Roe, Asmund Treu;Smith, Nicolas P.
心率的增加通过改变Ca2+瞬态作为生理需求的反应来影响心脏收缩的强度。这是由力-频率响应（FFR）来描述的，即发展力随起搏频率的变化。大多数哺乳动物，包括人类，FFR呈阳性，心脏收缩强度随心率增加而增加。然而，大鼠和小鼠是例外，大多数研究报告阴性FFR，而其他研究报告双相或阳性FFR。了解人类和大鼠之间FFR的差异是在人类生理学背景下解释基于大鼠的实验结果的基础。我们开发了一种新的大鼠心室电生理和钙动力学模型，主要来自生理条件下记录的实验数据。作为FFR的测量，我们测试了刺激频率和细胞外钙浓度的变化对模拟Ca2+瞬态特性的影响，并显示了双相钙峰-频率关系，这与最近观察到的FFR从负向正的转变一致，当接近大鼠生理频率范围时。我们验证了以下假设：(1)抑制Ca2+/钙调素依赖性蛋白激酶II （CAMKII）介导的sarco/内质网Ca2+- atp酶（SERCA）活性的增加；(2)CAMKII调节SERCA、l型通道和瞬时外向K+电流活性；(3)Na+/K+泵动力学在大鼠FFR中发挥重要作用。结果显示CAMKII调节SERCA在Ca2+频率峰值响应中的主要作用，最显著的是由细胞质钙缓冲系统和舒张期Ca2+的变化驱动。
An increase in heart rate affects the strength of cardiac contraction by altering the Ca2+ transient as a response to physiological demands. This is described by the force-frequency response (FFR), a change in developed force with pacing frequency. The majority of mammals, including humans, have a positive FFR, and cardiac contraction strength increases with heart rate. However, the rat and mouse are exceptions, with the majority of studies reporting a negative FFR, while others report either a biphasic or a positive FFR. Understanding the differences in the FFR between humans and rats is fundamental to interpreting rat-based experimental findings in the context of human physiology. We have developed a novel model of rat ventricular electrophysiology and calcium dynamics, derived predominantly from experimental data recorded under physiological conditions. As a measure of FFR, we tested the effects of changes in stimulation frequency and extracellular calcium concentration on the simulated Ca2+ transient characteristics and showed a biphasic peak calcium-frequency relationship, consistent with recent observations of a shift from negative to positive FFR when approaching the rat physiological frequency range. We tested the hypotheses that (1) inhibition of Ca2+/calmodulin-dependent protein kinase II (CAMKII)-mediated increase in sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity, (2) CAMKII modulation of SERCA, L-type channel and transient outward K+ current activity and (3) Na+/K+ pump dynamics play a significant role in the rat FFR. The results reveal a major role for CAMKII modulation of SERCA in the peak Ca2+-frequency response, driven most significantly by the cytosolic calcium buffering system and changes in diastolic Ca2+.