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. Copyright © 2007 John Wiley & Sons, Ltd. Deducing microscopic processes constitutes a major MRI limitation. This investigation circumvents this hindrance, contributing an MRI‐based myocardial Ca2+‐transporter assay that probes the Na+/Ca2+‐exchanger (NCX) with Mn2+. Normoxic hyperkalemia (A) suppresses L‐type Ca2+‐channel (LTC). Under hypoxia (B), intracellular pH (pHi) falls, Na+/H+‐exchanger (NHE) mediates a pHi‐dependent [Nai+] rise, hypoxia‐induced ATP deficit eventually limits Na+/K+‐ATPase (NKA); and finally, NKA impairment vis‐à‐vis NHE “stimulation” promotes NCX‐mediated [Cai2+] and [Mni2+] rise. This important mechanism is ubiquitous to myocardial insults that impart [Nai+] increases.