Effects and metabolism of fumarate in the perfused rat heart. a
13c-mass isotopomer study.
Laplante, Annick; Vincent, Genevi[grave]eve; Poirier, Myriame; and Des
Rosiers, Christine.
Department of Biochemistry and Nutrition, University of Montreal,
Montr[acute]eal, Qu[acute]ebec, Canada
APStracts 3:0190E, 1996.
The cardioprotective effects of fumarate has 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 [13C]substrates and took advantage of 13C-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
[1-13C]octanoate and 0.04 or 0.4 mM [U-13C4]fumarate. Upon
reoxygenation after 40 min of severe hypoxia, hearts perfused with
0.4 fumarate showed a better recovery contractile function (greater
dP/dt) and released less lactate dehydrogenase (an index of cellular
necrosis) than those perfused with 0.04 Mm fumarate. The 13C-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.
Received 15 March 1996; accepted in final form 21 August 1996.
APS Manuscript Number E130-6.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 19 September 1996