Na⁺/Ca²⁺-exchanger-mediated Mn²⁺-enhanced ¹H₂O MRI in hypoxic, perfused rat myocardium

Paramagnetic Mn²⁺ has emerged in the search for non-invasive magnetic resonance imaging (MRI) techniques to monitor Ca²⁺ in diagnostic and prognostic cardiovascular disease tests because it both alters MRI contrast and behaves as a Ca²⁺ 'surrogate' in vivo. However, the reliance on macroscopically averaged measurements to infer microscopic processes constitutes a major limitation of MRI. This investigation circumvents this limitation and contributes an MRI-based myocardial Ca²⁺-transporter assay, which probes the Na⁺/Ca²⁺-exchanger involvement in Mn²⁺ (and presumably Ca²⁺) transport by virtue of its response to pharmacological inhibition. In the model employed herein, ex vivo arrested rat hearts underwent normoxia and then hypoxia while a constant (hyperkalemic) perfusion minimized flow (and uncontrolled Ca²⁺-channel) contributions to Mn²⁺ enhanced MRI measurements. The results (i) demonstrate that Mn²⁺ (and presumably Ca²⁺) accumulates via Na⁺/Ca²⁺ -exchanger-mediated transport during hyperkalemic hypoxia and further, (ii) implicate hypo-perfusion (rather than the diminished participation of an isolated sarcolemmal Ca²⁺-transporter) as the mechanism that underlies the reported reductions of Mn²⁺ accumulation (relative to healthy myocardium) subsequent to myocardial insults in MRI studies. Although myriad studies have employed Mn²⁺-enhanced MRI in myocardial investigations, this appears to be the first attempt to assay the Na⁺/Ca²⁺-exchanger with MRI under highly circumscribed conditions. MRI-based Ca²⁺-transporter assays, such as the Na⁺/Ca²⁺-exchanger assay utilized here, will inevitably impact disciplines in the medical sciences and beyond.