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

Abstract

We have used a previously published computer model of the rat cardiac ventricular myocyte to investigate the effect of changing the distribution of Ca2+efflux pathways (SERCA, Na+/Ca2+exchange, and sarcolemmal Ca2+ATPase) between the dyad and bulk cytoplasm and the effect of adding exogenous Ca2+buffers (BAPTA or EGTA), which are used experimentally to differentially buffer Ca2+in the dyad and bulk cytoplasm, on cellular Ca2+cycling. Increasing the dyadic fraction of a particular Ca2+efflux pathway increases the amount of Ca2+removed by that pathway, with corresponding changes in Ca2+efflux from the bulk cytoplasm. The magnitude of these effects varies with the proportion of the total Ca2+removed from the cytoplasm by that pathway. Differences in the response to EGTA and BAPTA, including changes in Ca2+-dependent inactivation of the L-type Ca2+current, resulted from the buffers acting as slow and fast “shuttles,” respectively, removing Ca2+from the dyadic space. The data suggest that complex changes in dyadic Ca2+and cellular Ca2+cycling occur as a result of changes in the location of Ca2+removal pathways or the presence of exogenous Ca2+buffers, although changing the distribution of Ca2+efflux pathways has relatively small effects on the systolic Ca2+transient.