TU-D-332-04: Modulating Mn2+ Efflux with SEA0400, Using Cardiac Manganese-Enhanced MRI (MEMRI) T1-Mapping in a Murine Model

Purpose: Ca 2+ is an important regulator of contractile function in the heart. Efflux mechanisms of the intracellular Ca 2+ concentration are regulated by the Na + / Ca 2+ exchanger (NCX) and plasma membrane Ca 2+ ‐ATPase (PMCA). During myocardial ischemic‐reperfusion intracellular Ca 2+ overloads via the reverse mode of the NCX, exacerbating myocardial injuries. Protocols that selectively inhibit this exchanger have shown potential therapeutic effects. Cardiac manganese‐enhanced MRI (MEMRI) can be implemented to quantify Mn 2+ concentration in vivo, where Mn 2+ has be sugested as a surrogate marker for Ca 2+ . This study introduces a potential technique to study cardiac Mn 2+ efflux by inhibiting the NCX using SEA0400. Method and Materials: Male C57Bl/6 mice (6–13 weeks) were separated into two groups to study the rate of Mn 2+ efflux; a control group and a group treated with SEA0400. Both groups were infused with a single dose of 190±2 nmoles/g BW Mn 2+ . The SEA0400 group were injected with 50 mg/kg SEA0400 one hour post‐ Mn 2+ infusion. Images were acquired on a horizontal 7.0 T Bruker BioSpec MRI spectrometer equipped with a micro imaging gradient. T1‐maps were acquired pre‐ Mn 2+ infusion and at various time points post‐ Mn 2+ infusion using an ECG‐gated, flow‐compensated Look‐Locker MRI pulse sequence. The change in relaxivity, ΔR1, in the left ventricular free wall (LV Wall), was calculated at different time points post‐infusion. Results: In the LV Wall 50% of the signal enhancement is attenuated within ∼3–4 hours post‐ Mn 2+ infusion. SEA0400 demonstrates the effectiveness of reducing the rate of Mn 2+ efflux. At a SEA0400 dose of 50 mg/kg the Mn 2+ efflux half‐life was approximately two times longer than the control group. Conclusion: This T1‐mapping technique can be used to quantify Mn 2+ efflux rates from the myocardium. By using a NCX inhibiting agent this technique can potentially be employed to interrogate individual Mn 2+ efflux mechanisms and rates in vivo.