EFFECTS AND METABOLISM OF FUMARATE IN THE PERFUSED RAT-HEART - A C-13MASS ISOTOPOMER STUDY

The cardioprotective effects of fumarate have been Linked to its metab olism to succinate through both oxidative and reductive pathways. To d ate, the relative contribution of these pathways is a subject of contr oversy. To address this question, we designed a protocol with C-13 sub strates and took advantage of C-13 isotopomer analysis by gas chromato graphy-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 hy poxia, hearts perfused with 0.4 mM fumarate showed a better recovery o f contractile function and released less lactate dehydrogenase (an ind ex of cellular necrosis) than those perfused with 0.04 mM fumarate. Th e C-13 data showed that, in hypoxic hearts, fumarate conversion to suc cinate occurred only through reduction, although it accounted for only 16% of total succinate release. Most of the succinate was formed thro ugh 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 effect s of fumarate were associated with its predominant metabolism to succi nate through the reductive pathway.