Mathematical Model for β1-Adrenergic Regulation of the Mouse Ventricular Myocyte Contraction

Abstract

The β₁-adrenergic regulation of cardiac myocyte contraction plays an important role in regulating heart function. Activation of this system leads to an increased heart rate and stronger myocyte contraction. However, chronic stimulation of the β₁-adrenergic signaling system can lead to cardiac hypertrophy and heart failure. To understand the mechanisms of action of β₁-adrenoceptors, a mathematical model of cardiac myocyte contraction that includes the β₁-adrenergic system was developed and studied. The model was able to simulate major experimental protocols for measurements of steady-state force-calcium relationships, cross-bridge release rate and force development rate, force-velocity relationship, and force redevelopment rate. It also reproduced quite well frequency and isoproterenol dependencies for intracellular Ca²⁺ concentration ([Ca²⁺]_i) transients, total contraction force, and sarcomere shortening. The mathematical model suggested the mechanisms of increased contraction force and myocyte shortening on stimulation of β₁-adrenergic receptors is due to phosphorylation of troponin I and myosin-binding protein C and increased [Ca²⁺]_i transient resulting from activation of the β₁-adrenergic signaling system. The model was used to simulate work-loop contractions and estimate the power during the cardiac cycle as well as the effects of 4-aminopyridine and tedisamil on the myocyte contraction. The developed mathematical model can be used further for simulations of contraction of ventricular myocytes from genetically modified mice and myocytes from mice with chronic cardiac diseases.