Cytosolic redox state mediates postischemic response to pyruvate dehydrogenase stimulation.
Augmented pyruvate oxidation via pharmacological stimulation of pyruvate dehydrogenase (PDH) during reperfusion has been related to improved recovery of postischemic hearts independent of glycolytic activity. This study examined recovery of postischemic rabbit hearts during activation of PDH with dichloroacetate (DCA) in the presence of lactate, as a source of pyruvate, to determine the response to substrate-dependent changes in cytosolic redox state. After 10 min of ischemia, isolated hearts were reperfused with either 2.5 mM or 0. 5 mM pyruvate (Pyr) or 2.5 mM lactate (Lac), with or without 5 mM DCA. (13)C-enriched substrates allowed NMR assessment of metabolic perturbations. During normal perfusion, Pyr and Lac supported similar mechanical work. Increasing Pyr oxidation restored postischemic rate-pressure product to 82 +/- 4 and 88 +/- 6% of preischemic values during reperfusion with 2.5 and 0.5 mM Pyr, respectively, vs. 61 +/- 6 and 45 +/- 14% for untreated 2.5 and 0.5 mM Pyr, respectively (P < 0.05). In contrast, increasing Lac oxidation did not benefit recovery of RPP in untreated (44 +/- 7%) vs. DCA-treated 36 +/- 4% hearts. Thus the benefit of PDH activation for contractile recovery of postischemic hearts is mediated by the source of pyruvate, which also influences cytosolic redox state.
White
L T
LT
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
O'Donnell
J M
JM
Griffin
J
J
Lewandowski
E D
ED
D000818:Animals; D003600:Cytosol / Q000378:metabolism*; D006321:Heart / Q000503:physiopathology; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000503:physiopathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism; D011817:Rabbits
D011768:Pyruvate Dehydrogenase Complex; D019344:Lactic Acid; D019289:Pyruvic Acid