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

Purpose: [formula omitted] is an important regulator of contractile function in the heart. Efflux mechanisms of the intracellular [formula omitted] concentration are regulated by the [formula omitted] exchanger (NCX) and plasma membrane [formula omitted]‐ATPase (PMCA). During myocardial ischemic‐reperfusion intracellular [formula omitted] 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 [formula omitted] concentration in vivo, where [formula omitted] has be sugested as a surrogate marker for [formula omitted]. This study introduces a potential technique to study cardiac [formula omitted] 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 [formula omitted] efflux; a control group and a group treated with SEA0400. Both groups were infused with a single dose of 190±2 nmoles/g BW [formula omitted]. The SEA0400 group were injected with 50 mg/kg SEA0400 one hour post‐[formula omitted] 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‐[formula omitted] infusion and at various time points post‐[formula omitted] 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‐[formula omitted] infusion. SEA0400 demonstrates the effectiveness of reducing the rate of [formula omitted] efflux. At a SEA0400 dose of 50 mg/kg the [formula omitted] efflux half‐life was approximately two times longer than the control group. Conclusion: This T₁‐mapping technique can be used to quantify [formula omitted] efflux rates from the myocardium. By using a NCX inhibiting agent this technique can potentially be employed to interrogate individual [formula omitted] efflux mechanisms and rates in vivo.