Modeling Regulation of Cardiac KATPand 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 KATPand L-type Ca2+channels influences excitation-contraction coupling, we incorporated equations for intracellular ATP and MgADP regulation of the KATPcurrent 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 KATPcurrent, 2), simulates effects of ADP in modulating ATP sensitivity of KATPchannel, 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 KATPcurrent, 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.