Simulation analysis of intracellular Na and Cl homeostasis during β1-adrenergic stimulation of cardiac myocyte |
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Authors: | Masanori Kuzumoto Ayako Takeuchi Hiroyuki Nakai Chiaki Oka Akinori Noma Satoshi Matsuoka |
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Institution: | aCell/Biodynamics Simulation Project Kyoto University, Graduate School of Medicine, Kyoto University, Japan;bDepartment of Physiology and Biophysics, Graduate School of Medicine, Kyoto University, Yoshida-Konoe Sakyo-ku, Kyoto, 606-8501, Japan;cDiscovery Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan |
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Abstract: | To quantitatively understand intracellular Na+ and Cl− homeostasis as well as roles of Na+/K+ pump and cystic fibrosis transmembrane conductance regulator Cl− channel (ICFTR) during the β1-adrenergic stimulation in cardiac myocyte, we constructed a computer model of β1-adrenergic signaling and implemented it into an excitation-contraction coupling model of the guinea-pig ventricular cell, which can reproduce membrane excitation, intracellular ion changes (Na+, K+, Ca2+ and Cl−), contraction, cell volume, and oxidative phosphorylation. An application of isoproterenol to the model cell resulted in the shortening of action potential duration (APD) after a transient prolongation, the increases in both Ca2+ transient and cell shortening, and the decreases in both Cl− concentration and cell volume. These results are consistent with experimental data. Increasing the density of ICFTR shortened APD and augmented the peak amplitudes of the L-type Ca2+ current (ICaL) and the Ca2+ transient during the β1-adrenergic stimulation. This indirect inotropic effect was elucidated by the increase in the driving force of ICaL via a decrease in plateau potential. Our model reproduced the experimental data demonstrating the decrease in intracellular Na+ during the β-adrenergic stimulation at 0 or 0.5 Hz electrical stimulation. The decrease is attributable to the increase in Na+ affinity of Na+/K+ pump by protein kinase A. However it was predicted that Na+ increases at higher beating rate because of larger Na+ influx through forward Na+/Ca2+ exchange. It was demonstrated that dynamic changes in Na+ and Cl− fluxes remarkably affect the inotropic action of isoproterenol in the ventricular myocytes. |
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Keywords: | β 1-adrenergic signaling Kyoto model CFTR Na+/K+ pump Inotropic effect |
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