Biomedical Engineering Laboratory - DEIS, University of Bologna, Via Venezia 52, 47521 Cesena, Italy.
J Physiol. 2012 Sep 15;590(18):4483-99. doi: 10.1113/jphysiol.2012.229435. Epub 2012 Jun 18.
The cellular basis of cardiac pacemaking is still debated. Reliable computational models of the sinoatrial node (SAN) action potential (AP) may help gain a deeper understanding of the phenomenon. Recently, novel models incorporating detailed Ca(2+)-handling dynamics have been proposed, but they fail to reproduce a number of experimental data, and more specifically effects of 'funny' (I(f)) current modifications. We therefore developed a SAN AP model, based on available experimental data, in an attempt to reproduce physiological and pharmacological heart rate modulation. Cell compartmentalization and intracellular Ca(2+)-handling mechanisms were formulated as in the Maltsev-Lakatta model, focusing on Ca(2+)-cycling processes. Membrane current equations were revised on the basis of published experimental data. Modifications of the formulation of currents/pumps/exchangers to simulate I(f) blockers, autonomic modulators and Ca(2+)-dependent mechanisms (ivabradine, caesium, acetylcholine, isoprenaline, BAPTA) were derived from experimental data. The model generates AP waveforms typical of rabbit SAN cells, whose parameters fall within the experimental ranges: 352 ms cycle length, 80 mV AP amplitude, -58 mV maximum diastolic potential (MDP), 108 ms APD(50), and 7.1 Vs(-1) maximum upstroke velocity. Rate modulation by I(f) -blocking drugs agrees with experimental findings: 20% and 22% caesium-induced (5mM) and ivabradine-induced (3 μM) rate reductions, respectively, due to changes in diastolic depolarization (DD) slope, with no changes in either MDP or take-off potential (TOP). The model consistently reproduces the effects of autonomic modulation: 20% rate decrease with 10 nM acetylcholine and 28%increase with 1 μM isoprenaline, again entirely due to increase in the DD slope,with no changes in either MDP or TOP. Model testing of BAPTA effects showed slowing of rate, -26%, without cessation of beating. Our up-to-date model describes satisfactorily experimental data concerning autonomic stimulation, funny-channel blockade and inhibition of the Ca(2+)-related system by BAPTA, making it a useful tool for further investigation. Simulation results suggest that a detailed description of the intracellular Ca(2+) fluxes is fully compatible with the observation that I(f) is a major component of pacemaking and rate modulation.
心脏起搏的细胞基础仍存在争议。可靠的窦房结 (SAN) 动作电位 (AP) 计算模型可能有助于更深入地了解这一现象。最近，提出了一些新的模型，这些模型包含详细的 Ca(2+) 处理动力学，但它们无法再现许多实验数据，特别是“有趣”(I(f))电流修改的效果。因此，我们根据现有的实验数据开发了一个 SAN AP 模型，试图重现生理和药理学的心率调节。细胞区室化和细胞内 Ca(2+) 处理机制如 Maltsev-Lakatta 模型所述，重点是 Ca(2+) 循环过程。根据已发表的实验数据修订了膜电流方程。根据实验数据，对电流/泵/交换器的公式进行了修改，以模拟 I(f) 阻断剂、自主调节剂和 Ca(2+) 依赖性机制 (异搏定、铯、乙酰胆碱、异丙肾上腺素、BAPTA)。该模型生成的 AP 波形典型的兔 SAN 细胞，其参数落在实验范围内：352 ms 周期长度、80 mV AP 幅度、-58 mV 最大舒张电位 (MDP)、108 ms APD(50)和 7.1 Vs(-1)最大上升速度。I(f) 阻断药物的速率调节与实验结果一致：由于舒张去极化 (DD) 斜率的变化，5mM 铯和 3 μM 异搏定分别引起 20%和 22%的速率降低，而 MDP 或起飞电位 (TOP) 没有变化。该模型一致地再现了自主调节的作用：10 nM 乙酰胆碱引起 20%的速率降低，1 μM 异丙肾上腺素引起 28%的速率增加，同样完全是由于 DD 斜率的增加，而 MDP 或 TOP 没有变化。BAPTA 作用的模型测试显示，速率减慢 26%，但不会停止跳动。我们最新的模型令人满意地描述了自主刺激、有趣通道阻断和 BAPTA 抑制 Ca(2+) 相关系统的实验数据，使其成为进一步研究的有用工具。模拟结果表明，详细描述细胞内 Ca(2+) 通量与 I(f) 是起搏和速率调节的主要组成部分的观察结果完全兼容。
