Effect of Ca2+Efflux Pathway Distribution and Exogenous Ca2+Buffers on Intracellular Ca2+Dynamics in the Rat Ventricular Myocyte: A Simulation Study

We have used a previously published computer model of the rat cardiac ventricular myocyte to investigate the effect of changing the distribution of Ca 2+ efflux pathways (SERCA, Na + /Ca 2+ exchange, and sarcolemmal Ca 2+ ATPase) between the dyad and bulk cytoplasm and the effect of adding exogenous Ca 2+ buffers (BAPTA or EGTA), which are used experimentally to differentially buffer Ca 2+ in the dyad and bulk cytoplasm, on cellular Ca 2+ cycling. Increasing the dyadic fraction of a particular Ca 2+ efflux pathway increases the amount of Ca 2+ removed by that pathway, with corresponding changes in Ca 2+ efflux from the bulk cytoplasm. The magnitude of these effects varies with the proportion of the total Ca 2+ removed from the cytoplasm by that pathway. Differences in the response to EGTA and BAPTA, including changes in Ca 2+ -dependent inactivation of the L-type Ca 2+ current, resulted from the buffers acting as slow and fast “shuttles,” respectively, removing Ca 2+ from the dyadic space. The data suggest that complex changes in dyadic Ca 2+ and cellular Ca 2+ cycling occur as a result of changes in the location of Ca 2+ removal pathways or the presence of exogenous Ca 2+ buffers, although changing the distribution of Ca 2+ efflux pathways has relatively small effects on the systolic Ca 2+ transient.