Is accelerated oxidation of lactate required for dichloroacetate to lower the level of lactate in blood?
We examined mechanisms by which dichloroacetate (DCA), an activator of pyruvate dehydrogenase (PDH), led to a decrease in the concentration of lactate in blood in a unique "metabolic setting," where the concentration of lactate in blood was 5.4 +/- 0.5 mmol/L. Elevated levels of lactate were induced in anaesthetized rabbits by the administration of a large dose of insulin. The rate of consumption of oxygen was 1.2 +/- 0.1 mmol/min, the respiratory quotient was close to unity, and close to half of the PDH was in its active form; therefore, virtually all ATP synthesis should require flux through PDH. Hence, we predicted that DCA should not cause a significant decrease in the concentration of lactate in blood in this model. In contrast, if DCA was effective, new insights could be obtained into its mechanisms of action, at least in this setting. During steady-state hyperlactatemia, DCA was given as its sodium salt, 2 mmol/kg (n = 10); a control group (n = 5) received equimolar NaCl. Forty minutes later, the level of lactate in blood in the DCA group was 1.3 +/- 0.2 mmol/L, significantly lower than in the NaCl group (4.2 +/- 0.6 mmol/L). To determine the organ(s) responsible for removing lactate, arteriovenous differences were measured in organs drained by the jugular, femoral, and hepatic veins. There was no net uptake of lactate in these drainage beds after DCA was administered. From a quantitative analysis of the rate of removal of lactate and the rate of consumption of oxygen, it seems unlikely that the majority of the decrease in lactate could be directly attributed to an increase in its oxidation.
Kamel
K S
KS
Renal Division, St. Michael's Hospital, University of Toronto, Ont., Canada.
Cheema-Dhadli
S
S
Halperin
M L
ML
D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007773:Lactates / Q000097:blood*; D019344:Lactic Acid; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009132:Muscles / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D011817:Rabbits
D007328:Insulin; D007773:Lactates; D011768:Pyruvate Dehydrogenase Complex; D019344:Lactic Acid; D003999:Dichloroacetic Acid