Effects of dichloroacetate on mechanical recovery and oxidation of physiologic substrates after ischemia and reperfusion in the isolated heart.
The effects of dichloroacetate (DCA) on fatty acid oxidation and flux through pyruvate dehydrogenase (PDH) were studied in ischemic, reperfused myocardium supplied with glucose, long-chain fatty acids, lactate, pyruvate, and acetoacetate. The oxidation rates of all substrates were determined by combined 13C nuclear magnetic resonance (NMR) spectroscopy and oxygen-consumption measurements, and PDH flux was assessed by lactate plus pyruvate oxidation. In nonischemic control hearts, DCA increased PDH flux more than eightfold (from 0.68 +/- 0.28 to 5.81 +/- 1.16 micromol/min/g dry weight; n = 8 each group; p < 0.05) and significantly inhibited the oxidation of acetoacetate and fatty acids. DCA also improved mechanical recovery after 30 min of ischemia plus 30 min of reperfusion but did not significantly increase PDH flux measured at the end of the reperfusion period (1.35 +/- 0.42 micromol/min/g dry weight) compared with untreated ischemic hearts (0.87 +/- 0.28 micromol/min/g dry weight; n = 8 each group; p = NS). Although DCA had a modest effect on functional recovery in the reperfused myocardium, this beneficial effect was not associated with either marked stimulation of PDH flux or inhibition of fatty acid oxidation.
Barak
C
C
Department of Surgery, University of Texas Southwestern Medical Center at Dallas, 75235-8879, USA.
Reed
M K
MK
Maniscalco
S P
SP
Sherry
A D
AD
Malloy
C R
CR
Jessen
M E
ME
D000090:Acetoacetates / Q000378:metabolism; D000818:Animals; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D007773:Lactates / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000090:Acetoacetates; D005227:Fatty Acids; D007773:Lactates; C016635:acetoacetic acid; D019289:Pyruvic Acid; D003999:Dichloroacetic Acid; D005947:Glucose; D010100:Oxygen