Pyruvate dehydrogenase activity and malonyl CoA levels in normal and ischemic swine myocardium: effects of dichloroacetate.
The purposes of this study were to: (1) assess myocardial pyruvate dehydrogenase (PDH) activity and substrate exchange under well-perfused and ischemic conditions; (2) determine the metabolic effects of an intra-coronary infusion of the PDH activator, dichloroacetate (DCA); and (3) measure the effects of ischemia and DCA on malonyl CoA levels. Experiments were performed in anesthetised open-chest swine under non-ischemic conditions, followed by 40 min with a 60% reduction in left anterior descending coronary artery (LAD) blood flow. Myocardial needle biopsies for measurement of PDH activity were taken after an intracoronary infusion of either saline or DCA (1 mM in LAD blood) under aerobic conditions, and after 37 min of ischemia. Pyruvate dehydrogenase activity was measured with and without maximal activation by swine PDH phosphatase. Malonyl CoA and acetyl CoA were measured after 40 min of LAD ischemia in myocardium from the ischemic DCA- or saline-treated LAD bed, and the non-ischemic untreated left circumflex coronary artery (CFX) perfusion bed. Net glucose, lactate and free fatty acid (FFA) uptakes were measured across the LAD perfusion bed throughout the study. Dichloroacetate treatment increased the amount of active dephosphorylated PDH to 88% of the total activity under aerobic conditions, compared to 55% with saline (P < 0.01). Ischemia did not significantly change PDH activation state in either group. Acetyl CoA and malonyl CoA contents were significantly elevated in ischemic DCA-treated myocardium compared to saline-treated ischemic myocardium. Dichloroacetate treatment significantly lowered rates of myocardial FFA uptake under both aerobic and ischemic conditions, but did not effect glucose uptake or lactate exchange. Free fatty acid uptake was negatively correlated to malonyl CoA levels (r = -0.68) during ischemia. It is proposed that the inhibition of FFA uptake observed with DCA in ischemic myocardium is due to malonyl CoA inhibition of carnitine palmitoyl transferase I.
Stanley
W C
WC
Syntex Discovery Research, Palo Alto, California, USA.
Hernandez
L A
LA
Spires
D
D
Bringas
J
J
Wallace
S
S
McCormack
J G
JG
D000818:Animals; D003999:Dichloroacetic Acid / Q000008:administration & dosage*; D007261:Infusions, Intra-Arterial; D008297:Male; D008316:Malonyl Coenzyme A / Q000032:analysis* / Q000378:metabolism; D017202:Myocardial Ischemia / Q000201:enzymology*; D011768:Pyruvate Dehydrogenase Complex / Q000032:analysis* / Q000378:metabolism; D013552:Swine
D011768:Pyruvate Dehydrogenase Complex; D008316:Malonyl Coenzyme A; D003999:Dichloroacetic Acid