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 |
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. |