Assessing manganese efflux using SEA0400 and cardiac T1‐mapping manganese‐enhanced MRI in a murine model

The sodium–calcium exchanger (NCX) is one of the transporters contributing to the control of intracellular calcium (Ca²⁺) concentration by normally mediating net Ca²⁺ efflux. However, the reverse mode of the NCX can cause intracellular Ca²⁺ concentration overload, which exacerbates the myocardial tissue injury resulting from ischemia. Although the NCX inhibitor SEA0400 has been shown to therapeutically reduce myocardial injury, no in vivo technique exists to monitor intracellular Ca²⁺ fluctuations produced by this drug. Cardiac manganese‐enhanced MRI (MEMRI) may indirectly assess Ca²⁺ efflux by estimating changes in manganese (Mn²⁺) content in vivo, since Mn²⁺ has been suggested as a surrogate marker for Ca²⁺. This study used the MEMRI technique to examine the temporal features of cardiac Mn²⁺ efflux by implementing a T₁‐mapping method and inhibiting the NCX with SEA0400. The change in ¹H₂O longitudinal relaxation rate, ΔR₁, in the left ventricular free wall, was calculated at different time points following infusion of 190 nmol/g manganese chloride (MnCl₂) in healthy adult male mice. The results showed 50% MEMRI signal attenuation at 3.4 ± 0.6 h post‐MnCl₂ infusion without drug intervention. Furthermore, treatment with 50 ± 0.2 mg/kg of SEA0400 significantly reduced the rate of decrease in ΔR₁. At 4.9–5.9 h post‐MnCl₂ infusion, the average ΔR₁ values for the two groups treated with SEA0400 were 2.46 ± 0.29 and 1.72 ± 0.24 s^?1 for 50 and 20 mg/kg doses, respectively, as compared to the value of 1.27 ± 0.28 s^?1 for the control group. When this in vivo data were compared to ex vivo absolute manganese content data, the MEMRI T₁‐mapping technique was shown to effectively quantify Mn²⁺ efflux rates in the myocardium. Therefore, combining an NCX inhibitor with MEMRI may be a useful technique for assessing Mn²⁺ transport mechanisms and rates in vivo, which may reflect changes in Ca²⁺ transport. Copyright © 2009 John Wiley & Sons, Ltd.