Ionic mechanisms of cardiac cell swelling induced by blocking Na+/K+ pump as revealed by experiments and simulation.
Ionic mechanisms of cardiac cell swelling induced by blocking Na+/K+ pump as revealed by experiments and simulation.
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DOI：
10.1085/jgp.200609646
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发表时间：
2006-11
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影响因子：
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通讯作者：
Noma A
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作者：
Takeuchi A;Tatsumi S;Sarai N;Terashima K;Matsuoka S;Noma A
虽然Na+/K+泵是维持细胞体积的关键机制之一，但我们在实验中观察到，豚鼠心室肌细胞暴露于哇巴因90分钟期间，细胞体积几乎保持不变。使用综合心脏细胞模型（包含Cl−和水通量的京都模型）模拟这一发现，预测了质膜Ca 2 +-ATP酶（PMCA）和Na+/Ca 2+交换剂在维持细胞体积方面的作用，以及Na+和Cl−的低膜渗透性。PMCA可能有助于维持跨膜[Ca ~（2+）]梯度，从而促进由[Na ~+]i增加刺激的反向Na ~+/Ca ~（2+）交换以及膜去极化。通过Na+/Ca 2+交换的Na+挤出延迟Na+/K+泵阻断期间的细胞肿胀。支持这些模型的预测，我们观察到心室细胞肿胀后，阻断Na+/Ca 2+交换与KB-R7943或SEA 0400哇巴因的存在。当在哇巴因治疗期间用异丙肾上腺素激活通过囊性纤维化跨膜传导调节器（CFTR）的Cl−传导时，细胞显示出初始收缩至94.2 ± 0.5%，然后在药物应用后52.0 ± 4.9分钟出现明显肿胀。伴随着肿胀的发生，观察到膜电位的快速跳跃。这些实验观测结果可以很好地重现模型模拟。也就是说，通过CFTR的Cl−流出伴随着伴随的阳离子流出导致初始体积减少。然后，Na+/K+泵阻断引起的膜渐进去极化激活L型钙电流的窗口电流，使[Ca ~（2+）]i增加。最后，Ca 2+依赖性阳离子电导的激活引起膜电位的跳跃，细胞内Na+的快速积累伴随着Cl−通过CFTR内流，导致细胞肿胀。在模拟中预测的L型Ca 2+通道的关键作用在实验中得到了证实，其中阻断Ca 2+通道导致细胞肿胀延迟得多。
Although the Na+/K+ pump is one of the key mechanisms responsible for maintaining cell volume, we have observed experimentally that cell volume remained almost constant during 90 min exposure of guinea pig ventricular myocytes to ouabain. Simulation of this finding using a comprehensive cardiac cell model (Kyoto model incorporating Cl− and water fluxes) predicted roles for the plasma membrane Ca2+-ATPase (PMCA) and Na+/Ca2+ exchanger, in addition to low membrane permeabilities for Na+ and Cl−, in maintaining cell volume. PMCA might help maintain the [Ca2+] gradient across the membrane though compromised, and thereby promote reverse Na+/Ca2+ exchange stimulated by the increased [Na+]i as well as the membrane depolarization. Na+ extrusion via Na+/Ca2+ exchange delayed cell swelling during Na+/K+ pump block. Supporting these model predictions, we observed ventricular cell swelling after blocking Na+/Ca2+ exchange with KB-R7943 or SEA0400 in the presence of ouabain. When Cl− conductance via the cystic fibrosis transmembrane conductance regulator (CFTR) was activated with isoproterenol during the ouabain treatment, cells showed an initial shrinkage to 94.2 ± 0.5%, followed by a marked swelling 52.0 ± 4.9 min after drug application. Concomitantly with the onset of swelling, a rapid jump of membrane potential was observed. These experimental observations could be reproduced well by the model simulations. Namely, the Cl− efflux via CFTR accompanied by a concomitant cation efflux caused the initial volume decrease. Then, the gradual membrane depolarization induced by the Na+/K+ pump block activated the window current of the L-type Ca2+ current, which increased [Ca2+]i. Finally, the activation of Ca2+-dependent cation conductance induced the jump of membrane potential, and the rapid accumulation of intracellular Na+ accompanied by the Cl− influx via CFTR, resulting in the cell swelling. The pivotal role of L-type Ca2+ channels predicted in the simulation was demonstrated in experiments, where blocking Ca2+ channels resulted in a much delayed cell swelling.