Ammonia production by the small intestine of the rat

Anderson, Norma McFarlane; Bennett, Franklin I.; Alleyne, George A.O.

doi:10.1016/0304-4165(76)90365-2

Cited by 36 publications

(8 citation statements)

References 10 publications

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“…Glutamine is a non-essential amino acid which is abundant in protein and constitutes 50% of the body's free amino acid pool (14). Glutamine and glutamate are therefore central to organ and whole body nitrogen balance serving as either a nitrogen donor or acceptor; with glutamine acting as a sink for excess ammonia (via GS), or its source (via PAG) (15).…”

Section: Relationship Between Ammonia Glutamine and Glutamatementioning

confidence: 99%

“…In addition to dietary protein and intestinal bacterial ammonia production, studies on post‐absorptive healthy animals show that 50% of intestinal ammonia is generated from amino acids derived from its blood supply (Fig. 1) (15, 20, 21). The main energy source for enterocytes is circulating glutamine, which is converted by PAG to ammonia and glutamate, for later release into the mesenteric vein (22).…”

Section: Interorgan Ammonia and Amino Acid Metabolismmentioning

confidence: 99%

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Interorgan ammonia metabolism in liver failure: the basis of current and future therapies

Wright

Noiret

Damink

et al. 2011

Liver International

133

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Hepatic encephalopathy complicates the course of both acute and chronic liver disease and its treatment remains an unmet clinical need. Ammonia is thought to be central in its pathogenesis and remains an important target of current and future therapeutic approaches. In liver failure, the main detoxification pathway of ammonia metabolism is compromised leading to hyperammonaemia. In this situation, the other ammonia-regulating pathways in multiple organs assume important significance. The present review focuses upon interorgan ammonia metabolism in health and disease describing the role of the key enzymes, glutamine synthase and glutaminase. Better understanding of these alternative pathways are leading to the development of new therapeutic approaches.For over 100 years, ammonia has been thought to be central in the pathogenesis of hepatic encephalopathy (1). Many organs are involved in regulating whole body ammonia homeostasis (2), with the regulation of arterial levels dependent upon 'interorgan ammonia metabolism' in the context of urea cycle disruption and portalsystemic shunting. Previous meta-analysis suggest that current therapeutic strategies aimed at targeting ammonia fall short of the desired impact on clinical HE (3, 4). This review describes interorgan ammonia and amino acid metabolism in health and in patients with liver failure and how these concepts may lead to the development of more targeted therapies. Ammonia metabolism in healthNitrogen is necessary for cellular structure and energy. Humans must therefore assimilate reduced nitrogenous compounds as part of our diet, such as protein, free amino acids and ammonia (derived from the splitting of urea and other amino acids). In the body, ammonia (NH 3 ) is co-existent with its charged form ammonium (NH 4 1 ). Their relative concentrations are dependent on pH (5). At physiological pH, 98% of total ammonia exists as NH 4 1 , with gaseous NH 3 the main diffusible form transported across biological membranes. In this review, we will refer to NH 3 /NH 4 1 as simply, 'ammonia' . Ammonia is hydrophilic and easily transported in plasma. In health, ammonia transport and metabolism are tightly regulated to maintain low plasma concentrations (normal range 10-40 mmol/L), but exists in the mmol/L range in organs such as intestine or kidney. Transport of unionized ammonia into the cell is through diffusion despite low lipid solubility. In metabolic alkalosis, the conversion of NH 4 1 to NH 3 is increased, thus increasing membrane permeability. Conversely within the cell, negatively charged mitochondria show very poor permeability to NH 3 , but high NH 4 1 permeability (6). Transmembrane transport of ammonia can be facilitated by constitutive ion channels and transporters such as the Rhesus proteins (7-9) and Aquaporin (10-12), however, their precise role in whole body ammonia metabolism remains unclear.

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Section: Relationship Between Ammonia Glutamine and Glutamatementioning

confidence: 99%

Section: Interorgan Ammonia and Amino Acid Metabolismmentioning

confidence: 99%

Interorgan ammonia metabolism in liver failure: the basis of current and future therapies

Wright

Noiret

Damink

et al. 2011

Liver International

133

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“…Studies of interorgan metabolism in liver failure have suggested that when the ammonia‐removing capacity of the liver is reduced, the muscles, gut, and the kidneys interact to try and maintain ammonia levels 7–10. Glutamine acts as both a sink for excess ammonia, by ammonia combining with glutamate to produce glutamine (through the enzyme glutamine synthetase), or as a source for ammonia release (through the enzyme glutaminase) 11. Skeletal muscle glutamine synthetase activity is normally low, but has been shown to be up‐regulated in liver failure 7, 12.…”

mentioning

confidence: 99%

L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats #

et al. 2009

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Treatment of hyperammonemia and hepatic encephalopathy in cirrhosis is an unmet clinical need. The aims of this study were to determine whether L-ornithine and phenylacetate/phenylbutyrate (administered as the pro-drug phenylbutyrate) (OP) combined are synergistic and produce sustained reduction in ammonia by L-ornithine acting as a substrate for glutamine synthesis, thereby detoxifying ammonia, and the phenylacetate excreting the ornithine-derived glutamine as phenylacetylglutamine in the urine. Sprague-Dawley rats were studied 4 weeks after bile duct ligation (BDL) or sham operation. Study 1: Three hours before termination, an internal carotid sampling catheter was inserted, and intraperitoneal saline (placebo), OP, phenylbutyrate, or L-ornithine were administered after randomization. BDL was associated with significantly higher arterial ammonia and brain water and lower brain myoinositol (P < 0.01, respectively), compared with sham-operated controls, which was significantly improved in the OP-treated animals; arterial ammonia (P < 0.001), brain water (P < 0.05), brain myoinositol (P < 0.001), and urinary phenylacetylglutamine (P < 0.01). Individually, L-ornithine or phenylbutyrate were similar to the BDL group. In study 2, BDL rats were randomized to saline or OP administered intraperitoneally for 6 hours or 3, 5, or 10 days and were sacrificed between 4.5 and 5 weeks. The results showed that the administration of OP was associated with sustained reduction in arterial ammonia (P < 0.01) and brain water (P < 0.01) and markedly increased arterial glutamine (P < 0.01) and urinary excretion of phenylacetylglutamine (P < 0.01) in each of the OP treated groups. Conclusion: The results of this study provide proof of the concept that L-ornithine and phenylbutyrate/phenylacetate act synergistically to produce sustained improvement in arterial ammonia, its brain metabolism, and brain water in cirrhotic rats. ( H epatic encephalopathy (HE) incorporates a spectrum of mental disturbances observed in patients with liver disease, ranging from minimal effects on quality of life to coma and death. 1 Hyperammonemia is considered central to the pathogenesis of HE, with arterial ammonia levels correlating with severity of intracranial hypertension and prediction of deaths from cerebral herniation in acute liver failure commensurate with an increase in brain delivery and uptake of ammonia. 2,3 In cirrhosis, induction of hyperammonemia has been shown to be associated with deterioration in neuropsychometric tests, worsening of brain osmolytes, and

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“…For example, a major recent review of ammonia metabolism 11 cited five key papers on the impact of feeding on intestinal ammonia generation. Of these, 2 utilized animal models 12 , 13 , one utilized urinary protein measurement over multiple days and therefore could not assess the immediate impact of a food bolus 14 , and one was a small uncontrolled case series 15 . Only one article evaluated the response of blood ammonia and amino acid profiles to oral protein challenges in humans 16 .…”

Section: Discussionmentioning

confidence: 99%

Repeated Measures of Blood and Breath Ammonia in Response to Control, Moderate and High Protein Dose in Healthy Men

Spacek

Strzepka

Saha

et al. 2018

Sci Rep

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Ammonia physiology is important to numerous disease states including urea cycle disorders and hepatic encephalopathy. However, many unknowns persist regarding the ammonia response to common and potentially significant physiologic influences, such as food. Our aim was to evaluate the dynamic range of ammonia in response to an oral protein challenge in healthy participants. We measured blood and breath ammonia at baseline and every hour for 5.5 hours. Healthy men (N = 22, aged 18 to 24 years) consumed a 60 g protein shake (high dose); a subset of 10 consumed a 30 g protein shake (moderate dose) and 12 consumed an electrolyte drink containing 0 g protein (control). Change in blood ammonia over time varied by dose (p = 0.001). Difference in blood ammonia was significant for control versus high (p = 0.0004) and moderate versus high (p = 0.03). Change in breath ammonia over time varied by dose (p < 0.0001). Difference in breath ammonia was significant for control versus moderate (p = 0.03) and control versus high (p = 0.0003). Changes in blood and breath ammonia were detectable by fast, minimally-invasive (blood) or non-invasive (breath) point-of-care ammonia measurement methods. These pilot data may contribute to understanding normal ammonia metabolism. Novel measurement methods may aid research into genetic and metabolic ammonia disorders.

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Ammonia production by the small intestine of the rat

Cited by 36 publications

References 10 publications

Interorgan ammonia metabolism in liver failure: the basis of current and future therapies

Interorgan ammonia metabolism in liver failure: the basis of current and future therapies

L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats #

Repeated Measures of Blood and Breath Ammonia in Response to Control, Moderate and High Protein Dose in Healthy Men

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