Modeling Regulation of Cardiac KATP and L-type Ca2+ Currents by ATP, ADP, and Mg2+

Changes in cytosolic free Mg2+ and adenosine nucleotide phosphates affect cardiac excitability and contractility. To investigate how modulation by Mg2+, ATP, and ADP of KATP and L-type Ca2+ channels influences excitation-contraction coupling, we incorporated equations for intracellular ATP and MgADP regulation of the KATP current and MgATP regulation of the L-type Ca2+ current in an ionic-metabolic model of the canine ventricular myocyte. The new model: 1), quantitatively reproduces a dose-response relationship for the effects of changes in ATP on KATP current, 2), simulates effects of ADP in modulating ATP sensitivity of KATP channel, 3), predicts activation of Ca2+ current during rapid increase in MgATP, and 4), demonstrates that decreased ATP/ADP ratio with normal total Mg2+ or increased free Mg2+ with normal ATP and ADP activate KATP current, shorten action potential, and alter ionic currents and intracellular Ca2+ signals. The model predictions are in agreement with experimental data measured under normal and a variety of pathological conditions.