Simulation of the effects of moderate stimulation/inhibition of the β1-adrenergic signaling system and its components in mouse ventricular myocytes

Abstract

The β1-adrenergic signaling system is one of the most important protein signaling systems in cardiac cells. It regulates cardiac action potential duration, intracellular Ca2+concentration ([Ca2+]i) transients, and contraction force. In this paper, a comprehensive experimentally based mathematical model of the β1-adrenergic signaling system for mouse ventricular myocytes is explored to simulate the effects of moderate stimulations of β1-adrenergic receptors (β1-ARs) on the action potential, Ca2+and Na+dynamics, as well as the effects of inhibition of protein kinase A (PKA) and phosphodiesterase of type 4 (PDE4). Simulation results show that the action potential prolongations reach saturating values at relatively small concentrations of isoproterenol (∼0.01 μM), while the [Ca2+]itransient amplitude saturates at significantly larger concentrations (∼0.1–1.0 μM). The differences in the response of Ca2+and Na+fluxes to moderate stimulation of β1-ARs are also observed. Sensitivity analysis of the mathematical model is performed and the model limitations are discussed. The investigated model reproduces most of the experimentally observed effects of moderate stimulation of β1-ARs, PKA, and PDE4 inhibition on the L-type Ca2+current, [Ca2+]itransients, and the sarcoplasmic reticulum Ca2+load and makes testable predictions for the action potential duration and [Ca2+]itransients as functions of isoproterenol concentration.