Effects and metabolism of fumarate in the perfused rat heart. A C-13 mass isotopomer study

The cardioprotective effects of fumarate have been Linked to its metabolism to succinate through both oxidative and reductive pathways. To date, the relative contribution of these pathways is a subject of controversy. To address this question, we designed a protocol with C-13 substrates and took advantage of C-13 isotopomer analysis by gas chromatography-mass spectrometry. Rat hearts were perfused with 11 mM glucose, 1 mM lactate, 0.2 mM pyruvate, 0.2 mM [1-C-13]octanoate, and 0.04 or 0.4 mM [U-C-13(4)]fumarate. On reoxygenation after 40 min of severe hypoxia, hearts perfused with 0.4 mM fumarate showed a better recovery of contractile function and released less lactate dehydrogenase (an index of cellular necrosis) than those perfused with 0.04 mM fumarate. The C-13 data showed that, in hypoxic hearts, fumarate conversion to succinate occurred only through reduction, although it accounted for only 16% of total succinate release. Most of the succinate was formed through the oxidation of alpha-ketoglutarate or its precursors (50 +/- 5%) and by another yet-unidentified pathway (34 +/- 4%). These data show that, in a model of hypoxia-reoxygenation, the cardioprotective effects of fumarate were associated with its predominant metabolism to succinate through the reductive pathway.