TY - JOUR
T1 - Simulation analysis of intracellular Na+ and Cl- homeostasis during β1-adrenergic stimulation of cardiac myocyte
AU - Kuzumoto, Masanori
AU - Takeuchi, Ayako
AU - Nakai, Hiroyuki
AU - Oka, Chiaki
AU - Noma, Akinori
AU - Matsuoka, Satoshi
N1 - Funding Information:
The authors thank Dr. Keiko Ishihara and members in Cell/Biodynamics Simulation Project Kyoto University for their helping model development and analysis. This study was supported by the Leading Project for Biosimulation and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to A.N., A.T., S.M.).
PY - 2008/1
Y1 - 2008/1
N2 - 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.
AB - 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.
KW - CFTR
KW - Inotropic effect
KW - Kyoto model
KW - Na/K pump
KW - β1-adrenergic signaling
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U2 - 10.1016/j.pbiomolbio.2007.07.005
DO - 10.1016/j.pbiomolbio.2007.07.005
M3 - Review article
C2 - 17826821
AN - SCOPUS:43049112487
SN - 0079-6107
VL - 96
SP - 171
EP - 186
JO - Progress in Biophysics and Molecular Biology
JF - Progress in Biophysics and Molecular Biology
IS - 1-3
ER -