Commentary on a review on the mechanism of Ackee-induced vomiting sickness

A recent review article concluded that glutamic acid probable plays a central role in the vomiting and neurological features of ackee poisoning. The present article draws attention to misconceptions in the basis of that hypothesis, and reviews important evidence suppporting a different role (AU)

Magnesium chloride induced acidosis in malnutrition - abstract

Because their is a total body deficit of magnesium in malnutrition, magenesium salts are routinely prescribed in treatment. Several children were observed to develop severe hyperchloraemic acidosis after admission to the ward, and urine from recovering children was found to be highly acidic. This study tested the hypothesis that the acidosis was iatrogenically induced by the magnesium chloride supplement. Six malnourished and 5 recovering children were treated in the standard way except that they were given magnesium chloride (1 mmol/kg/d) for 4 days and then magnesium acetate for 4 days. The order of the salts was changed in alternate children. Jugular venous Astrup and timed urine collections were made at the end of each period. The malnourished children developed sytemic acidosis on the magnesium chloride supplement (pH 7.3 ñ 0.01 vs - #.6 ñ 1.1). Those children who were given the acetate salt first remained in acid-base equilibrium whereas those who were given the chloride first had not regained normal acid base status after 4 days on the acetate. On the chloride salt the urinary pH was lower (5.0 ñ 0.3 vs 6.5 ñ 0.3), the titratable acidity higher (1.5 ñ 0.2 vs 0.4 ñ 0.3 æEq/min) and the total acid (TA = ammonia - HCO3) output higher (5.5 ñ 0.8 vs 2.1 ñ 0.4 æEq/min), than on the acetate salt. The recovering children also developed a mild systemic acidosis on the chloride (Base excess - 5.5 ñ 0.9 vs 2.3 ñ 0.5) and excreted a highly acid urine, pH 4.8 ñ 0.1; on the acetate the urine was also acid pH 5.1 ñ 0.1. The total acidity output was 20.4 ñ 1.1 æEq/min on the chloride and 15.3 ñ 1.4æEq/min on the acetate. It is concluded that magnesium chloride is the cause of the iatrogenic systemic acidosis seen in our malnourished children. Whilst malnourished they excrete a maximally acid urine, however the total acid output is small and leads to a progressively positive hydrogen ion balance, which the child cannot correct within four days of ceasing the chloride load. This work was supported by the Wellcome Trust (AU)

Glutamine metabolism in metabolic acidosis

In chronic metabolic acidosis in the rat, there is increased ammoniagenesis, gluconeogenesis and renal extraction of gluatmine with induction of renal phosphate-dependent glutaninase (PDG). Because the stimulus for these changes is not yet clear and also because acute acidosis is the more common clinical problem, the present study deals mainly with the metabolism of glutamine in acute metabolic acidosis. When acute metabolic acidosis is produced in rats by administration of mineral acid or by causing them to swim, thus inducing a severe lactic acidosis, a factor is found in the plasma which stimulates renal glutamine uptake and ammoniagenesis in vivo as well as in vitro. Acute acidosis dose not induce synthesis of PDG in the kidney but causes a change in enzyme kinetics. The plasma factor not only enhances glutamine entry into cells, but apparently causes a conformational change in PDG, as shown by an increase in V1.0mM/Vmax. Intestinal metabolism of glutamine is also stimulated in vivo and in vitro by the plasma factor of acute acidosis. (AU)

[15N]Glycine metabolism in normal man: the metabolic O-amino-nitrogen pool

[15N]Glycine was infused into fed, fasted or acidotic humans. In all metabolic states there was considerable transfer of labelled nitrogen to urea and amonia, but alanine and glutamate did not become enriched. The findings show that free exchange of nitrogen between all amino acids does not take place. Glycine, serine, threonine, lysine and histidine cannot be considered part of the a-amino-nitrogen pool as classically conceived, although they form up to one-half of that pool. (AU)

The effect of acidosis on the renal metabolism of glutamine in the rat

Glutamine is the major source of urinary ammonia and this study examines the metabolism of that amino acid in rats under varying acid-base conditions. Other workers have shown that in acidosis there is enhanced renal oxidation of glutamine, which requires increased amounts of acetyl CoA. The present study has shown that during acidosis there was no change in the activity of oxaloacetate decarboxylase and malic enzyme, two enzymes capable of increasing the formation of acetyl CoA. This study also showed that 3-mercaptopicolinic acid inhibited PEPCK - the rate limiting enzyme of gluconeogenesis - and thereby inhibited ammoniagenesis from glutamine mainly by inhibiting deamination. Metabolic acidosis was induced with NH4C1 or HC1. In rats given NH4C1 there was an immediate increase in blood ammonia levels and urinary excretion of ammonia, but this did not occur with rats fed HC1 which showed no change in urinary ammonia but a decrease in urea excretion. Rats fed either NH4C1 or HC1 had similar increases in the plasma concentrations of glutamine, renal PEPCK activity, ammonia and glucose production by renal cortical slices. The time course of changes in metabolic intermediates was measured in rats given NH4C1 or HC1. NH4C1 caused a striking decrease in renal levels of malate, 2-oxoglutarate and phosphoenol pyruvate. Similar changes were observed with HC1, but in addition the levels of glucose and glucose-6-phosphate were elevated. The results of the studies with 3-mercaptopicolinic acid and the metabolite profile in response to acidosis are both constant with the theory that displacement of the glutamic dehydrogenase equilibrium is an important mechanism in the control of glutamine utilisation and the ammoniagenic response to acidosis (AU)

Ammonia production by the small intestine of the rat

Slices of duodenum and jejunum produce ammonia from glutamine in vitro. Ammoniagenesis does not increase in response to acidosis or potassium deficiency, two conditions known to cause enhanced ammoniagenesis in the kidney. Gut contains glutamine 1 as well as ç-glutamyl transpeptidase. These enzymes do not show any increase during starvation (SUMMARY)

The effect of malnutrition on the pattern of growth in the rat kidney and the renal response to acidosis

The kidneys of normal rats were analysed for water, fat, protein, RNA and DNA, at 10, 21 and 36 d after birth. The effects on growth caused by two types of malnutrition were investigated. An increase in the RNA:DNA ratio was demonstrated between 10 and 36 d, contrary to previous evidence that this ratio is fixed at birth. Energy deficiency during the first 21 d of life resulted mainly in fewer kidney cells, whereas protein-energy deficiency between 21 and 36 d reulted mainly in a smaller cellular content of RNA and protein. In response to metabolic acidosi, both groups of malnourished rats increased urinary excretion of ammonia and there was enhanced gluconeogenesis in vitro; the basal rate of gluconeogenesis was lower in the protein-energy-deficient rats than in the controls. Protein-energy-deficient rats did not exhibit the renal hypertrophy shown by the control rats in response to acidosis (AU)

Regulation of renal cortex ammoniagenesis. I. Stimulation of renal cortex ammoniagenesis in vitro by plasma isolated from acutely acidotic rats

We studied the acute renal metabolic response in rats made acidotic by a single oral dose of ammonium chloride. Cortical slices from acutely (2-h) acidotic rats utilized more glutamine and produced more ammonia and glucose from glutamine than slices from normal animals. When cortical slices from normal rats were pretreated in vitro with plasma isolated from acutely acidotic rats, they achieved similar increases in glutamine utilization, ammonia formation, and gluconeogensis from glutamine. We did not observe such stimulation in normal cortical slices pretreated in a low pH-low bicarbonate medium. Our data show that a non-dialysable factor is present plasma from acutely acidotic rats that may be responsible for the early increase in the urinary ammonia observed in such animals (AU)

Control of renal cortex ammoniagenesis and its relationship to renal cortex gluconeogenesis

The metabolism of glutamate by kidney cortical slices from normal and acutely acidotic rats and the effect of acidosis in vitro on the metabolism of these two substrates has been investigated. The effects of calcium on all these processes was also studied. Kidney cortical slices from acutely acidotic rats utilized more glutamine and formed more ammonia, glucose and glutamate than slices from rats. Increased glutamine utilization and ammoniagenesis by cortical slices from acidotic rats was not detected when Ca2+ was omitted from the medium, although glucose formation was still enhanced and glutamate formation decreased. With in vitro acidosis there was no change in glutamine uptake in the presence or absence of calcium but with calcium, ammonia production fell. Although there was no change in glutamate uptake by cortical slices from acidotic rats, there was an increase in ammoniagenesis and gluconeogenesis with or without calcium. With in vitro acidosis the only significant changes were an increase in ammoniagenesis and gluconeogenesis in the absence of calcium. The results show that ammoniagenesis from glutamine is controled by a rate-limiting step distinct from that which controls deamination of glutamate and gluconeogenesis from glutamine and glutamate. Possible control points and the interrelationship between ammoniagenesis and gluconeogenesis are discussed (AU)

The effect of steroids and ammonium chloride acidosis on phosphoenolpyruvate carboxykinase in rat kidney cortex. II. The kinetics of enzyme induction

The kinetics of the induction of rat kidney phosphoenolpyruvate carboxykinase activity after triamcinolone and ammonium chloride administration have been investigated with a view to the further differentiation of the two processes. The half-life of kidney phosphoenolpyruvate carboxykinase activity, as measured from the decay curve after a single dose of triamcinolone, is approximately 1.4 hr. This compares with a half-life for the enzyme from acidotic kidney of approximately 3.4 hr. Analysis of the data indicates that the induction of phosphoenolpyruvate carboxykinase activity by triamcinolone may be attributed to an increase in de novo protein synthesis. Induction by acidosis is qualitatively distinct and is partly attributed to a reduction in the rate of decay of phosphoenolpyruvate carboxykinase activity. The activities of the gluconeogenic enzymes glucose-6-phosphotase, fructose-1,6-diphosphotase and phosphoenolpyruvate carboxykinase in both liver and kidney have been measured in animals separately treated with triamcinolone and ammonium chloride. Triamcinolone significantly increases the activities of liver phosphoenolpyruvate carboxykinase, kidney glucose-6-phosphatase, and kidney phosphoenolpyruvate carboxykinase only; ammonium chloride stimulates a 200 percent increase in kidney phosphoenolpyruvate carboxykinase, but has no effect on the other enzymes. The induction processes whereby triamcinolone increases phosphoenolpyruvate carboxykinase activities in liver and kidney differ qauntitatively. (AU

Phosphoenolpyruvate carboxykinase of kidney

A method for the assay of phosphoenolpyruvate carboxykinase is presented, based on the enzymic determination of the phosphoenolpyruvate produced by the enzyme reaction. The subcellular distribution of phosphoenolpyruvate carboxykinase in the kidney of several animal species resembled the distribution in the liver. The rise in enzyme activity in the kidney cortex of rats made acidotic by feeding with ammonium chloride was not prevented by the administration of ethionine or actinomycin. The possibility is suggested that in the kidney acidosis causes activation of an inactive form of the enzyme already present. (AU)

Some effects of metabolic acidosis on carbohydrate metabolism in the rat

Metabolic acidosis was induced by feeding ammonium chloride to rats which were maintained on a carbohydrate diet for 48h. Fasting blood glucose was the same in acidotic and control animals, but there was an increase in liver glycogen in the former. Muscle glucogen was unchanged. In vitro glycogenesis was the same in liver slices from normal rats when incubated at a range of pH from 6.90 to 7.40. The peak blood glucose in response to intraperitoneal injections of glucagon was the same in control and acidotic rats. The rate of disappearence of glucose was slower in acidotic rats both after the glucagon induced hyperglycaemia and after intravenously injected glucose. Liver phosphorylase, total glycogen synthetase and the I form of this enzyme were unchanged in acidosis. The data are compatible with the hypothesis that in the acidotic rat there is a block in glycolysis-possibly at the phosphofructokinase step (Summary)

Malignant hypertonic hyperpyrexia

A case of malignant hypertonic hyperpyrexia is reported, occurring in a 2 1/2 year old Chinese boy living in Jamaica. The illness progressed rapidly with a fatal outcome, in spite of active resuscitation. Aetiology, diagnosis and treatment of the condition are briefly discussed (AU)

Acid-base balance in adults with sickle cell anaemia

This study of acid-base balance in adults with sickle cell anaemia was undertaken because of the reports of severe metabolic acidosis during "Painful Crisis". Metabolic acidosis has been incriminated as the cause of the "Painful Crisis" and it has been claimed that alkali treatment can prevent and even abort these painful episodes. It was therefore possible that a defect in urinary acidification could explain this tendency to develop acidosis with its serious consequences. The results of acid-base parameters during the steady state showed a mild respiratory alkalosis which is a non-specific finding in patients with severe anaemia. The response to oral NH4Cl loading revealed a slight but significant defect in urinary acidification (minimum pH in SCA 5.38 against 4.83 for controls). Titratable Acid excretion was reduced but the urinary NH4+ though reduced was normal when related to the urine pH. The glomerular filtration rate was normal. These findings are compatible with the syndrome of Incomplete Renal Tubular Acidosis. The administration of oral neutral phosphate resulted in a marked increase in titratable acid excretion but the defect in urinary acidification persisted. A maximal acidifying stimulus (Na2SO4 infusion) produced intense urinary acidification in both normal controls (minimum pH 4.55) and patients with SCA (minimum pH 4.59). Since the sulfate infusion is a known test of distal tubular acidification, a gradient type defect (Distal RTA) was ruledout. The threshold for bicarbonate excretion was reduced in 3 of 6 patients and it was therefore suggested that these patients have a form of Proximal Renal Tubular Acidosis due to defective bicarbonate reabsorption. There was no evidence of metabolic acidosis during "Painful Crisis". This would suppport our belief that Alkalis are of little use in the treatment or prevention of "Painful Crises", at least in our population (AU)