Comparative metabolic effects of acetate and dichloroacetate infusion in the anesthetized dog

Abstract

The comparative effects of acetate (10 mmol/h/kg) and dichloroacetate (DCA) (1 mmol/h/kg and 10 mmol/h/kg) on acid-base and intermediary metabolism were assessed using the fasted anesthetized dog, undergoing controlled ventilation, as a metabolic model. Infusion of acetate resulted in a marked metabolic alkalemia and a decline in Pao 2, while DCA had minimal effects on acid-base state and oxygen consumption. Serum glucose decreased with both DCA and acetate infusion, although only significantly with the latter. At infusion rates of 10 mmol/h/kg, acetate caused marked decreases, while DCA caused marked increases, in serum potassium and phosphorus. Acetate and DCA also had opposing effects on lactate and citrate levels, the former caused increases and the latter decreases in both metabolites. Pyruvate levels decreased similarly in response to both infusates. Acetoacetate and β-hydroxybutyrate levels increased significantly with both acetate and DCA infusions; however, the increases were much greater with acetate than with DCA infusion. Blood alanine levels decreased significantly during the infusion of both acetate and DCA, whereas, free fatty acids tended to increase with acetate infusion, remained unchanged with low dose DCA and fell significantly with high dose DCA. Plasma insulin levels were sustained during acetate infusion, but fell abruptly with termination of infusion. In contrast, insulin levels fell markedly with DCA infusion and remained depressed throughout the infusion and recovery periods. Blood levels of acetate and DCA rose markedly during infusion; however, while acetate levels decreased nearly to control values during the recovery period, DCA levels remained elevated. We observed a dose dependent effect of DCA on intermediary metabolism, such that the effect of DCA on serum lactate levels was seen to decrease at the higher dose of DCA; this dose dependency may possibly be mediated by changes in cellular energy status. Acetate also perturbed intermediary metabolism. However, unlike DCA, it was effective in generating bicarbonate. Differences between their effects on metabolism may indicate different roles for DCA and acetate in the treatment of lactic acidosis.