Evaluation of sodium acetate as a source of alkali therapy in an experimental aerobic model of lactic acidosis due to decreased pyruvate oxidation.
An "in vitro" model of one type of lactic acidosis was produced in rat hemi-diaphragms with inhibitors of pyruvate oxidation. In order to obtain this inhibition in the absence of hypoxia, two actions were sought; inhibiting the mitochondrial pyruvate transporter and lowering the rate of pyruvate diffusion into these mitochondria. alpha-Cyano-3-hydroxy cinnamate (CNCM) was utilized because it is a specific inhibitor of the mitochondrial pyruvate transporter. Aminooxyacetate (AOA) was employed because it leads indirectly to inhibition of the entry of cytoplasmic reducing power into mitochondria. As a result of the addition of this latter compound, pyruvate levels fell and this should decrease the rate of pyruvate diffusion into the mitochondria. Glucose was the only substrate provided to this tissue and its entry into the cells was promoted by insulin. The oxidation of U-14C glucose to 14CO2 was significantly reduced in the presence of CNCM and AOA, presumably reflecting the inhibition of pyruvate oxidation. Under these conditions, lactate accumulated and pyruvate fell; however, there was a significant accumulation of lactate plus pyruvate during the incubation period. This "in vitro" lactic acidosis was markedly diminished when acetate was also present. These results are consistent with the hypothesis that provision of an alternate substrate to the TCA cycle for ATP synthesis could lead to a decreased rate of glycolysis and thereby to a decreased rate of lactic acid accumulation in this "in vitro" model of lactic acidosis.
D000085:Acetates / Q000627:therapeutic use*; D000138:Acidosis / Q000188:drug therapy*; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D003373:Coumaric Acids / Q000494:pharmacology; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D007773:Lactates / Q000097:blood*; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism; D010084:Oxidation-Reduction; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism*; D019289:Pyruvic Acid; D051381:Rats
D000085:Acetates; D003373:Coumaric Acids; D007773:Lactates; D011768:Pyruvate Dehydrogenase Complex; D011773:Pyruvates; D000625:Aminooxyacetic Acid; C018254:alpha-cyano-3-hydroxycinnamate; D019289:Pyruvic Acid; D005947:Glucose