Elevation of plasma glutamate in gout. Its possible role in the pathogenesis of hyperuricemia.
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Biomedical subjects
Publications and source records attributed to A D Goodman.
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In studies employing rat renal cortical slices, the addition of adenosine 3',5'-monophosphate (cyclic AMP) to the incubation medium caused an increase in production of glucose from glutamine, glutamate, alpha-ketoglutarate, fumarate, malate, and oxalacetate, but not from glycerol and fructose. These observations suggest that cyclic AMP accelerates a rate-limiting gluconeogenic reaction between oxalacetate and the triose phosphates. The addition to the medium of parathyroid hormone, which is known to increase renal cortical cyclic AMP, also stimulated glucose production from glutamine. When renal cortical slices were incubated in the presence of glutamine, the addition of cyclic AMP caused a fall in tissue glutamate concentration and a rise in ammonia production, as well as an increase in gluconeogenesis. These changes are similar to those observed in renal cortex of rats with induced metabolic acidosis. The present observations are consistent with a previously advanced hypothesis that cortical gluconeogenesis, ammonia production, and glutamate concentration may be interdependent.
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In previous studies it was found that renal cortical slices from rats with induced metabolic acidosis have an increased capacity to produce glucose, whereas cortical slices from rats with metabolic alkalosis manifest decreased gluconeogenesis. To evaluate the relative influence of extracellular fluid pH, [HCO(3) (-)], and carbon dioxide tension on renal gluconeogenesis, we observed glucose production by cortex from rats with induced respiratory acidosis, and by cortex taken from normal animals and incubated in acid and alkaline media. We found glucose production to be increased in cortex from rats with respiratory acidosis, as is the case in metabolic acidosis. Glucose production by slices from normal rats was increased in media made acidic by reducing [HCO(3) (-)], and decreased in media made alkaline by raising [HCO(3) (-)]. These effects were evident whether the gluconeogenic substrate employed was glutamine, glutamate, alpha-ketoglutarate, or oxalacetate. Glucose production was also increased in media made acidic by raising CO(2) tension and decreased in media made alkaline by reducing CO(2) tension. These data indicate that both in vivo and in vitro, pH, rather than CO(2) tension or [HCO(3) (-)], is the most important acid-base variable affecting renal gluconeogenesis. The findings suggest that a decrease in extracellular fluid pH enhances renal gluconeogenesis through direct stimulation of one of the rate-limiting reactions involved in the conversion of oxalacetate to glucose. We hypothesize that the resultant increase in the rate of removal of glutamate, a precursor of oxalacetate, may constitute an important step in the mechanism by which acidosis increases renal ammonia production.
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