title: The effect of hyperpolarized tracer concentration on myocardial uptake and metabolism.
abstract: Hyperpolarized (13)C-labeled substrates directly provide a source of magnetic resonance (MR) signal to observe the substrates' real-time uptake and enzymatic conversion. The aim of this study was to optimize the concentration of hyperpolarized [1-(13)C]pyruvate infused as a metabolic tracer, by observing the mitochondrial conversion of pyruvate to H(13)CO(3)(-) in heart tissue. Hyperpolarized pyruvate was infused into rats at concentrations between 20 mM and 80 mM and the relationships between [1-(13)C]lactate, [1-(13)C]alanine, and H(13)CO(3)(-) production and the infused pyruvate concentration were investigated. H(13)CO(3)(-) production reached saturation above 40 mM infused pyruvate concentration, indicating that hyperpolarized MR experiments performed at this concentration maximize the H(13)CO(3)(-) signal with minimal alterations to in vivo substrate composition. Additionally, the linear dependence of alanine production on pyruvate concentration confirmed that hyperpolarized MR methods in the heart reveal enzyme activity, rather than cellular uptake. H(13)CO(3)(-) production demonstrated evidence of sigmoidal enzyme kinetics, a reflection of the allosteric nature of the pyruvate dehydrogenase (PDH) enzyme complex. This protocol could be useful to optimize the infused concentration of other hyperpolarized metabolites in different organs, to ensure adequate MR signal with minimum metabolic perturbation.
authors.affiliation: Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Schroeder
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Atherton
authors.forename: Lowri E
authors.initials: LE
authors.lastname: Cochlin
authors.forename: Kieran
authors.initials: K
authors.lastname: Clarke
authors.forename: George K
authors.initials: GK
authors.lastname: Radda
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Tyler
mesh_terms: D000409:Alanine / Q000493:pharmacokinetics*; D000818:Animals; D002247:Carbon Isotopes / Q000493:pharmacokinetics*; D003287:Contrast Media / Q000493:pharmacokinetics; D006321:Heart / Q000033:anatomy & histology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D008657:Metabolic Clearance Rate; D009206:Myocardium / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002247:Carbon Isotopes; D003287:Contrast Media; D019275:Radiopharmaceuticals; D000409:Alanine