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PubMed2005

Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts.

Patients with liver disease with overt or minimal hepatic encephalopathy show impaired intellectual capacity. The underlying molecular mechanism remains unknown. Rats with portacaval anastomosis or with hyperammonemia without liver failure also show impaired learning ability and impaired function of the glutamate-nitric oxide-cyclic guanine monophosphate (glutamate-NO-cGMP) pathway in brain. We hypothesized that pharmacological manipulation of the pathway in order to increase cGMP content could restore learning ability. We show by in vivo brain microdialysis that chronic oral administration of sildenafil, an inhibitor of the phosphodiesterase that degrades cGMP, normalizes the function of the glutamate-NO-cGMP pathway and extracellular cGMP in brain in vivo in rats with portacaval anastomosis or with hyperammonemia. Moreover, sildenafil restored the ability of rats with hyperammonemia or with portacaval shunts to learn a conditional discrimination task. In conclusion, impairment of learning ability in rats with chronic liver failure or with hyperammonemia is the result of impairment of the glutamate-NO-cGMP pathway. Moreover, chronic treatment with sildenafil normalizes the function of the pathway and restores learning ability in rats with portacaval shunts or with hyperammonemia. Pharmacological manipulation of the pathway may be useful for the clinical treatment of patients with overt or minimal hepatic encephalopathy.

Administration, Oral↗
PubMed2004

Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.

BACKGROUND/AIMS: Studies in acute liver failure show correlation between evidence of a systemic inflammatory response syndrome (SIRS) and progression of hepatic encephalopathy (HE). We tested the hypothesis that SIRS mediators, such as nitric oxide and proinflammatory cytokines, may exacerbate the neuropsychological effects of hyperammonemia in cirrhosis. METHODS: Ten patients with cirrhosis were studied, 24-36 h after admission with clinical evidence of infection, and following its resolution. Hyperammonemia was induced by oral administration of an amino-acid (aa) solution mimicking hemoglobin composition. Inflammatory mediators, nitrate/nitrite, ammonia, aa profiles and a battery of neuropsychological tests were measured. RESULTS: The hyperammonemia generated in response to the aa solution was similar prior to, and after resolution, of the inflammation (P=0.77). With treatment of the infection there were significant reductions in white blood cell count (WBC), C-reactive protein (CRP), nitrate/nitrite, interleukin-6, interleukin-1beta and tumour necrosis factor alpha. Induced hyperammonemia resulted in significant worsening of the neuropsychological scores when patients showed evidence of SIRS but not after its resolution. CONCLUSIONS: The significant deterioration of neuropsychological test scores following induced hyperammonemia during the inflammatory state, but not after its resolution, suggests that the inflammation and its mediators may be important in modulating the cerebral effect of ammonia in liver disease.

Amino Acids↗
PubMedDate not supplied

Chronic hyperammonemia alters protein phosphorylation and glutamate receptor-associated signal transduction in brain.

There is substantial evidence that hyperammonemia is one of the main factors contributing to the neurological alterations found in hepatic encephalopathy. The mechanisms by which chronic moderate hyperammonemia affects brain function involves alterations in neurotransmission at different steps. This article reviews the effects of hyperammonemia on phosphorylation of key brain proteins involved in neurotransmission (the microtubule-associated protein (MAP-2), Na+/K+-ATPase and NMDA receptors). The physiological function of these proteins is modulated by phosphorylation and its altered phosphorylation in hyperammonemia may contribute to impairment of neurotransmission. The effects of chronic hyperammonemia on signal transduction pathways associated to glutamate receptors, such as the glutamate-nitric oxide (NO)-cGMP pathway, are also reviewed. The possible contribution of the impairment of this pathway in brain in vivo to the neurological alterations present in patients with hepatic encephalopathy is discussed.

Animals↗
PubMed2001

Hyperammonemia in urea cycle disorders: role of the nephrologist.

Hyperammonemia associated with inherited disorders of amino acid and organic acid metabolism is usually manifested by irritability, somnolence, vomiting, seizures, and coma. Although the majority of these patients present in the newborn period, they may also present in childhood, adolescence, and adulthood with failure to thrive, persistent vomiting, developmental delay, or behavioral changes. Persistent hyperammonemia, if not treated rapidly, may cause irreversible neuronal damage. After the diagnosis of hyperammonemia is established in an acutely ill patient, certain diagnostic tests should be performed to differentiate between urea cycle defects and other causes of hyperammonemic encephalopathy. In a patient with a presumed inherited metabolic disorder, the aim of therapy should be to normalize blood ammonia levels. Recent experience has provided treatment guidelines that include minimizing endogenous ammonia production and protein catabolism, restricting nitrogen intake, administering substrates of the urea cycle, administering compounds that facilitate the removal of ammonia through alternative pathways, and, in severe cases, dialysis therapy. Initiation of dialysis in the encephalopathic patient with hyperammonemia is indicated if the ammonia blood level is greater than three to four times the upper limit of normal. Hemodialysis is the most effective treatment for rapidly reducing blood ammonia levels. Continuous hemofiltration and peritoneal dialysis are also effective modalities for reducing blood ammonia levels. An improved understanding of the metabolism of ammonia and neurological consequences of hyperammonemia will assist the nephrologist in providing optimal care for this high-risk patient population.

Algorithms↗
PubMed2002

Cerebral blood flow in hyperammonemia: heterogeneity and starling forces in capillaries.

In the brain hyperammonemia interferes with ion homeostasis, membrane potentials, neurotransmission, and neurotransmitter recycling and reduces metabolic rates for oxygen and glucose. Because, cerebral blood flow (CBF) is closely coupled to metabolism, CBF is most often reduced in diseases associated with hyperammonemia. However, in severe cases of hyperammonemia, as in patients with acute liver failure, Reye's syndrome, and inherited metabolic disorders of the urea cycle, the normal regulation of CBF is also impaired. One of the most prominent findings is a failure of CBF autoregulation that uncouples metabolism from CBF. Clinically failure of autoregulation may imply that both cerebral hypoxia and hyperaemia may develop in the patient depending on the driving pressure of the brain, i.e., cerebral perfusion pressure. In addition a gradual "nonreactive" dilatation of the cerebral arterioles often aggravates the mismatch between nutritive demands and delivery in the brain. The reason for arteriolar dilation and homogeneous capillary blood flow is not settled but seems not to be mediated by excessive release of nitro oxide. More likely the arachidonic acid cascade with increased synthesis of prostaglandins, cytochrome P450 metabolites, and potassium channel activation are implicated in this vasodilatation. The combination of cerebral hyperaemia, increased hydrostatic capillary blood pressure, and accumulation of organic and nonorganic osmolytes within the brain during hyperammonemia clearly will favor cerebral capillary water influx. This imbalance between colloid osmotic and hydrostatic pressures in patients with severe hyperammonemia means that simple interventions based on physiological principles may help ameliorate cerebral hyperaemia and water influx. Thus, it is suggested that not only monitoring of intracranial pressure (ICP) and cerebral perfusion are pivotal to help prevent high ICP but also basic clinical information, such as Tp, PaCO2, and plasma sodium/glucose concentrations, should be closely followed and corrected.

Capillaries↗
PubMed2002

Mechanisms of hyperammonemia.

Hyperammonemia is mainly found in hepatic encephalopathy and in genetic defects of the urea cycle or other pathways of the intermediary metabolism. Clinically a difference has to be made between chronic moderate hyperammonemia and acutely increased concentrations. Pathogenetic mechanisms of ammonia toxicity to the brain are partly unraveled. In some animal models confounding variables, such as the reduced intake of food and amino acid imbalance due to liver insufficiency, do not allow to establish unequivocal causal relationships between the ammonia concentration and measured effects. In chronic moderate hyperammonemia an increased flux through the serotonin pathway is a key factor. It is caused by an increased transport of large neutral amino acids (including tryptophan) through the blood-brain barrier, accentuated by the imbalance of plasma amino acids in hepatic insufficiency. It is stimulated by D- or L-glutamine. Evidence is presented showing that a functioning gamma-glutamyl cycle (glutathione formation) is a prerequisite. In acute hyperammonemia involvement of NMDA receptors, glutamate, NO and cGMP plays an additional role. In hyperammonemic crises the increased cerebral blood flow leads to brain edema; factors discussed here are increased osmolytes in astrocytes and serotoninergic activity. Recent data indicate that axonal development is affected by ammonia and can be normalized in vitro by creatine supplementation in developing mixed brain cell aggregate cultures, thus reviving the old hypothesis of the impact of hyperammonemia on energy metabolism in the developing brain that could cause mental retardation.

Amino Acids↗
PubMed1993

Neuronal and glial marker proteins in encephalopathy associated with acute liver failure and acute hyperammonemia in the rabbit.

Neuronal and glial cell marker proteins were quantified in order to evaluate the possibility of increased proteolysis in the brain of rabbits with acute liver failure and acute hyperammonemia. Acute liver failure was induced by a two-stage devascularization procedure. Acute hyperammonemia was induced by a prolonged infusion of ammonium acetate, which simulates the plasma ammonia level in acute liver failure. Control animals received an infusion of sodium/potassium acetate. After development of severe encephalopathy, the animals were sacrificed (13.7 +/- 1.3 hours for rabbits with acute liver failure and 20.2 +/- 0.8 hours for rabbits with hyperammonemia) (x +/- S.E.M./n = 6) and their brains were dissected into cerebral cortex, hippocampus, cerebellum and brain stem. The total protein content and the concentrations of the neuronal cell marker proteins NSE (neuron specific enolase), NF68 and NF200 (68 kD and 200 kD neurofilament polypeptides) and the glial cell marker proteins GFAP (glial fibrillary acidic protein) and S-100 were determined. Total protein content was decreased in the brain stem in acute hyperammonemia only. The content of neuronal and glial cell markers was not affected in either of the two conditions. However, low molecular weight proteolytic fragments of the NF 68 kD polypeptide were observed in the hippocampus of three out of six animals in both experimental groups. No proteolytic degradation of GFAP was observed. The results show that, in experimental encephalopathy due to acute liver failure and acute hyperammonemia, no major changes occur in the marker proteins. The finding of proteolytic fragments of the NF68 polypeptide indicates that the neuronal population is affected prior to glial alterations. These findings are in agreement with the concept that acute hepatic encephalopathy is reversible and induces only slight structural changes.

Acute Disease↗
PubMed1992

Changes in brain ECF amino acids in rats with experimentally induced hyperammonemia.

Using microdialysis, we studied brain extracellular fluid (ECF) amino acid metabolism in rats with experimentally induced hyperammonemia and regional elevation of brain ECF ammonia levels. The total brain ECF amino acid level was increased by an elevation of the blood ammonia level. Hyperammonemia elevated brain ECF aromatic amino acids and reduced arterial blood branched chain amino acids. When rats with hyperammonemia were intravenously administered norleucine, the brain ECF norleucine level rose markedly, suggesting increased permeability of the blood-brain barrier. When rats with hyperammonemia were infused with a branched chain amino acid-rich preparation, the elevated brain ECF aromatic amino acids level was not suppressed. Following local intracerebral ammonia infusion, only glutamate levels showed a marked elevation. These results suggest that impairment of the blood-brain barrier related to hyperammonemia increases the inflow of low molecular weight substances including amino acids. Furthermore, the ammonia-induced increase of glutamate in the cerebral ECF suggests that high ammonia levels may increase the excitability of the brain. Thus, ammonia may serve as a key factor in the onset of hepatic encephalopathy.

Amino Acids↗
PubMed1994

45CaCl2 autoradiography in brain from rabbits with encephalopathy from acute liver failure or acute hyperammonemia.

In experimental hepatic encephalopathy and hyperammonemia, extracellular levels of glutamate are increased in hippocampus and cerebral cortex. It has been suggested that overstimulation of glutamate receptors causes a pathological entry of calcium into neurons via receptor-operated (NMDA- and AMPA-type) or voltage-dependent calcium channels leading to calcium overload and cell death. Neurodegeneration as a result of exposure to excitotoxins, including glutamate, can be localized and quantified using 45CaCl2 autoradiography. This approach was used to study cerebral calcium accumulation in rabbits with acute liver failure and acute hyperammonemia. Acute liver failure was induced in 6 rabbits, acute hyperammonemia in 4 rabbits; 4 control rabbits received sodium-potassium-acetate. At the start of the experiment 500 microCi 45CaCl2 was given intravenously. After development of severe encephalopathy, the animals were killed by decapitation. All rabbits with acute liver failure or acute hyperammonemia developed severe encephalopathy, after 13.2 +/- 1.7 and 19.3 +/- 0.5 hours respectively (mean +/- SEM). Plasma ammonia levels were 425 +/- 46 and 883 +/- 21 mumol/l, respectively (p < 0.05). Control rabbits maintained normal plasma ammonia levels (13 +/- 5 mumol/l), demonstrated normal behaviour throughout the study and were sacrificed after 16 hours. 45Ca(2+)-autoradiograms of 40 microns brain sections were analyzed semiquantitatively using relative optical density and computerized image analysis. As compared to background levels 45Ca was not increased in hippocampus or any other brain area of rabbits with severe encephalopathy from acute liver failure or acute hyperammonemia. This suggests that, despite increased extracellular brain glutamate levels in these conditions, glutamate neurotoxicity was not important for the development of encephalopathy in these rabbits.

Acetates↗
PubMed1988

Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases.

PURPOSE: The syndrome of idiopathic hyperammonemia occurs in patients who have received high-dose cytoreductive therapy for the treatment of hematologic malignancy. It is characterized by abrupt alteration in mental status and respiratory alkalosis associated with markedly elevated plasma ammonium levels in the absence of any identifiable cause, and frequently results in intractable coma and death. Our goal was to survey clinical and pathologic manifestations of the disorder and discuss treatment options. PATIENTS AND METHODS: Plasma ammonium levels were measured in patients on the acute leukemia service or on the bone marrow transplant service at The Johns Hopkins Hospital, and a level more than twice normal was considered diagnostic of hyperammonemia. The syndrome was identified in nine patients; in eight, hyperammonemia occurred after administration of intensive cytoreductive therapy that resulted in profound leukopenia. The disorder occurred in the ninth patient two months after allogeneic bone marrow transplantation. RESULTS: Three of the nine patients survived an episode of idiopathic hyperammonemia; one patient subsequently died of leukemia and one of recurrent idiopathic hyperammonemia. The one long-term survivor is currently alive and well without neurologic sequelae 250 days after autologous bone marrow transplantation. CONCLUSION: Because neurologic function can deteriorate rapidly, early recognition of this disorder and close monitoring of the patient's neurologic status are critical.

Adolescent↗
PubMed1999

Surgical indications for patients with hyperammonemia.

BACKGROUND/PURPOSE: The authors surgically treated seven of eight patients with congenital portosystemic shunt and hyperammonemia. This entity is uncommon in children. METHODS: The patients included five boys and three girls with a mean age of 8 years (range, 7 months to 24 years). Preoperative symptoms included hyperammonemia. Hepatic encephalopathy was evident in five patients. Diagnosis and assessment were made by ultrasound scan, magnetic resonance imaging (MRI), angiography, and 123 I-iodoamphetamine per-rectal portal scintigraphy. Surgical banding was done for five patients and transvenous coil embolization for two. One patient was not a surgical candidate because there were no intrahepatic portal veins. RESULTS: In four of the five patients treated using surgical banding, and in both patients who underwent coil embolizations, hyperammonemia and clinical symptoms improved soon after surgery. However, in the remaining patient, hyperammonemia worsened after surgery, and reoperation was needed because of a severe portal hypertension, possibly caused by malconformation of hepatic veins. CONCLUSIONS: For patients with congenital portosystemic shunt, early diagnosis and surgery are needed to prevent damage to central nerves caused by persistent hyperammonemia. Maldevelopment of the intrahepatic portal veins is a surgical option, if the patient has a normal liver architecture, but malconformation of hepatic veins or severe anomalies such as cardiac defects would rule out surgical intervention.

Adolescent↗
PubMed1992

Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of six patients.

We report the clinical, electrophysiologic, ophthalmologic, and neuropsychologic features of six patients with hyperammonemia-hyperornithinemia-homocitrullinuria syndrome, an inborn error of ornithine metabolism. Pyramidal signs, decreased vibration sense, bucco-facio-lingual dyspraxia, and learning difficulties or subnormal intelligence were found in the majority. Anomalies of peripheral nerve conduction velocity and of evoked potentials were common, and one patient had markedly abnormal white matter images on cranial magnetic resonance imaging. One patient had retinal depigmentation and chorioretinal thinning. The clinical severity varied greatly among patients; in general, the three younger patients had less neurologic and intellectual impairment than did the three older patients. Only two of our patients have had episodes of symptomatic hyperammonemia. We conclude that hyperammonemia-hyperornithinemia-homocitrullinuria syndrome can be associated with widespread manifestations in the central and peripheral nervous systems. Although the control of hyperammonemia is an essential element in the treatment of these patients, the relationship of hyperammonemia to the chronic neuropsychologic problems of these patients is unclear.

Adolescent↗
PubMed1984

Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis.

Although normal plasma ammonium levels can be maintained in children with inborn errors of ureagenesis, these children are vulnerable to episodic hyperammonemia often resulting in coma and death. To treat such episodes, we designed a therapeutic protocol that included prompt recognition of hyperammonemia, therapy with intravenous sodium benzoate, sodium phenylacetate, and arginine, and nitrogen-free intravenous alimentation. Dialysis was performed if the hyperammonemia was unresponsive to drug therapy. Twelve episodes of hyperammonemia in seven children deficient in carbamyl phosphate synthetase, ornithine transcarbamylase, or argininosuccinic acid synthetase were treated; one patient died and the others recovered. In two patients measurement of the distribution of urinary nitrogen revealed that hippurate nitrogen and phenylacetylglutamine nitrogen together accounted for 60 per cent of "effective" urinary waste nitrogen. Successful therapy of episodic hyperammonemia plays an important part in the long-term management of disorders of the urea cycle.

Amino Acid Metabolism, Inborn Errors↗
PubMed1998

Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene.

BACKGROUND: A new form of congenital hyperinsulinism characterized by hypoglycemia and hyperammonemia was described recently. We hypothesized that this syndrome of hyperinsulinism and hyperammonemia was caused by excessive activity of glutamate dehydrogenase, which oxidizes glutamate to alpha-ketoglutarate and which is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver. METHODS: We measured glutamate dehydrogenase activity in lymphoblasts from eight unrelated children with the hyperinsulinism-hyperammonemia syndrome: six with sporadic cases and two with familial cases. We identified mutations in the glutamate dehydrogenase gene by sequencing glutamate dehydrogenase complementary DNA prepared from lymphoblast messenger RNA. Site-directed mutagenesis was used to express the mutations in COS-7 cells. RESULTS: The sensitivity of glutamate dehydrogenase to inhibition by guanosine 5'-triphosphate was a quarter of the normal level in the patients with sporadic hyperinsulinism-hyperammonemia syndrome and half the normal level in patients with familial cases and their affected relatives, findings consistent with overactivity of the enzyme. These differences in enzyme insensitivity correlated with differences in the severity of hypoglycemia in the two groups. All eight children were heterozygous for the wild-type allele and had a mutation in the proposed allosteric domain of the enzyme. Four different mutations were identified in the six patients with sporadic cases; the two patients with familial cases shared a fifth mutation. In two clones of COS-7 cells transfected with the mutant sequence from one patient, the sensitivity of the enzyme to guanosine 5'-triphosphate was reduced, findings similar to those in the child's lymphoblasts. CONCLUSIONS: The hyperinsulinism-hyperammonemia syndrome is caused by mutations in the glutamate dehydrogenase gene that impair the control of enzyme activity.

Ammonia↗
PubMed1992

Valproate use associated with persistent hyperammonemia and mitochondrial injury in a child with Down's syndrome.

Valproate is a commonly prescribed anticonvulsant drug that may cause potentially fatal hepatotoxicity, bone-marrow toxicity, and pancreatitis. Toxicity usually resolves, though, after discontinuation of the medication. We report a 9-year-old boy who had Down's syndrome and who developed valproate-associated bone marrow toxicity, and hepatotoxicity that persisted greater than 2 years after discontinuation of valproate therapy. Three years after starting valproate, he developed erythrocyte aplasia with a severe, normochromic, macrocytic anemia requiring several blood transfusions. Several months later while still receiving valproate, he developed progressive hyperammonemia and decreased hepatic synthetic function. The macrocytic anemia resolved and hepatic synthetic function improved after discontinuation of valproate therapy. However, hyperammonemia, steatosis, mitochondrial injury, and marked hepatic iron accumulation persisted greater than 2 years after the valproate was discontinued. The persistent hyperammonemia was responsive to lactulose therapy. A decrease in hepatic iron content by serial phlebotomies did not result in any improvement in the hyperammonemia or hepatic synthetic function. This is the first report of persistent hyperammonemia and hepatic mitochondrial injury after valproic acid therapy.

Ammonia↗
PubMed1994

Encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit. A clinical and biochemical study.

To study the molecular basis of ammonia toxicity, highly reproducible models of acute liver failure and acute hyperammonemia in the rabbit were developed. Acute liver failure was induced by two-stage liver devascularization, and acute hyperammonemia by prolonged ammonia infusion such that the plasma ammonia pattern found in acute liver failure was simulated. Clinical symptoms, spectral analysis of the EEG, biochemistry (blood gases, renal function, electrolytes and markers of hepatic injury) and the presence of cerebral edema were studied. During acute liver failure severe encephalopathy developed after 10.2 +/- 1.9 h (n = 6, mean +/- SEM). Other liver-failure-associated abnormalities were cerebral edema, lactic acidosis, renal dysfunction, hypothermia and septicemia. During acute hyperammonemia, severe encephalopathy developed after 18.2 +/- 0.4 h (n = 6, mean +/- SEM). Other abnormalities found were cerebral edema and lactic acidosis. In both animal models comparable EEG changes were observed (a decrease in mean dominant frequency and theta-activity, and an increase in delta activity). However, these changes were not statistically significant, and non-specific as they also occurred in control rabbits despite their clinical wellbeing. This study demonstrates in the rabbit the similarity between encephalopathy due to acute ischemic liver failure and that due to hyperammonemia. An observed difference in hyperammonemia-induced encephalopathy was pronounced ataxia, which did not occur during acute liver failure, whereas hypothermia, sepsis and renal failure occurred exclusively in acute liver failure. Our models appear satisfactory for the study of hepatic encephalopathy and ammonia toxicity.

Ammonia↗
PubMed2005

Glutamine-dependent inhibition of pial arteriolar dilation to acetylcholine with and without hyperammonemia in the rat.

Glutamine has been shown to influence endothelial-dependent relaxation and nitric oxide production in vitro, possibly by limiting arginine availability, but its effects in vivo have not been well studied. Hyperammonemia is a pathophysiological condition in which glutamine is elevated and contributes to depressed CO(2) reactivity of cerebral arterioles. We tested the hypothesis that acute hyperammonemia decreases pial arteriolar dilation to acetylcholine in vivo and that this decrease could be prevented by inhibiting glutamine synthetase with L-methionine-S-sulfoximine (MSO) or by intravenous infusion of L-arginine. Pial arteriolar diameter responses to topical superfusion of acetylcholine were measured in anesthetized rats before and at 6 h of infusion of either sodium or ammonium acetate. Ammonium acetate infusion increased plasma ammonia concentration from approximately 30 to approximately 600 microM and increased cerebral glutamine concentration fourfold. Arteriolar dilation to acetylcholine was intact after infusion of sodium acetate in groups pretreated with vehicle or with MSO plus methionine, which was coadministered to prevent MSO-induced seizures. In contrast, dilation in response to acetylcholine was completely blocked in hyperammonemic groups pretreated with vehicle or methionine alone. However, MSO plus methionine administration before hyperammonemia, which maintained cerebral glutamine concentration at control values, preserved acetylcholine dilation. Intravenous infusion of L-arginine during the last 2 h of the ammonium acetate infusion partially restored dilation to acetylcholine without reducing cerebral glutamine accumulation. Superfusion of 1 or 2 mM L-glutamine through the cranial window for 1 h in the absence of hyperammonemia attenuated acetylcholine dilation but had no effect on endothelial-independent dilation to nitroprusside. We conclude that 1) hyperammonemia reduces acetylcholine-evoked dilation in cerebral arterioles, 2) this reduction depends on increased glutamine rather than ammonium ions, and 3) increasing arginine partially overcomes the inhibitory effect of glutamine.

Acetylcholine↗
PubMed1989

Neonatal hyperammonemia associated with carnitine deficiency.

We report a case of neonatal hyperammonemia associated with secondary carnitine deficiency. She suffered from hyperammonemia soon after the birth, and then presented severe metabolic acidosis at 2 months of age. She was successfully treated for acidosis with oral administration of L-carnitine (100 mg/kg/day). Since hyperammonemia recurred with the increase of protein intake, it was necessary to increase the dose of carnitine to 150 mg/kg/day. Urea cycle enzymopathies were excluded from the laboratory data. The urinary organic acid profiled by gas chromatography mass spectrometry revealed no abnormalities. It was found that the carnitine contents in serum urine and muscle were decreased. After we investigated the carnitine status in other members of the family, the brother of this patient, who had died of metabolic acidosis and hyperammonemia of unknown etiology in the neonatal period, was also revealed to have carnitine deficiency. Since specific enzyme defects which caused secondary carnitine deficiency could not be detected in our patients, further biochemical characterization would be necessary to clarify the cause of hyperammonemia.

Ammonia↗