Modeling Nitric Oxide Regulation Of Ec Coupling In Cardiac Myocytes

Abstract

Nitric oxide (NO) signaling is a potent modulator of cardiac contractility in conditions of increased heart rate or ß-adrenergic signaling. Changes in nitric oxide synthase (NOS), the enzyme responsible for NO production, play a significant role in EC coupling observed in heart failure following myocardial infarction. NO signaling is thought to modulate cardiac function by targeting a range of EC coupling proteins including ryanodine receptor, phospholamban, L-type Ca2+ channel and myosin. However, the mechanisms underlying NO signaling and the relative importance of NO targets are unclear. Previous computational models of ß-adrenergic signaling and EC coupling have not accounted for NO regulation. We propose a new model that incorporates NO metabolism and effects of eNOS and nNOS activity on EC coupling. This integrated model provides a consistent framework to quantitatively predict the combined effects of NO on EC coupling and explain discrepancies in prior experimental results.