Excretion Of Arginine Research Articles

Plasma Levels and Renal Handling of Amino Acids Contribute to Determination of Risk of Mortality or Feed of Ventilation in Patients with COVID-19.

COVID-19 infection may lead to serious complications, e.g., need for mechanical ventilation or death in some cases. A retrospective analysis of patients referred to our COVID Emergency Department, indiscriminately, was performed. A routine lab analysis measured amino acids in plasma and urine of patients. Data of surviving and deceased patients and those requiring or not requiring mechanical ventilation were compared, and logistic regression analyses have been performed. Deceased patients were older, had higher blood glucose, potassium, AST, LDH, troponin, d-dimer, hsCRP, procalcitonin, interleukin-6 levels (p < 0.05 for all). They had lower plasma serine, glycine, threonine, tryptophan levels (p < 0.01), higher tyrosine and phenylalanine levels (p < 0.05), and higher fractional excretion of arginine, methionine, and proline (p < 0.05) than survivors. In a regression model, age, severity score of COVID-pneumonia, plasma levels of threonine and phenylalanine were predictors of in-hospital mortality. There was a difference in ventilated vs. non-ventilated patients in CT-scores, glucose, and renal function (p < 0.001). Using logistic regression, CT-score, troponin, plasma level, and fractional excretion of glycine were predictors of ventilation. Plasma levels and renal excretion of certain amino acids are associated with the outcome of COVID-19 infection beside other parameters such as the CT-score or age.

The first knock-in rat model for glutaric aciduria type I allows further insights into pathophysiology in brain and periphery

Glutaric aciduria type I (GA-I, OMIM # 231670) is an inborn error of metabolism caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). Patients develop acute encephalopathic crises (AEC) with striatal injury most often triggered by catabolic stress. The pathophysiology of GA-I, particularly in brain, is still not fully understood.We generated the first knock-in rat model for GA-I by introduction of the mutation p.R411W, the rat sequence homologue of the most common Caucasian mutation p.R402W, into the Gcdh gene of Sprague Dawley rats by CRISPR/CAS9 technology. Homozygous Gcdhki/ki rats revealed a high excretor phenotype, but did not present any signs of AEC under normal diet (ND). Exposure to a high lysine diet (HLD, 4.7%) after weaning resulted in clinical and biochemical signs of AEC.A significant increase of plasmatic ammonium concentrations was found in Gcdhki/ki rats under HLD, accompanied by a decrease of urea concentrations and a concomitant increase of arginine excretion. This might indicate an inhibition of the urea cycle. Gcdhki/ki rats exposed to HLD showed highly diminished food intake resulting in severely decreased weight gain and moderate reduction of body mass index (BMI). This constellation suggests a loss of appetite. Under HLD, pipecolic acid increased significantly in cerebral and extra-cerebral liquids and tissues of Gcdhki/ki rats, but not in WT rats. It seems that Gcdhki/ki rats under HLD activate the pipecolate pathway for lysine degradation. Gcdhki/ki rat brains revealed depletion of free carnitine, microglial activation, astroglyosis, astrocytic death by apoptosis, increased vacuole numbers, impaired OXPHOS activities and neuronal damage. Under HLD, Gcdhki/ki rats showed imbalance of intra- and extracellular creatine concentrations and indirect signs of an intracerebral ammonium accumulation.We successfully created the first rat model for GA-I. Characterization of this Gcdhki/ki strain confirmed that it is a suitable model not only for the study of pathophysiological processes, but also for the development of new therapeutic interventions. We further brought up interesting new insights into the pathophysiology of GA-I in brain and periphery.

Метаболизм L-аргинина у гипертензивных крыс при угнетении аргиназы L-норвалином

The hypotensive effect of arginase inhibition in the experiment [1] can be realized in two ways: by relaxation of blood vessels by an increase in the concentration of nitric oxide (NO) and/or a decrease in the amount of circulating fluid. The first effect occurs with an increase in the availability of the substrate of NO synthase (NOS) - arginine (ARG). The second - with an increase in diuresis. To clarify the ways in which arginase affects the regulation of blood pressure (BP) we have analyzed the metabolic characteristics of the amino acid L-arginine in hyper- and normotonic rats during inhibition of arginase activity by the administration of its inhibitor L-norvaline. The concentration of arginine and its metabolite ornithine in blood, urine, and in the homogenate of kidney tissue was measured using high-performance liquid chromatography with the separation on a reversed-phase sorbent and with a fluorescence detection. Norvaline was injected intraperitoneally (ip) once a day at a dose of 30 mg/kg for 7 days. In experiments under the influence of norvaline, no significant increase in the concentration of amino acids in the blood plasma was found either in hypertensive rats (ISIAH strain) or in normotensive control (WAG strain). The concentration of arginine in the urine of ISIAH animals treated with norvaline was found doubled, while in WAG rats it did not change. The daily excretion of arginine under norvaline increased in normotonics only slightly, and in hypertensive rats it increased almost threefold. At the same time, norvaline increased diuresis only in hypertensive animals. Under the influence of norvaline, the content of arginine per 1 g of kidney weight increased almost twofold in hypertensive rats, while in normotensive rats it did not change. The studies performed allow us to conclude, that inhibition of arginase by norvaline had a stronger hypotensive effect in hypertensive rats than in normotensive rats. At the same time, the hypotensive effect of norvaline in normotonic rats can be provided by the nitric oxide system, whereas in hypertensive rats this function is taken over by diuresis.

Arginine as a Significant Regulator of Supersaturation in Calcium Oxalate Lithiasis: the Physiological Evidence

Background: At present, the possible effect of arginine as a natural regulator of calcium oxalate (CaOX) supersaturation and crystallization in human urine has been analyzed. Methods: Two types of experiments have been discussed: clinical laboratory analysis on the urine excretion of arginine (Arg) in patients with CaOX lithiasis and detailed measurements of the kinetics of the dissolution of CaOX calculi in artificial urine, containing various concentrations of Arg. Results: A detailed analysis showed that 80% of stone formers (SFs) eliminated pathological values: 30% of patients had lower plasma levels compared to controls and about 50% of SFs showed higher concentration. Urine concentrations in these two groups were not reported. Conclusions: The in vitro analytical measurements demonstrate even a possibility to dissolve CaOX stones in human urine, in which increased concentration of Arg has been established. Discussions have arisen to use increased concentration of Arg in urine both as a solubilizator of CaOX stones in humans and on the purpose of a prolonged metaphylactic treatment. World J Nephrol Urol. 2015;4(1):173-177 doi: http://dx.doi.org/10.14740/wjnu199w

Differential cystine and dibasic amino acid handling after loss of function of the amino acid transporter b0,+AT (Slc7a9) in mice

Cystinuria is an autosomal recessive disease caused by mutations in SLC3A1 (rBAT) and SLC7A9 (b(0,+)AT). Gene targeting of the catalytic subunit (Slc7a9) in mice leads to excessive excretion of cystine, lysine, arginine, and ornithine. Here, we studied this non-type I cystinuria mouse model using gene expression analysis, Western blotting, clearance, and brush-border membrane vesicle (BBMV) uptake experiments to further characterize the renal and intestinal consequences of losing Slc7a9 function. The electrogenic and BBMV flux studies in the intestine suggested that arginine and ornithine are transported via other routes apart from system b(0,+). No remarkable gene expression changes were observed in other amino acid transporters and the peptide transporters in the intestine and kidney. Furthermore, the glomerular filtration rate (GFR) was reduced by 30% in knockout animals compared with wild-type animals. The fractional excretion of arginine was increased as expected (∼100%), but fractional excretions of lysine (∼35%), ornithine (∼16%), and cystine (∼11%) were less affected. Loss of function of b(0,+)AT reduced transport of cystine and arginine in renal BBMVs and completely abolished the exchanger activity of dibasic amino acids with neutral amino acids. In conclusion, loss of Slc7a9 function decreases the GFR and increases the excretion of several amino acids to a lesser extent than expected with no clear regulation at the mRNA and protein level of alternative transporters and no increased renal epithelial uptake. These observations indicate that transporters located in distal segments of the kidney and/or metabolic pathways may partially compensate for Slc7a9 loss of function.

Urea synthesis and excretion in Aedes aegypti mosquitoes are regulated by a unique cross-talk mechanism.

Aedes aegypti mosquitoes do not have a typical functional urea cycle for ammonia disposal such as the one present in most terrestrial vertebrates. However, they can synthesize urea by two different pathways, argininolysis and uricolysis. We investigated how formation of urea by these two pathways is regulated in females of A. aegypti. The expression of arginase (AR) and urate oxidase (UO), either separately or simultaneously (ARUO) was silenced by RNAi. The amounts of several nitrogen compounds were quantified in excreta using mass spectrometry. Injection of mosquitoes with either dsRNA-AR or dsRNA-UO significantly decreased the expressions of AR or UO in the fat body (FB) and Malpighian tubules (MT). Surprisingly, the expression level of AR was increased when UO was silenced and vice versa, suggesting a cross-talk regulation between pathways. In agreement with these data, the amount of urea measured 48 h after blood feeding remained unchanged in those mosquitoes injected with dsRNA-AR or dsRNA-UO. However, allantoin significantly increased in the excreta of dsRNA-AR-injected females. The knockdown of ARUO mainly led to a decrease in urea and allantoin excretion, and an increase in arginine excretion. In addition, dsRNA-AR-injected mosquitoes treated with a specific nitric oxide synthase inhibitor showed an increase of UO expression in FB and MT and a significant increase in the excretion of nitrogen compounds. Interestingly, both a temporary delay in the digestion of a blood meal and a significant reduction in the expression of several genes involved in ammonia metabolism were observed in dsRNA-AR, UO or ARUO-injected females. These results reveal that urea synthesis and excretion in A. aegypti are tightly regulated by a unique cross-talk signaling mechanism. This process allows blood-fed mosquitoes to regulate the synthesis and/or excretion of nitrogen waste products, and avoid toxic effects that could result from a lethal concentration of ammonia in their tissues.

Endogenous Regulators of NO Bioavailability in Rats with Acute Renal Failure

We studied the impact of acute glycerol-induced renal failure on blood levels and daily urinary excretion of arginine, monomethylarginine, and asymmetric and symmetric dimethylarginine. Acute renal failure was accompanied by enhanced daily excretion of asymmetric and symmetric dimethylarginine, increased plasma level of symmetric dimethylarginine, and decreased plasma level of arginine. Reabsorption of arginine and its methylated analogues decreased, thus compensating for reduced glomerular filtration rate. These data attest to increased production of dimethylarginines during acute renal failure. These changes can decrease NO bioavailability.

Urinary urea and arginine excretion in chickens infused with urea, arginine and lysine.

Urinary urea and arginine excretion in chickens infused with urea, arginine and lysine.

Arginine-responsive asymptomatic hyperammonemia in the premature infant

We found that more than 50% of premature infants have elevated plasma ammonium levels during the first 2 months of life. Ammonium levels were twice normal and were unaccompanied by clinical symptoms of vomiting or lethargy. Ten of these infants were given supplements of arginine (1 to 2 mmol/kg/day PO) for 1 to 2 weeks preceded and followed by control periods. In each infant, plasma ammonium levels fell significantly within 2 days of start of arginine supplementation, and increased once arginine was discontinued. We studied 59 additional premature infants, of whom 26 had normal ammonium levels and 33 were hyperammonemic. Plasma arginine and ornithine levels were significantly lower in the hyperammonemic group, but there was no difference in urinary excretion of arginine or ornithine between groups. Half of the hyperammonemic infants received arginine supplementation between 2 and 8 weeks of age. Plasma ammonium levels in the arginine group was 33 + 1 mumol/L., compared to 45 + 2 mumol/L in the untreated group. Follow-up at 18 months of age showed similar IQ scores in all groups, suggesting that significant neurologic deficits do not result from this transient metabolic defect. The mechanism of the hyperammonemia is unclear.

Renal tubule reabsorption of amino acids after lysine loading of cystinuric dogs

The renal reabsorption of cystine, lysine, arginine, and ornithine as well as other amino acids has been determined before and after lysine infusion in four normal and five cystinuric dogs. The large filtered load of lysine caused defective reabsorption of cystine in three of four normals and augmented the basal defect in all of the cystinuric dogs. Two of the cystinuric dogs responded with cystine clearances in excess of the glomerular filtration rate. The magnitude of increase of the reabsorptive defect for cystine observed after lysine infusion into the cystinuric dogs was unrelated to the extent of the basal defect. Two of the normal dogs and four of the five cystinuric dogs demonstrated defective arginine reabsorption after lysine loading, one of the cystinuric dogs having greater arginine excretion than the filtered load. Although normal dogs showed a moderate inability to reabsorb the large filtered load of lysine, three of the cystinuric dogs exhibited a −60 to −70% reabsorption, consistent with lysine secretion. Both normal and cystinuric dogs showed defective glycine absorption after lysine loading, but only cystinuric dogs showed variable defects in threonine, serine, histidine, methionine, and tyrosine when the basic amino acid was infused. Each cystinuric dog responded to lysine infusion in a different way, and the overall pattern of response differed from the normal, with evidence of induced secretion of cystine, lysine, and arginine in the affected dogs.

Effect of arginine, urea and .ALPHA.-aminoisobutyric acid on the urinary nitrogen excretion in adult chicks.

The relations among urinary excretion of dietary urea, metabolic one derived from arginine degradation and arginine and the effects of α-aminoisobutyric acid (AIB) on these relationships were studied using adult chicks with an artificial anus. In chicks fed the basal diet containing a normal amount of arginine, the urinary excretion of arginine was negligible. On the day when chicks were fed the excess arginine (2%) diet, urinary excretion of urea and arginine was highly increased. The excess feeding of arginine for the AIB-treated chicks further increased the excretion of urinary arginine and undetermined nitrogen, but the urea excretion was significantly lower than that of the excess arginine chicks. In chicks fed the 1% urea diet with or without AIB, a significantly higher excretion of urea and undetermined nitrogen was observed than those in the control chicks.These results showed that AIB has the following functions for arginine and urea excretion in chicks. (1) AIB supplemented to the excess arginine diet decreases the urea formation through suppression for kidney arginase activity. (2) AIB promotes the urinary excretion of excess dietary arginine by means of a depression of renal reabsorption of this amino acid. (3) When AIB is added to the 1% urea diet, this material gives no effect on urinary excretion of urea.

Urinary pyrimidine excretion in arginase deficiency.

A high-performance liquid-chromatographic method was used to separate and identify uracil, uridine, pseudouridine and orotic acid after preliminary extraction in two patients (McKusick 20780). Urinary uracil excretion was 10-35 times normal in both patients with arginase deficiency. Uridine and orotic acid, not normally detected, were excreted in large amounts and were directly influenced by protein intake. Their excretions were correlated with urinary arginine excretion. Urinary uracil levels remained consistently high and showed minimal variations with increased protein intake or urinary arginine levels. The measurement of urinary pyrimidines appears to be useful for the detection, differential diagnosis and dietary monitoring of patients with urea cycle disorders. The data presented extends this observation to include patients with arginase deficiency.

Hyperlysinemia with saccharopinuria due to combined lysine-ketoglutarate reductase and saccharopine dehydrogenase deficiencies presenting as cystinuria

A 7-year-old boy with speech delay, hyperactive behavior, and minor neurologic abnormalities had been found in the past to have "intermittent cystinuria." A more detailed investigation revealed hyperlysinemia and hyperlysinuria, with lesser increases in urinary excretion of arginine and cystine. The plasma and urine abnormalities increased on a diet of 3 gm of protein/kg body weight/day. Saccharopine, a normal metabolite of lysine not found in the body fluids of normal people, was present in plasma, cerebrospinal fluid, and urine of the patient. Lysine-ketoglutarate reductase and saccharopine dehydrogenase activities were not detectable in extracts of cultured skin fibroblasts. Re-examination of the urine of previously studied cases of this double enzyme deficiency suggests that saccharopinuria of variable degree is the rule and not the exception.

Influence of Dietary Potassium on Lysine Metabolism in the Chick

High levels of dietary cations have been reported to spare the arginine requirement of chicks fed a diet containing excess lysine. The present studies were conducted to determine the nature of this effect, using potassium as the variable cation. The inclusion of 1.8% potassium in a high lysine diet improved growth but did not affect consistently the efficiency of feed utilization, nor did it have a significant effect on arginine metabolism as measured by renal arginase activity, urea excretion or arginine excretion. Lysine catabolism was markedly increased, however. Chicks fed the potassium supplemented diet converted approximately 23% of an oral loading dose of 14C lysine to respiratory 14CO2 over a 6-hour period, in contrast to approximately 9% of the dose in chicks fed the unsupplemented diet containing 0.4% potassium. The activity of hepatic lysine-alpha-ketoglutarate reductase, an initial enzyme in the catabolism of lysine, was increased in response to potassium or arginine supplementation. It is proposed that high levels of potassium or other cations may improve the growth of chicks fed diets containing excess lysine by increasing lysine catabolism. The effect on growth may be mediated primarily by increasing food intake and to a lesser extent by alleviation of the other metabolic manifestation of the lysine-arginine antagonism.

The function of the anal vesicle in respiration and excretion in the braconid wasp, Microplitis croceipes

An investigation into the function of the anal vesicle of the larval braconid wasp, Microplitis croceipes demonstrated that the anal vesicle has no significant rôle in respiration. The experimental evidence also suggested that these larvae are falculatively anerobic. The anal vesicle does appear to function in the excretion of ammonia, HCO 3 − and possibly the excretion of arginine and alanine. Although the anal vesicle does function in the absorption of salts and is permeable to water it does not function as an effective osmoregulator.

Involvement of Food Intake in the Lysine-Arginine Antagonism in Chicks

Studies were conducted to evaluate the involvement of food intake in the lysine-arginine antagonism. Diets were formulated to compensate for the metabolic consequences of excess dietary lysine; induction of renal arginase activity, depression of heptic glycine transamidinase, and urinary losses of arginine. This was accomplished by inclusion of creatine in the basal diet, use of a moderate excess of lysine that did not increase urinary arginine excretion, and addition of the arginase depressors, alpha-aminoisobutyric acid (AIB) and L-threonine, to diets containing excess lysine. When chicks were fed diets containing excess lysine ad libitum, growth and efficiency of arginine retention were reduced. Supplementation of the diets with AIB and threonine markedly reduced the growth depression and restored efficiency of arginine utilization. When chicks were force-fed the diet containing excess lysine, growth was depressed, and body composition was altered. Inclusion of AIB and threonine in the diet containing excess lysine resulted in growth and body composition equivalent to levels of force-fed controls. In a second experiment the basal diet and basal supplemented with AIB and threonine were pair-fed to lysine-supplemented diets containing AIB and threonine. Body weight gains and body composition of all groups were similar. In other experiments, food intake increased within 24 hours (P less than 0.05) and probably within 12 hours (P less than 0.10) after removal of excess lysine from the diet. It is concluded that a portion of the lysine-arginine antagonism is due to a primary effect of lysine on regulation of food intake.

Synthesis of metabolism-resistant substrates for the transport system for cationic amino acids; their stimulation of the release of insulin and glucagon, and of the urinary loss of amino acids related to cystinuria

Several amino acids have been synthesized as model transport substrates building on the piperidine and cyclohexane rings. Only when the distal N atom is part of an unambiguously cationic structure are these compounds transported predominantly by the cationic amino acid system. These amino acids in labeled form are excreted rather slowly in unmodified state, very little 14CO 2 being released. Those which are unambiguously cationic (including also homoarginine) led to a greatly increased excretion of arginine, lysine, ornithine and citrulline. Those which might be expected to act as lysine analogs had little effect on the excretion of the basic amino acids, although the excretion of citrulline and the sum of glutamine plus asparagine was accelerated. Certain of the analogs intensified the excretion of citrulline in dissociation from effects on resorption of the basic amino acids, also in dissociation from effects on cystine resorption. These results indicate citrulline resorption does not occur principally by the same agency serving for the basic amino acids, nor by the agency serving for cystine, despite the observed interactions for resorption. The injection of either of three transport analogs for arginine into the rat leads to early increases in the circulating levels of immunologically reactive insulin and glucagon.

The effect of a single oral dose of lysine or arginine on the excretion of free amino acids by the starved laying hen.

Synopsis The excretion of free amino acids by laying hens was measured during the period 0 to 5 h after the oral administration of 0.1 g lysine HCl or 0.1 g arginine HCl. Lysine administration resulted in a significant increase in the excretion (μmoles) of arginine (6.8 to 25.9), ornithine (5.8 to 39.3) and tyrosine (3.2 to 5.1) while arginine administration resulted in a significant increase in the excretion (μmoles) of lysine (6.8 to 93.0), ornithine (4.1 to 71.9), tyrosine (2.3 to 5.5), histidine (10.8 to 88.3), threonine (16.8 to 33.3), serine (22.7 to 34.0) and glycine (17.3 to 56.3). The effect of arginine administration on lysine excretion was significantly greater than that of lysine on arginine excretion (P < 0.01). In the lysine experiment the overall pattern of changes in the hourly excretion rate of the affected amino acids was the same as that of administered lysine. The maximum hourly excretion rate of administered arginine occurred one hour earlier than the maximum for the amino acids affec...

Phenotypes and genotypes in cystinuria.

SummaryQuantitative data are presented on the cystine, lysine and arginine excretion in patients with cystine stone formation and in their relatives in twenty‐five families.It is suggested that two distinct abnormal phenotypes can be differentiated. Phenotype 1 is characterized by a greatly increased excretion of cystine, lysine, arginine and ornithine. Because of the high cystine concentration in the urine cystine stone formation is fairly frequent. Phenotype 2 is characterized by a moderately increased cystine and lysine excretion, whilst the arginine and ornithine excretion is normal or only slightly raised. In this phenotype stone formation occurs only very rarely.The families fall into two groups with regard to the occurrence of phenotype 2. In one group of families phenotype 2 is not found. In these families the segregation of phenotype 1 is consistent with the hypothesis that it represents the homozygote for a rare recessive gene. This type has been called ‘recessive cystinuria’. In the other group of families phenotype 2 is frequently found. Most of the propositi are of phenotype 1. The distribution of the two abnormal phenotypes in such families is consistent with the hypothesis that phenotype 1 represents the homozygote, and phenotype 2 the heterozygote, of a rare abnormal gene. Two families have propositi of phenotype 2 who, in this instance, happen to have formed stones. These families contain no individuals of phenotype 1. Phenotype 2 again segregates in a manner which suggests that it represents the heterozygote of an abnormal gene. In all families in which phenotype 2 is found the condition has been called ‘incompletely recessive cystinuria’.

The pattern of amino-acid excretion in cystinuria.

Summary1. Cystine, lysine and arginine determinations have been carried out on urines from twenty‐eight cystinuric patients and 121 of their relatives. Urines from 250 unselected individuals have also been examined. The cystine was determined polarographically and the lysine and arginine microbiologically. The urines have also been examined for amino‐acids by two‐dimensional paper chromatography and by paper ionophoresis at pH 11‐5.2. There is a high positive correlation between the cystine and lysine contents over the whole range which extends in the case of cystine from 20 up to 800 mg/g. of creatinine and of lysine from less than 25 up to 1800 mg./g. of creatinine.3. The arginine content of the urine remains at normal (&lt; 25 mg./g. creatinine) or near normal values until the cystine content reaches about 250 mg./g. creatinine and the lysine reaches about 550 mg./g. creatinine. Above these values large increases in arginine excretion up to 1800 mg./g. creatinine may be observed.4. It is suggested that there is normally a renal tubular resorptive mechanism which at one stage is common to and specific for cystine, lysine, arginine and ornithine, and that this mechanism is defective in cystinuria. When the process fails completely or nearly completely the four amino‐acids appear in the urine in large amounts. When it is only partially deranged, arginine and possibly ornithine are resorbed preferentially to cystine and lysine.The authors would like to thank Miss Barbara Warland and Miss Robin Worthington for considerable assistance with the family case work, and Mrs Ruth Jacobs and Mr B. Cohen for much help in the chemical determinations.Miss E. B. Robson was in receipt of a research grant from the Medical Research Council.The polarograph used in this work was purchased with a grant from the Central Research Fund of the University of London.