Model Study of ATP and ADP Buffering, Transport of Ca2+ and Mg2+,and Regulation of Ion Pumps in Ventricular Myocyte

AbstractWe extended the model of the ventricular myocyte by Winslow et al. (Circ. Res. 1999, 84:571–586) by incorporating equations for Ca2+ and Mg2+ buffering and transport by ATP and ADP and equations for MgATP regulation of ion transporters (Na+-K+ pump, sarcolemmal and sarcoplasmic Ca2+ pumps). The results indicate that, under normal conditions, Ca2+ binding by low-affinity ATP and diffusion of CaATP may affect the amplitude and time course of intracellular Ca2+ signals. The model also suggests that a fall in ATP/ADP ratio significantly reduces sarcoplasmic Ca2+ content, increases diastolic Ca2+, lowers systolic Ca2+, increases Ca2+ influx through L-type channels, and decreases the efficiency of the Na+/Ca2+ exchanger in extruding Ca2+ during periodic voltage-clamp stimulation. The analysis suggests that the most important reason for these changes during metabolic inhibition is the down-regulation of the sarcoplasmic Ca2+-ATPase pump by reduced diastolic MgATP levels. High Ca2+ concentrations developed near the membrane might have a greater influence on Mg2+, ATP, and ADP concentrations than that of the lower Ca2+ concentrations in the bulk myoplasm. The model predictions are in general agreement with experimental observations measured under normal and pathological conditions