Adaptation of renal ammonia production in the diabetic ketoacidotic rat

Adaptation of renal ammonia production in the diabetic ketoacidotic rat. Renal ammonia production was measured in diabetic, ketoacidotic rats. Rats were made diabetic by the i.v. injection of streptozotocin (150mg/kg of body wt). They were maintained on insulin for 1 week. Ketoacidosis was induced by withdrawing insulin for 3 days. At that time, blood and kidney ketone body (D-β-hydroxybutyrate and acetoacetate) levels were markedly elevated (approx. 6mM), and plasma total carbon dioxide concentration was strongly depressed (approx. 11mM). Renal ammonia production (ammonia released into renal vein plus that excreted in the urine) was stimulated sevenfold by the diabetic ketoacidosis. In a separate study, we examined the effects of ketone bodies on renal ammonia production in ammonium-chloride-induced acidotic, nondiabetic rats. Infusion of β-hydroxybutyrate had no significant effect on either urinary ammonia excretion (at relatively constant urinary pH), total renal ammonia production, or renal glutamine extraction. In vitro studies showed that β-hydroxybutyrate (4.0mM) markedly inhibited (61%) conversion ofL-glutamine (0.6mM) to ammonia by renal cortical slices prepared from normal rats. Inhibition was greatly reduced with slices prepared from kidneys of acidotic (ammonium-chloride-induced or diabetic ketoacidosis) rats. These results indicate that (1) renal ammonia production is markedly stimulated in diabetic ketoacidosis, and (2) in contrast to findings previously obtained by others in the acidotic dog, ketone bodies do not appear to inhibit renal ammonia production in vivo and only weakly in vitro in the acidotic rat. Adaptation de la production renale d'ammoniac chez le rat diabetique en acidocetose. La production renale d'ammoniaque a ete mesuree chez le rat diabetique en acidocetose. Les rats ont ete rendus diabetiques par une injection i.v. de streptozotocine (150 mg/kg body wt) et traites par l'insuline pendant une semaine. L'acidocetose a ete declenchee par la suppresion de l'insuline pendant trois jours. A ce moment, les concentrations sanguines et renales de corps cetoniques (D-β-hydroxybutyrate et aceto-acetate) etaient tres augmentees (approximativement 6mM) et le CO 2 total du plasma tres abaisse (approximativement 11mM). La production renale d'ammoniac (ammoniac de la veine renale plus ammoniaque de l'urine) etait multipliee par 7. Dans un protocole different, nous avons etudie les effets des corps cetoniques sur la production renale d'ammoniac chez des rats non diabetiques, en acidose parle chlorure d'ammonium. La perfusion de β-hydroxybutyrate n'a eu d'effet significatif ni sur l'excetion urinaire d'ammoniaque (a pH relativement constant), ni sur la production renale d'ammoniac ou l'extraction renale de la glutamine. Des etudes in vitro ont montre que le β-hydroxybutyrate (4,0mM) inhibe de facon importante (61%) la conversion de laL-glutamine (0,6mM) en ammoniac par les tranches de cortex de rein preparees a partir de rats normaux. L'inhibition est moindre avec des tranches preparees a partir de rats en acidose (chlorure d'ammonium ou acidocetose diabetique). Ces resultats indiquent que (1) la production renale d'ammoniac est fortement stimulee au cours de l'acidocetose diabetique et, (2) contrairement aux resultats obtenus par d'autres chez le chien en acidose, les corps cetoniques ne paraissent pas inhiber la production renale d'ammoniac in vivo, et seulement faiblement in vitro, chez le rat en acidose.