Simulation analysis of Na⁺ homeostasis during β-adrenergic stimulation in cardiac myocyte.

Abstract

To quantitatively understand intracellular Na⁺ homeostasis during the β1-adrenergic stimulation in cardiac myocyte, we constructed a computer model of β1-adrenergic signaling cascade based on a model by Saucermann et al. (2003), and implemented it into a comprehensive ventricular cell model (Kyoto model, Takeuchi et al. 2006), which can reconstruct membrane excitation, intracellular ion changes (Na⁺, K⁺, Ca²⁺ and Cl⁻), contraction, and osmotic volume change. An application of isoproterenol resulted in the shortening of action potential duration, the increases in both Ca²⁺ transient and cell shortening, and the decrease in both Cl⁻ concentration and cell volume. These results are consistent with experimental data. It has been experimentally reported that intracellular Na⁺ concentration decreases during the β1-adrenergic stimulation. Our model reproduced the decrease in Na⁺ under the condition of 0 or 0.5 Hz electrical stimulation. The decrease is attributable to the increase of Na⁺ affinity of Na⁺ pump by protein kinase A. However it was predicted that Na⁺ increases at physiological beating rate because of larger Na⁺ influx. We concluded that dynamic change of the intracellular Na⁺ concentrations as well as Ca²⁺ significantly contribute to the inotropic effect of β1-adrenergic stimulation on cardiac excitation-contraction coupling. [J Physiol Sci. 2007;57 Suppl:S197]