Simulation analysis of intracellular Na+ and Cl- homeostasis during beta 1-adrenergic stimulation of cardiac myocyte

Prog Biophys Mol Biol. Jan-Apr 2008;96(1-3):171-86. doi: 10.1016/j.pbiomolbio.2007.07.005. Epub 2007 Aug 1.

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 beta1-adrenergic stimulation in cardiac myocyte, we constructed a computer model of beta1-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 beta1-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 beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Calcium / physiology*
  • Cardiotonic Agents / pharmacology*
  • Computer Simulation*
  • Cystic Fibrosis Transmembrane Conductance Regulator / physiology
  • Guinea Pigs
  • Homeostasis / drug effects*
  • Isoproterenol / pharmacology
  • Models, Cardiovascular*
  • Myocardial Contraction / drug effects
  • Myocytes, Cardiac / drug effects*
  • Receptors, Adrenergic, beta / metabolism*
  • Signal Transduction / physiology
  • Sodium / physiology*
  • Sodium-Calcium Exchanger / physiology

Substances

  • Cardiotonic Agents
  • Receptors, Adrenergic, beta
  • Sodium-Calcium Exchanger
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Sodium
  • Isoproterenol
  • Calcium