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

Ben Waghorn, Yuhui Yang, Akemichi Baba, Toshio Matsuda, Autumn Schumacher, Nathan Yanasak, Tom C C Hu

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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 reducemyocardial 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, ΔR 1, in the left ventricular free wall, was calculated at different time points following infusion of 190 nmol/g manganese chloride (MnCl 2) 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 T 1-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.

Original languageEnglish (US)
Pages (from-to)874-881
Number of pages8
JournalNMR in Biomedicine
Volume22
Issue number8
DOIs
StatePublished - Dec 2 2009

Keywords

  • Calcium efflux
  • Cardiac MRI
  • Manganese efflux
  • Murine model
  • SEA0400
  • Sodium-calcium exchanger
  • T-mapping

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Spectroscopy

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