MECHANISMS BY WHICH DICHLOROACETATE LOWERS LACTIC-ACID LEVELS - THE KINETIC INTERRELATIONSHIPS BETWEEN LACTATE, PYRUVATE, ALANINE, AND GLUCOSE

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.