Altered glutamine metabolism in rat portal drained viscera and hindquarter during hyperammonemia

Dejong, Cornelis H. C.; Kampman, Margitta T.; Deutz, Nicolaas E. P.; Soeters, Peter B.

doi:10.1016/0016-5085(92)90180-7

Cited by 56 publications

(48 citation statements)

References 49 publications

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“…The urine bladder was drained via a cystotomy. Blood and urine samples were collected on ice at the times for measurement of blood flow and processed as described previously (10). Tissue samples were freeze clamped with Wollenberger tongs cooled in liquid nitrogen (17) and frozen at Ϫ80°C.…”

Section: Methodsmentioning

confidence: 99%

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Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

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Ytrebø

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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In acute liver failure (ALF), the hyperdynamic circulation is believed to be the result of overproduction of nitric oxide (NO) in the splanchnic circulation. However, it has been suggested that arginine concentrations (the substrate for NO) are believed to be decreased, limiting substrate availability for NO production. To characterize the metabolic fate of arginine in early-phase ALF, we systematically assessed its interorgan transport and metabolism and measured the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) in a porcine model of ALF. Female adult pigs (23-30 kg) were randomized to sham (N ϭ 8) or hepatic devascularization ALF (N ϭ 8) procedure for 6 h. We measured plasma arginine, citrulline, ornithine levels; arginase activity, NO, and ADMA. Whole body metabolic rates and interorgan flux measurements were calculated using stable isotope-labeled amino acids. Plasma arginine decreased Ͼ85% of the basal level at t ϭ 6 h (P Ͻ 0.001), whereas citrulline and ornithine progressively increased in ALF (P Ͻ 0.001 and P Ͻ 0.001, vs. sham respectively). No difference was found between the groups in the whole body rate of appearance of arginine or NO. However, ALF showed a significant increase in de novo arginine synthesis (P Ͻ 0.05). Interorgan data showed citrulline net intestinal production and renal consumption that was related to net renal production of arginine and ornithine. Both plasma arginase activity and plasma ADMA levels significantly increased in ALF (P Ͻ 0.001). In this model of early-phase ALF, arginine deficiency or higher ADMA levels do not limit whole body NO production. Arginine deficiency is caused by arginase-related arginine clearance in which arginine production is stimulated de novo.arginine; asymmetric dimethylarginine; arginase ACUTE LIVER FAILURE (ALF) is characterized by sudden and severe liver dysfunction with rapid progression to coagulopathy, encephalopathy, and multiorgan failure. Without liver transplantation, mortality from ALF is about 50% (4). A hallmark of ALF is the presentation of systemic hypotension and a hyperdynamic circulation (39). This is associated with increased guanylate cyclase (GC) activation by nitric oxide (NO) (33), which converts guanidine triphosphate to cyclic guanidine monophosphate and is thought to cause the vasodilatation seen in ALF (34). Previously, we have reported the characteristics of the same devascularized porcine liver model of ALF, which was shown to have a hyperdynamic circulation as evidenced by a high cardiac output and low mean arterial pressure and systemic vascular resistance (50). However, in this hyperacute model of ALF, no significant changes in the metabolites of NO were observed. Indeed, the kinetics of NO in this model and whether it is involved in the initiation of the vasodilation of ALF remain unknown.L-Arginine has several important biological functions (2, 3, 5), one of which is to be the nitrogen-donating substrate for endothelial NO synthase (eNOS) to produce NO and citrulline in stoichiometric quantities (...

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Section: Methodsmentioning

confidence: 99%

“…Tissue samples were freeze clamped with Wollenberger tongs cooled in liquid nitrogen (17) and frozen at Ϫ80°C. Ammonia, urea, and PAH concentrations were determined spectrophotometrically (10). Amino acids concentrations were determined using HPLC (20).…”

Section: Methodsmentioning

confidence: 99%

Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

Sharma

Have

Ytrebø

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Additionally, there are remarkable interspecies differences in muscle ammonia handling, and we could not show muscle ammonia uptake in experimental portacaval shunted rats. 41,42 The huge interspecies difference in the glutamine concentration gradient between the arterial and muscle glutamine pool could be an explanation, but further research is necessary to address this question.…”

Section: Discussionmentioning

confidence: 99%

Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS

et al. 2002

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Ammonia is central to the pathogenesis of hepatic encephalopathy. This study was designed to determine the quantitative dynamics of ammonia metabolism in patients with cirrhosis and previous treatment with a transjugular intrahepatic portosystemic stent shunt (TIPSS). We studied 24 patients with cirrhosis who underwent TIPSS portography. Blood was sampled and blood flows were measured across portal drained viscera, leg, kidney, and liver, and arteriovenous differences across the spleen and the inferior and superior mesenteric veins. The highest amount of ammonia was produced by the portal drained viscera. The kidneys also produced ammonia in amounts that equaled total hepatosplanchnic area production. Skeletal muscle removed more ammonia than the cirrhotic liver. The amount of nitrogen that was taken up by muscle in the form of ammonia was less than the glutamine that was released. The portal drained viscera consumed glutamine and produced ammonia, alanine, and citrulline. Urea was released in the splenic and superior mesenteric vein, contributing to whole-body ureagenesis in these cirrhotic patients. In conclusion, hyperammonemia in metabolically stable, overnight-fasted patients with cirrhosis of the liver and a TIPSS results from portosystemic shunting and renal ammonia production. Skeletal muscle removes more ammonia from the circulation than the cirrhotic liver. Muscle releases excessive amounts of the nontoxic nitrogen carrier glutamine, which can lead to ammonia production in the portal drained viscera (PDV) and kidneys. Urinary ammonia excretion and urea synthesis appear to be the only way to remove ammonia from the body.

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“…Plasma was stored at Ϫ80°C for spectrophotometric determination of ammonia (CobasMiraS; Hoffman-LaRoche, Basel, Switzerland) and high-performance liquid chromatography measurement of amino acids at a later date. 32,33 …”

Section: Blood Sampling and Analysismentioning

confidence: 99%

Induced Hyperammonemia Alters Neuropsychology, Brain Mr Spectroscopy and Magnetization Transfer in Cirrhosis

et al. 2003

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Hyperammonemia is a universal finding after gastrointestinal hemorrhage in cirrhosis. We administered an oral amino acid solution mimicking the hemoglobin molecule to examine neuropsychological changes, brain glutamine levels, and brain magnetization transfer ratio (MTR). Forty-eight metabolically stable patients with cirrhosis and no evidence of "overt" hepatic encephalopathy (HE) were randomized to receive 75 g of amino acid solution or placebo; measurements were performed before and 4 hours after administration. Neuropsychological tests included the Trails B Test, Digit Symbol Substitution Test, memory subtest of the Randt battery, and reaction time. Plasma was collected for ammonia and amino acid measurements, and brain metabolism was studied using proton magnetic resonance (MR) spectroscopy in the first 16 randomized patients. In 7 other patients, MTR was measured. A significant increase in ammonia levels was observed in the amino acid group (amino acid group, 76 ؎ 7.3 to 121 ؎ 6.4 mol/L; placebo, 83 ؎ 3.3 to 78 ؎ 2.9 mol/L; P < .001). Neuropsychological function improved significantly in the placebo group, but no significant change in neuropsychological function was observed in the amino acid group. Brain glutamate/glutamine (Glx)/creatine (Cr) ratio increased significantly in the amino acid group. MTR decreased significantly from 30 ؎2.9 to 23 ؎ 4 (P < .01) after administration of the amino acid solution. In conclusion, an improvement in neuropsychological test results followed placebo, which was not observed in patients administered the amino acid solution. Induced hyperammonemia resulted in an increase in brain Glx/Cr ratio and a decrease in MTR, which may indicate an increase in brain water as the operative mechanism. A mmonia is believed to be central in the pathogenesis of hepatic encephalopathy (HE). [1][2][3][4] It is well known that upper gastrointestinal bleeding in cirrhotic patients produces hyperammonemia and precipitates HE. [1][2][3][4][5][6] Simulating the metabolic effects of upper gastrointestinal bleeding by oral administration of erythrocytes has been shown to induce hyperammonemia and behavioral disturbance in portacaval-shunted rats. 7 In an uncontrolled study, we showed that oral administration of an amino acid solution that is identical to the amino acid profile of hemoglobin results in deterioration in memory test results, suggesting that this may be a clinically valid model to study the pathogenesis of HE. 8 Although the data relating arterial ammonia concentration to the severity of HE are controversial, there is growing evidence that greater arterial ammonia concentrations are observed in more severe states of HE. 3,4,9 In a recent study in patients with acute liver failure, an arterial concentration of ammonia greater

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Altered glutamine metabolism in rat portal drained viscera and hindquarter during hyperammonemia

Cited by 56 publications

References 49 publications

Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS

Induced Hyperammonemia Alters Neuropsychology, Brain Mr Spectroscopy and Magnetization Transfer in Cirrhosis

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