Inhibition of the sodium-calcium exchanger via SEA0400 altered manganese-inducedT1changes in isolated perfused rat hearts

Abstract

Manganese (Mn(2+) )-enhanced MRI (MEMRI) provides the potential for the in vivo evaluation of calcium (Ca(2+) ) uptake in the heart. Recent studies have also suggested the role of the sodium-calcium (Na(+) -Ca(2+) ) exchanger (NCX) in Mn(2+) retention, which may have an impact on MEMRI signals. In this study, we investigated whether MEMRI with fast T(1) mapping allowed the sensitive detection of changes in NCX activity. We quantified the dynamics of the Mn(2+) -induced T(1) changes in isolated perfused rat hearts in response to SEA0400, an NCX inhibitor. The experimental protocol comprised 30 min of Mn(2+) perfusion (wash-in), followed by a 30-min wash-out period. There were three experimental groups: 1, NCX inhibition by 1 µ m SEA0400 during Mn(2+) wash-in only (SEAin, n=6); 2, NCX inhibition by 1 µ m SEA0400 during Mn(2+) wash-out only (SEAout, n=6); 3, no NCX inhibition during both wash-in and wash-out to serve as the control group (CNTL, n=5). Rapid T(1) mapping at a temporal resolution of 3 min was performed throughout the perfusion protocol using a triggered saturation-recovery Look-Locker sequence. Our results showed that NCX inhibition during Mn(2+) wash-in caused a significant increase in relaxation rate (R(1) ) at the end of Mn(2+) perfusion. During the wash-out period, NCX inhibition led to less reduction in R(1) . Further analysis of Mn(2+) content in myocardium with flame atomic absorption spectroscopy was consistent with the MRI findings. These results suggest that Mn(2+) accumulation and retention in rat hearts are, in part, dependent on NCX activity. Hence, MEMRI may provide an imaging method that is also sensitive to changes in NCX activity.