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From the Institute of Cardiovascular Sciences, University of Manitoba, St. Boniface General Hospital Research Centre, Winnipeg,
Manitoba, Canada, R2H 2A6
Cardiac muscle fails to relax upon replacement of extracellular Ca2+ with Ba2+. Among the manifold
consequences of this intervention, one major possibility is that Na+-Ba2+ exchange is inadequate to support normal relaxation. This could occur due to reduced transport rates of Na+-Ba2+ exchange and/or by failure of Ba2+
to activate the exchanger molecule at the high affinity regulatory Ca2+ binding site. In this study, we examined
transport and regulatory properties for Na+-Ca2+ and Na+-Ba2+ exchange. Inward and outward Na+-Ca2+ or Na+-Ba2+ exchange currents were examined at 30°C in giant membrane patches excised from Xenopus oocytes expressing the cloned cardiac Na+-Ca2+ exchanger, NCX1. When excised patches were exposed to either cytoplasmic
Ca2+ or Ba2+, robust inward Na+-Ca2+ exchange currents were observed, whereas Na+-Ba2+ currents were absent
or barely detectable. Similarly, outward currents were greatly reduced when pipette solutions contained Ba2+
rather than Ca2+. However, when solution temperature was elevated from 30°C to 37°C, a substantial increase in
outward Na+-Ba2+ exchange currents was observed, but not so for inward currents. We also compared the relative
abilities of Ca2+ and Ba2+ to activate outward Na+-Ca2+ exchange currents at the high affinity regulatory Ca2+
binding site. While Ba2+ was capable of activating the exchanger, it did so with a much lower affinity (KD ~ 10 µM) compared with Ca2+ (KD ~ 0.3 µM). Moreover, the efficiency of Ba2+ regulation of Na+-Ca2+ exchange is
also diminished relative to Ca2+, supporting ~60% of maximal currents obtainable with Ca2+. Ba2+ is also much
less effective at alleviating Na+i-induced inactivation of NCX1. These results indicate that the reduced ability of
NCX1 to adequately exchange Na+ and Ba2+ contributes to failure of the relaxation process in cardiac muscle.
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