F. Jahoor et al., MECHANISMS BY WHICH DICHLOROACETATE LOWERS LACTIC-ACID LEVELS - THE KINETIC INTERRELATIONSHIPS BETWEEN LACTATE, PYRUVATE, ALANINE, AND GLUCOSE, Proceedings of the Society for Experimental Biology and Medicine, 205(1), 1994, pp. 44-51
Dichloroacetate (DCA) is gaining use as an alternative to bicarbonate
therapy in the treatment of lactic acidosis. To determine the mechanis
m(s) by which DCA lowers blood lactate levels, we studied its effect o
n the kinetic interrelationships between pyruvate, lactate, alanine, a
nd glucose in the hindlimb of dogs during hormonal stimulation of pyru
vate production (Ra) and its conversion to lactate. Three groups of do
gs (n = 6) were infused with 1-C-13-pyruvate to measure whole body pyr
uvate Ra, and pyruvate Ra and utilization (Rd) across the hindlimb dur
ing either a 4-hr infusion of saline (controls), or somatostatin, gluc
agon, and epinephrine (SGE), or SGE plus dichloroacetate (SGE + DCA).
Pyruvate Ra was used as an index of rate of glycolysis and Rd as an in
dex of pyruvate oxidation. In the controls, all kinetic parameters wer
e constant during the saline infusion. Hindlimb pyruvate Ra and Rd wer
e almost equal, and lactate release negligible. Compared to controls,
SGE administration significantly increased (P < 0.05) wholebody pyruva
te Ra (48.5 +/- 6.2 vs 33.6 +/- 2.4 mu mol/kg/min) and blood lactate l
evels (P < 0.05). Hindlimb pyruvate Ra increased by similar to 150%, b
ut Rd remained unchanged resulting in marked increases in lactate and
alanine effluxes. Adding DCA to the SGE infusion significantly reduced
wholebody pyruvate Ra (P < 0.05) and blood lactate levels (P similar
to 0.01). In the hindlimb, however, there was no decrease in lactate o
utput, despite a 91% increase in pyruvate utilization because pyruvate
Ra also increased. These results suggest that during stimulation of r
ate of glycolysis, DCA lowers lactate levels by reducing the overall a
vailability of pyruvate for lactate synthesis. This is accomplished by
suppressing the rate of glycolysis in tissues other than skeletal mus
cle and stimulating pyruvate oxidate.