Inhibition of lactate-induced swelling by dichloroacetate in human astrocytoma cells.
High levels of tissue lactate exacerbate tissue damage that results from cerebral ischemia and reperfusion injury that follows. Post-ischemic treatment with dichloroacetate (DCA) facilitates a decrease in lactate in the central nervous system (CNS) of animals during reperfusion following experimental ischemia, thus it may help to ameliorate ischemic cell damage. It has been suggested that the lactate lowering effect is mediated through a stimulatory effect of DCA on pyruvate dehydrogenase (PDHC) activity. We have studied such a hypothesis in a human astrocytoma derived cell line, UC-11MG. Under conditions resembling those of the ischemic tissue (i.e. high lactate and low pH) these cells accumulate lactate, driven by the inwardly directed proton gradient, and swell as a consequence of the osmotic effect of intracellular lactate. We have demonstrated that DCA increases PDHC activity and also reduces lactate-induced swelling. However, we also found that these two effects could be uncoupled and that the ability of DCA to prevent swelling is still present in the absence of any stimulation of PDHC. We also demonstrated that DCA competitively inhibits the uptake of lactate (Ki = 1.9 mM) and increases the efflux of lactate in a trans-acting manner that suggests the presence of a lactate-DCA exchange. We present a mechanism by which reduction in the rate of lactate uptake could account for the observed inhibition of swelling. This effect of DCA on lactate transport indicates another possible mechanism of action for DCA in facilitating the decrease in lactate observed in vivo during reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Tomsig
J L
JL
Department of Emergency Medicine, University of Cincinnati, College of Medicine, OH 45267.
Gruenstein
E
E
Dimlich
R V
RV
D001254:Astrocytoma; D001692:Biological Transport / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D007773:Lactates / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D008433:Mathematics; D008954:Models, Biological; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D012969:Sodium Fluoride / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D007773:Lactates; D011768:Pyruvate Dehydrogenase Complex; D012969:Sodium Fluoride; D003999:Dichloroacetic Acid