Simulation analysis of intracellular Na+ and Cl- homeostasis during β1-adrenergic stimulation of cardiac myocyte

Masanori Kuzumoto, Ayako Takeuchi, Hiroyuki Nakai, Chiaki Oka, Akinori Noma, Satoshi Matsuoka

Research output: Contribution to journalReview article

48 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)171-186
Number of pages16
JournalProgress in Biophysics and Molecular Biology
Volume96
Issue number1-3
DOIs
StatePublished - Jan 1 2008

Keywords

  • CFTR
  • Inotropic effect
  • Kyoto model
  • Na/K pump
  • β1-adrenergic signaling

ASJC Scopus subject areas

  • Biophysics
  • Molecular Biology

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