Effect of 3',5'-GMP and 3',5'-IMP on production of glucose and ammonia by renal cortex

As, Pagliara; Ad, Goodman

doi:10.1152/ajplegacy.1970.218.5.1301

Cited by 23 publications

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“…It has been suggested previously that the fall in cortical glutamate provoked by severe metabolic acidosis (4,5), and by exposure of cortical slices to cyclic AMP, cyclic IMP, or 5'-IMP (9,10), is due to the fact that these factors enhance conversion of glutamate to glucose. However, in the present study it was observed that in some experimental situations cortical gluconeogenesis can be altered substantially without an associated inverse change in glutamate.…”

Section: Resultsmentioning

confidence: 99%

“…Further, although the effect of potassium deficiency on cortical glutamate has not been studied previously, it has been noted that in potassiumdepleted rats there is an increase in cortical gluconeogenesis as well as in ammonia production (3,8). Additional support for the hypotesis has been derived from studies of the effects of 3',5'-adenosine monophosphate (cyclic AMP), 3',5'-inosine monophosphate (cyclic IMP), and 5'-inosine monophosphate (5'-IMP) on the metabolism of cortical slices; these nucleotides, which enhance cortical glucose production, also lower glutamate content and increase production of ammonia from glutamine (9,10).…”

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confidence: 99%

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Relation of renal cortical gluconeogenesis, glutamate content, and production of ammonia

Pagliara¹,

Goodman²

1970

J. Clin. Invest.

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A B S T R A C T Glutamate is an inhibitor of phosphate dependent glutaminase (PDG), and renal cortical glutamate is decreased in metabolic acidosis. It has been postulated previously that the rise in renal production of ammonia from glutamine in metabolic acidosis is due primarily to activation of cortical PDG as a consequence of the fall in glutamate. The decrease in cortical glutamate has been attributed to the increase in the capacity of cortex to convert glutamate to glucose in acidosis.In the present study, administration of ammonium chloride to rats in an amount inadequate to decrease cortical glutamate increased the capacity of cortex to produce ammonia from glutamine in vitro and increased cortical PDG. Similarly, cortex from potassium-depleted rats had an increased capacity to produce ammonia and an increase in PDG, but glutamate content was normal. The glutamate content of cortical slices incubated at pH 7.1 was decreased, and that at 7.7 was increased, compared to slices incubated at 7.4, yet ammonia production was the same at all three pH levels. These observations suggest that cortical glutamate concentration is not the major determinant of ammonia production.In potassium-depleted rats there was a 90% increase in the capacity of cortex to convert glutamate to glucose, yet cortical glutamate was not decreased. In vitro, calcium more than doubled conversion of glutamate to glucose by cortical slices without affecting the glutamate content of the slices, and theophylline suppressed conversion of glutamate to glucose yet decreased glutamate content. These observations indicate that the rate of cortical gluconeogenesis is not the sole determinant of cortical glutamate concentration.The increase in cortical gluconeogenesis in acidosis and potassium depletion probably is not the primary Dr. Pagliara performed this work during the tenure of a Daland Fellowship of the American Philosophical Society.Received for publication 5 February 1970 and in revised form 29 June 1970. cause of the increase in ammonia production in these states, but the rise in gluconeogenesis may contribute importantly to the maintenance of increased ammoniagenesis by accelerating removal of the products of glutamine degradation. INTRODUCTIONIn metabolic acidosis there is a rise in renal ammonia production (1, 2), an increase in the capacity of renal cortex to produce glucose from glutamate and other substrates (3), and a decrease in cortical glutamate concentration (4, 5). We and others have suggested that the changes in ammonia production, gluconeogenesis, and glutamate content are causally related (3,4,6). According to this hypothesis, in acidosis the increased conversion of glutamate to glucose is the cause of the fall in cortical glutamate, and since glutamate is an inhibitor of phosphate-dependent glutaminase (4), the fall in glutamate causes activation of this enzyme, thereby increasing ammoniagenesis from glutamine. Consistent with this hypothesis, in metabolic alkalosis both cortical gluconeogenic capacity and ammonia product...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Relation of renal cortical gluconeogenesis, glutamate content, and production of ammonia

Pagliara¹,

Goodman²

1970

J. Clin. Invest.

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“…cGMP antagonizes the cAMP stimulated synthesis of flgalactosidase in cell-free bacterial extracts (3,4). In certain animal cells as well, cGMP appears as if it might also directly or indirectly counteract the effects of cAMP (5)(6)(7)(8)(9). We have, therefore, investigated the interaction between these cyclic nucleotides on the pleiotypic reactions and conclude that here, too, cGMP overcomes the actions of cAMP.…”

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confidence: 94%

Pleiotypic Control by Cyclic AMP: Interaction with Cyclic GMP and Possible Role of Microtubules

Kram

Tomkins

1973

Proc. Natl. Acad. Sci. U.S.A.

154

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Previous studies have shown that exogenous dibutyryl cyclic AMP inhibits the uptake of uridine, leucine, and 2-deoxyglucose by cultured mouse fibroblasts. 3':5'-cyclic GMP is shown here to counteract these inhibitory effects as well as the inhibition ofprecursor transport and leucine incorporation into proteins produced by prostaglandin E1. We conclude, therefore, that cyclic GMP antagonizes the "pleiotypic" effects of cyclic AMP in these cells.Colcemid and vinblastine, but not cytochalasin B., reverse the transport inhibition caused by cyclic AMP without affecting the intracellular concentrations of cyclic AMP. These results suggest the possibility that cyclic AMP regulates the membrane transport of certain substrates by influencing the organization of microtubules.Recent work from various laboratories has implicated cAMP in the regulation of cellular growth. In a preceding communication (1) we presented evidence that cAMP exerts this control by coordinately influencing several biochemical processes related to growth. This set of reactions was defined as the "pleiotypic" program, and its regulation as pleiotypic control (2). Earlier we had singled out this coordinated control as being of general significance since the same set of reactions is affected in various cell types by specific hormones and growthpromoting factors (2). The fact that cAMP controls the pleiotypic reactions provides a basis for relating differentiation, malignant transformation, and hormonal control of growth (1). We report here some observations pertaining to the mechanisms of cAMP control of the pleiotypic parameters.cGMP antagonizes the cAMP stimulated synthesis of flgalactosidase in cell-free bacterial extracts (3, 4). In certain animal cells as well, cGMP appears as if it might also directly or indirectly counteract the effects of cAMP (5-9). We have, therefore, investigated the interaction between these cyclic nucleotides on the pleiotypic reactions and conclude that here, too, cGMP overcomes the actions of cAMP. We also suggest, on the basis of studies with inhibitors of microtubule assembly, that the cyclic nucleotides may influence some membrane transport processes by their effects on colcemid-and vinblastine-sensitive structures, possibly the microtubular apparatus itself. MATERIALS AND METHODSThe Balb/c 3T3 mouse fibroblasts and their SV 40-transformed derivatives were grown in MEM plus 10% calf serum.The rates of precursor transport and incorporation into macromolecules were measured as described (2) In 3T3 cells, the rates of transport of uridine, leucine, and 2-deoxyglucose are depressed during serum deprivation and stimulated by the addition of serum again. We have reported(1) that (Bu)2cAMP + theophylline or PGE1 added to cells maintained in serum-containing medium mimic the response to serum starvation. These effectors also inhibit serumstimulated uptake of precursor by previously starved cells (1). We now show that cGMP antagonizes the effects of both (Bu)2cAMP + theophylline and PGE1 on these biochemical processes...

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“…The reduced ammonia production in alkalosis and after acetazolamide (9) could be caused, to some extent, by cGMP which inhibits ammonia production from glut amine (11). Whether the change of cGMP for mation in relation to alkalosis and acidosis is a part of physiological regulation of intracellular pH remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Since activation of renal adenylate cy clase by acetazolamide has been suggested (14), it was of interest to measure the renal tissue levels of cyclic adenosine 3':5'-monophosphate (cAMP) for their dependence on dosage and time after administration of the diuretic. A possible role of cyclic guanosine 3 ':5 '-mono phosphate (cGMP) in renal acid-base regulation is suggested by Pagliara and Goodman (11) who found in isolated rat kidney cortex slices that cGMP inhibited the formation of a-ketoglutarate from glutamate and decreased ammonia production. Renal bicarbonate reabsorption as well as ammonia production are involved in acid-base regulation and are inhibited by acetazolamidc (9).…”

Section: Introductionmentioning

confidence: 99%

Effects of Acetazolamide and Changes of Acid-Base Balance on the Content of Cyclic Nucleotides in the Rat Kidney

Oßwald¹,

Hawlina²

1979

Pharmacology

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Changes in tissue levels of cyclic adenosine 3’:5’-monophosphate (cAMP) and cyclic guanosine 3’:5’-monophosphate (cGMP) in the rat kidney in response to acid-base changes and administration of acetazolamide were measured. cAMP was determined according to the method described by Gilman and cGMP by radioimmunoassay. 1 mg/kg acetazolamide increased bicarbonate excretion 100-fold over the control values to 2.52 ± 0.5 mEq/min (mean ± SEM; n = 6), but did not influence cGMP and cAMP tissue content. 10 and 100 mg/kg acetazolamide increased cGMP tissue levels to 0.277 ± 0.048 and 0.482 ± 0.07 pmol/mg dry weight in comparison to 0.192 ± 0.04 in the controls, whereas no changes in cAMP levels occurred. Chronic as well as acute metabolic alkalosis induced an increase of cGMP levels (0.26 ± 0.03 and 0.29 ± 0.06 pmol/mg), whereas chronic metabolic and acute respiratory acidosis lowered cGMP levels to 0.14 ± 0.02 and 0.13 ± 0.02 pmol/mg. cAMP tissue levels were not affected by changes in acid-base balance. The data could suggest that cGMP participates in the regulation of acid-base balance and renal effects of acetazolamide.

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Effect of 3',5'-GMP and 3',5'-IMP on production of glucose and ammonia by renal cortex

Cited by 23 publications

References 0 publications

Relation of renal cortical gluconeogenesis, glutamate content, and production of ammonia

Relation of renal cortical gluconeogenesis, glutamate content, and production of ammonia

Pleiotypic Control by Cyclic AMP: Interaction with Cyclic GMP and Possible Role of Microtubules

Effects of Acetazolamide and Changes of Acid-Base Balance on the Content of Cyclic Nucleotides in the Rat Kidney

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