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PubMed1989

Selective regional distribution of tubulin induced in cerebrum by hyperammonemia.

Ingestion of ammonium induces hyperammonemia which increases tubulin content in cerebrum but not in cerebellum. We have dissected 11 discrete areas of cerebrum and quantified the tubulin content in control and hyperammonemic rats. An heterogeneity in the induction of tubulin is shown. The areas more affected are ventral hippocampus, dorsal hippocampus, hypothalamus, septum, reticular formation and frontal cortex, in which tubulin content increased by 63%, 27%, 32%, 48%, 45%, and 25%, respectively, after two months of feeding the ammonium diet.

Ammonia↗
PubMed1990

Hyperammonemia induces polymerization of brain tubulin.

Rats were made hyperammonemic by feeding them a diet containing ammonium acetate. The tubulin content in their brain increased greater than or equal to 30% after 20 days on the diet. All the increase was found in polymerized tubulin; no increase in free tubulin was noted. When rats on the ammonium diet were then fed the standard diet, the tubulin increased slightly on the first day but decreased markedly on the second day, reaching control values on the third day. It should be noted that brain tubulin synthesis, was not reduced on the first day of feeding the standard diet but was markedly inhibited (to approximately 40% of control) on the second day, returning to control values on the third day. On the first day of refeeding there is a remarkable disassembly of microtubules with a large, proportional increase (approximately 50%) of free tubulin. Both free and polymerized tubulin levels returned to control values on the third day. These results indicate that in hyperammonemia changes in the degree of polymerization of tubulin preceded those in tubulin synthesis.

Ammonia↗
PubMed1989

Intra- and extracellular amino acid concentrations in portacaval-shunted rabbits. Role of hyperammonemia and effects of branched-chain amino acid-enriched parenteral nutrition.

Intra- and extracellular amino acid concentrations were measured in rabbits in order to elucidate the possible role of hyperammonemia in lowering the postabsorptive plasma levels of branched-chain amino acids (BCAA) and to assess the effects of BCAA-enriched total parenteral nutrition (TPN) on the amino acid pattern of muscle. The pathophysiological part of this paper deals with portacaval anastomosis (PCA) and is aimed at substantiating or rejecting our hypothesis that excessive ammonia-by stimulating glutamine synthesis-reduces the intracellular glutamate pool which is then restored, at least in part, by an intensified BCAA degradation. Regarding infusion therapy, we were mainly interested in whether an amino acid solution adapted to the metabolism in liver cirrhosis causes an accumulation of BCAA in muscle or modifies the intracellular content of glutamate and glutamine. Eighteen rabbits did not undergo surgery and served as controls (group A), while 30 were given a portacaval end-to-side anastomosis (group B). Two weeks after creating the PCA, venous blood samples were taken and muscle biopsies (Bergström's technique) were performed postabsorptively. An 18-h TPN was then started, the regimen administered included dextrose, fat and, in addition, either a conventional (group B1, n = 15) or an adapted amino acid solution (group B2, n = 15). We obtained second blood specimens and muscle biopsies at the end of the infusion period. With the control animals, the same time schedule for blood sampling and muscle biopsies was followed. Fourteen days after the operation, the PCA rabbits displayed a mean plasma ammonia level 5.1 times higher than that measured in the controls (p less than or equal to 0.001). Conventional blood chemistry did not reveal any impairment of liver cell integrity or over-all hepatic function, whereas the nutritional state of the shunted animals worsened, as indicated by body weight and biochemical variables. Since in the PCA rabbits, the total amino acid pools of muscle and plasma were seen to be increased and decreased, respectively, the results concerning the individual amino acids are given in terms of both the absolute and percentage values, the latter more often revealing high levels of statistical significance. PCA induced a marked rise in the intra- and extracellular concentrations of glutamine, while the values of glutamate and alanine showed a decline in muscle and plasma. The extracellular levels of methionine, phenylalanine, and tyrosine were raised, while those of the BCAA were diminished.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗
PubMed1994

Hyperammonemia induced in rats by inhalation anesthesia with ether.

Transient hyperammonemia was observed in rats after inhalation anesthesia with ether. The elevation of blood ammonia concentration induced by ether anesthesia was greatest in carbon tetrachloride injured and indomethacin-treated rats, but not observed in phenobarbital-treated rats. The results suggest interaction between ether metabolism and ammonia metabolism in the liver.

Ammonia↗
PubMed1997

Effects of acute hyperammonemia in vivo on oxidative metabolism in nonsynaptic rat brain mitochondria.

The effects of hyperammonemia induced in vivo by injecting rats with ammonium acetate on oxidative phosphorylation, malate-aspartate shuttle, some related enzyme activities and metabolite levels in brain mitochondria were studied ex vivo. Rats were found to be either ammonia-sensitive (showing convulsions) or ammonia-resistant (without convulsions) after intraperitoneal injection of ammonium acetate (7 mmol/kg). Ammonium acetate administration to ammonia-sensitive rats led to inhibition of State 3 rates of brain mitochondria utilizing pyruvate, glutamate, isocitrate, and succinate as substrates and to decreased respiratory control index. In brain mitochondria isolated from ammonia-resistant animals, the ammonia-induced effect on such State 3 rates was not observed. In brain mitochondria from hyperammonemic rats without convulsions, a small increase in the activity of malate dehydrogenase was observed; glutamate dehydrogenase, succinate dehydrogenase, and aspartate aminotransferase were not affected. In brain mitochondria from rats with ammonia-induced convulsions, the activities of malate dehydrogenase and succinate dehydrogenase were reduced significantly. Ammonium acetate injection to rats was associated with a 5-fold increase in the brain mitochondrial ammonium ion content and a decrease (ca. 50%) in brain mitochondrial glutamate and aspartate; brain mitochondrial malate and 2-oxoglutarate levels remained unchanged. The rate of the malate-aspartate shuttle in brain mitochondria of hyperammonemic rats was decreased by 20% as compared to corresponding rate in control rats. We conclude that acute administration of ammonium acetate induces serious disturbances in the electron-transport chain, interferences of the malate-aspartate shuttle, alterations of the levels of shuttle intermediates and inhibition of the activities of malate and succinate dehydrogenases in brain mitochondria.

Acetates↗
PubMed1993

Changes in the permeability of the blood-brain barrier in acute hyperammonemia. Effect of dexamethasone.

This study was designed to determine the contribution of elevated plasma ammonia levels to blood-brain barrier (BBB) abnormalities in the presence of intact liver. The permeability changes of the BBB were investigated grossly with Evans blue (EB) and quantitatively by measuring the blood-to-brain transfer content for alpha-aminoisobutyric acid (AIB) in normal rats and rats subjected to sublethal doses of ammonium acetate (NH4OAc) (750 and 600 mg/kg ip; at 30-min intervals). Some rats were pretreated with dexamethasone (DXN). Injection of NH4OAc increased both plasma and brain ammonia concentrations about 16-and 5-fold, respectively, above the control level. In rats receiving NH4OAc injection, the blood-to-brain transfer constant (Ki) for AIB was increased 3- to 11-fold. The elevated Ki values were limited to certain gray matter areas and less pronounced permeability changes were detected in white matter. Extravasation sites of EB were more restricted and were especially observed in thalamus and cerebellum, whereas cortex and white matter were unaffected. Dexamethasone pretreatment for 3 d reduced both leakage of EB and the Ki for AIB in NH4OAc injected animals, whereas acute treatment appeared ineffective. Dexamethasone did not prevent the development of coma but slightly decreased the ammonia concentration in plasma and brain. The results obtained indicate that hyperammonemia may disrupt BBB integrity not only to AIB and EB but also enhance the transport of other solutes.

Acetates↗
PubMed1998

Hemodialysis catheter placement and recirculation in treatment of hyperammonemia.

A 2-year-old girl with carbamoyl phosphate synthetase deficiency underwent emergency hemodialysis (HD) for treatment of acute life-threatening hyperammonemia. HD was performed via catheters placed in each femoral vein serving as vascular access. The tip of one of the catheters (aspirating line) was in the left external iliac vein and the tip of the other catheter (the return line) was in the inferior vena cava (IVC). High blood flow rates were used in order to rapidly lower the blood ammonia (NH3) levels. However, unanticipated marked recirculation in the IVC, between the dialysis aspirating and return catheters, was encountered, preventing significant reduction in blood NH3. The recognition of this problem, suggested solutions, and prevention are described.

Ammonia↗
PubMed2001

Conscientious metabolic monitoring on a patient with hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome undergoing anaesthesia.

Currently we know not more than 50 patients who show an interesting combination of increased plasma ornithine concentrations, postprandial hyperammonemia, and homocitrullinuria (HHH-syndrome). Since exact knowledge of this severe, although rare syndrome is important for any perioperative or intensive medical treatment concerning therapy and progression of the disease, we report a comprehensive study on a 32-year old woman with this rare multifaceted disorder who had to undergo general anaesthesia. For the first time amino acid status in plasma, urine, cerebrospinal fluid and especially polymorphonuclear leucocytes, which in the investigation showed to be valuable tool for evaluating amino acid metabolism in nucleated cells in HHH-syndrome, and further important pathophysiologic indicators of cellular and metabolic function have been conscientiously investigated and compared. The pathophysiological repercussions of our results as well as the recommendations for conscientious therapeutical management are discussed.

Adult↗
PubMed1986

Hyperammonemia complicating mesenteric vein thrombosis.

Hyperammonemic coma developed in a 69-year-old woman with prolonged symptoms of abdominal pain, dysphagia, and fever. At laparotomy for an acute condition within the abdomen, mesenteric vein thrombosis was found and partial intestinal resection was performed. Following surgery, the patient regained consciousness and blood ammonia levels became normal. Hyperammonemia and coma complicating mesenteric vein thrombosis have not yet been described. Venous shunts are suggested as being responsible for this rare complication.

Abdomen↗
PubMed1992

Effects of congenital hyperammonemia on the cerebral and hepatic levels of the intermediates of energy metabolism in spf mice.

Sparse-fur (spf) mutant mice with X-linked ornithine transcarbamylase (OTC) deficiency were examined for hyperammonemia and its effect on energy metabolism. We compared the levels of ammonia, glutamine, glutamate and some of the intermediates of energy metabolism in the brain and liver of spf mice with those of control mice. In spf mice we observed significant increases in ammonia, glutamine, alpha-ketoglutarate and glucose with a significant decrease in ATP, glutamate and pyruvate in both brain and liver. The redox states of the brain and liver were also altered in spf mice. The results suggest that many of the metabolic alterations seen in spf mice could be due to the elevated ammonia levels. The spf mouse may, therefore, be an ideal model for the study of the neurotoxic effects of ammonia in chronic hyperammonemic syndromes.

Adenosine Triphosphate↗
PubMed1988

Protective effect of D,L-carnitine on valproate-induced hyperammonemia and hypoketonemia in primary cultured rat hepatocytes.

The effect of D,L-carnitine on sodium valproate (VPA)-induced hyperammonemia and hypoketonemia was investigated in primary cultures of rat hepatocytes. Administration of VPA (0.1 to 1.0 mM) resulted in an increase of ammonia and a decrease of ketone bodies in culture medium. When D,L-carnitine was added with VPA to the medium, the level of ammonia decreased significantly and that of ketone bodies increased. A significant negative relationship was found between the concentrations of ammonia and the ketone bodies in the medium following administration of D,L-carnitine. Our results suggested that VPA suppressed the urea cycle metabolism and that a protective effect of D,L-carnitine on ketone metabolism was probably due to the reversal of the inhibition of beta-oxidation.

Ammonia↗
PubMed1989

Valproate-induced hyperammonemia of renal origin. Effects of valproate on glutamine transport in rat kidney mitochondria.

The antiepileptic sodium valproate (VPA) systematically induces an asymptomatic hyperammonemia of renal origin in fasting normal human volunteers and in fasting rats, accompanied by an increased renal glutamine uptake. Fasting rats were injected with VPA and their mitochondria isolated, or isolated mitochondria of fasting rats were incubated with VPA. Transmembranal mitochondrial glutamine uptake and activities for five mitochondrial and three cytosolic enzymes involved in ammoniagenesis were measured. In VPA-incubated mitochondria, glutamine transport increased for VPA concentrations between 10(-3) and 10(-5) M; enzyme activities did not change. In mitochondria of VPA-treated rats, Km and Vmax were unaffected. These findings reflect membrane effects of VPA observed in other experimental settings.

Ammonia↗
PubMed1993

Effect of sodium benzoate on cerebral and hepatic energy metabolites in spf mice with congenital hyperammonemia.

The sparse-fur (spf) mutant mouse has an X-linked deficiency of ornithine transcarbamylase and develops congenital hyperammonemia similar to that seen in human patients. We studied the effect of sodium benzoate (2.5, 5 and 10 mmol/kg body wt) on ammonia, glutamine and glutamate, as well as various intermediates of energy metabolism in brain and liver of normal CD-1/Y and hyperammonemic spf/Y mice. The ammonia concentration of brain was decreased with 2.5 mmol sodium benzoate in spf/Y mice, whereas higher doses resulted in a significant increase in both liver and brain. Cerebral glutamine content decreased generally in a dose-dependent manner, both in normal and affected mice, following treatment with various doses of sodium benzoate. Cerebral glutamate concentrations were increased only in spf mice treated with sodium benzoate, whereas ATP and acetyl CoA were decreased (P < 0.001), in both normal and affected mice, indicating that glutamine synthesis may be affected by ATP availability. Free CoA levels were decreased (P < 0.05) only in liver in both groups of treated mice, whereas pyruvate concentrations were elevated (P < 0.05) in affected mice following sodium benzoate administration. The results demonstrate that a dose of 2.5 mmol sodium benzoate/kg body wt has a beneficial effect in reducing cerebral ammonia with a concomitant decrease in glutamine. However, the results suggest that many of the metabolite changes observed following higher doses of benzoate could be due to depletion of ATP, free CoA and acetyl CoA levels, possibly secondary to benzoyl CoA accumulation. The response of the spf/Y mouse to sodium benzoate was different from that of the control CD-1/Y mouse, which could be due to its urea cycle dysfunction and a chronic hyperammonemic state. Hence, the spf/Y mouse may be the ideal animal model for studying the pharmacology of sodium benzoate in hyperammonemic disorders at both the cerebral and hepatic levels.

Acetyl Coenzyme A↗
PubMed1982

Defective ornithine metabolism in cultured skin fibroblasts from patients with the syndrome of hyperornithinemia, hyperammonemia and homocitrullinuria.

The syndrome of hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) is a metabolic disorder resulting in protein intolerance and mental retardation. The primary metabolic defect has yet to be determined. We studied some aspects of ornithine metabolism in cultured skin fibroblasts from two patients from two patients with the HHH syndrome. The fibroblasts failed to incorporate 14C-label from ornithine into protein, a defect also observed in fibroblasts from patients with gyrate atrophy of the choroid and retina and a deficiency of ornithine aminotransferase activity. The defect can be corrected in heterokaryons formed between these two types of fibroblasts. These findings indicate that fibroblasts are suitable for further studying the underlying metabolic defect in HHH syndrome. The combination of the ornithine incorporation assay and genetic complementation analysis provide a confirmatory test for the diagnosis of this syndrome.

Amino Acid Metabolism, Inborn Errors↗
PubMed1991

Hyperammonemia and anorexia in Morris hepatoma-bearing rats.

Inoculation of Buffalo rats with Morris hepatoma produced significant anorexia within four weeks and reduced body weight within two weeks. Blood ammonia concentration was increased by 113% when the rats were euthanized, five days after the development of anorexia. Infusing ammonium salts into normal Buffalo rats also induced anorexia at a blood ammonia concentration comparable to that observed in the tumor-bearing rats. Although ammonia-infused rats exhibited expected increases in brain tyrosine, tryptophan, and metabolites of dopamine and serotonin, these alterations were attenuated in the tumor-bearing rats. These results indicate that hyperammonemia may be a general consequence of experimental cancer and that the increase in ammonia concentration may be of primary importance in the development of experimental cancer-induced anorexia. The rather small alterations in neurotransmitter metabolism in anorectic tumor-bearing rats deemphasize the role aberrations in DA and 5-HT systems in the development of experimental cancer anorexia.

Ammonia↗
PubMed1996

Hyperammonemia inhibits platelet aggregation in rats.

The effect of hyperammonemia on ex vivo platelet function and in vivo nitric oxide synthesis was evaluated in rats. In addition, mitochondrial energy production was assessed from the fluorescence intensity of tetramethylrhodamine ethyl ester (TMRE). Continuous ammonium acetate infusion significantly reduced ex vivo platelet aggregation concomitant with a decrease of the platelet cytoplasmic ATP level. The serum level of L-arginine, as well as the levels of nitrite and nitrate (oxidative by-products of nitric oxide), increased with ammonium infusion. Prior administration of N omega-nitro-L-arginine methyl ester, a competitive inhibitor of nitric oxide synthase, did not affect the ammonia-induced rise in L-arginine, but substantially attenuated the associated decrease of platelet ATP and TMRE fluorescence as well as diminishing the anti-aggregatory effect of ammonia infusion. These findings suggest that the synthesis of nitric oxide from L-arginine is accelerated by continuous ammonium infusion and inhibits ex vivo platelet aggregation in the rat, probably by reducing mitochondrial energy production.

Acetates↗
PubMed1992

Hyperammonemia induces transient GFAP immunoreactivity changes in goldfish spinal cord (Carassius auratus L.).

In this study we have demonstrated that high ammonia concentration in tank water induces changes in the glial fibrillary acidic protein (GFAP) of ependymal cells and radial astrocytes in the goldfish spinal cord. Hyperammonemia was induced by elevating the ammonia concentration in the tank water to 0.88 mM using ammonium chloride; ammonia in control water was less than 0.1 mM. Immunohistochemical methods were used for GFAP and vimentin, and levels were measured at 4, 8, 16, 30, 60, 90 and 120 days. GFAP quantification was made by means of a digital analysis system. The GFAP immunoreactivity was significantly lower at 30 and 60 days of treatment and at 90 days it had returned to control levels. However, no changes in vimentin immunoreactivity were appreciated in any case. GFAP loss was general and was not selective in any specific spinal cord region. To explain this transient generalized loss of GFAP and its posterior recuperation, a possible relation between glutamine synthetase distribution and GFAP changes is discussed.

Ammonia↗