Simulation of the Impact of Elevated Cytosolic Na+ on Ca2+ Handling, Mitochondrial Energetics and Cellular Electrophysiology in Guinea Pig Myocytes

Abstract

Chronic heart failure is one of the leading causes of morbidity and mortality in the United States. One of the classical strategies for treating heart failure is to inhibit sarcolemmal Na+/K+-ATPase (NKA). Blocking NKA can result in dramatic elevation of [Na+]i, increasing the sarcoplasmic reticulum (SR) Ca2+ load by acting on the plasmalemmal Na+/Ca2+ exchanger (NCX). Whether and how change of [Na+]i affects mitochondrial Ca2+ dynamics and energetics is still under investigation. Since intracellular Na+ is regulated by a complex system involving multiple ions, channels, exchangers and membrane potentials, unraveling its effect on cell physiology and function requires an integrative view of cardiomyocyte physiology. In the present study we developed a mathematical model of cardiomyocyte that incorporates mitochondrial energetics, ion channels and exchangers, and E-C coupling. Using this model, we simulated the effect of elevated cytosolic Na+ on Ca2+ handling, mitochondrial energetics and reactive oxygen species (ROS) generation. Model simulations show that inhibition of NKA (50%) dramatically increased [Na+] in both the cytosol and mitochondria, which consequently caused Ca2+ overload in the cytoplasm during increased workload. Elevated Na+ also decreased ATP concentration and increased mitochondrial ROS production. Concomitant inhibition of mitochondrial Na+/Ca2+ exchanger (mNCE) ameliorated these effects by attenuating cellular Ca2+ overload and increasing [Ca2+]m. Furthermore, inhibiting mNCE also prevented the [ATP]i drop and decreased ROS production. The findings indicate that increasing cytosolic Na+ has an adverse effect on mitochondrial energetics that can be attenuated by simultaneous inhibition of mNCE.