Ornithine Levels Research Articles

Nutrition of Atlantic Salmon ( Salmo salar): The Requirement and Metabolism of Arginine

This experiment was conducted to determine the dietary arginine requirement of medium sized Atlantic salmon (383 ± 62 g) given a high energy diet (26.1 KJ/g). Zein was used as major protein source in the experimental diets supplemented with synthetic amino acids resembling the amino acid pattern of fish meal, with the exception of arginine. Arginine content was 11.3 (2.7), 16.8 (4.0), 20.2 (4.8), 26.0 (6.2), and 28.6 (6.8) g/kg dietary dry matter (% of dietary protein). Expressed in terms of digestible energy the arginine content was 0.53, 0.78, 0.94, 1.21, and 1.33 g/MJ. Protein content on dry weight was 42% in all diets. Weight gain and protein efficiency parameters were together with increasing levels of urea and ornithine in plasma and free arginine in muscle and plasma used to indicate the requirement of arginine. The growth and protein retention obtained indicated that Atlantic salmon has a requirement of arginine of 21.2–21.6 g/kg dietary dry weight (5.0–5.1% of the protein) or 1.0 g/MJ digestible energy. The metabolic parameters indicated a requirement of 20.2 g/kg dietary dry weight (4.8% of the protein) or 0.94 g/MJ. Increased dietary levels of arginine seemed to interact with the tissue free concentrations of several indispensable amino acids.

Nitric Oxide Metabolism in Wounds

Arginine can be metabolized in wounds to nitric oxide and citrulline by nitric oxide synthase or to urea and ornithine by arginase. We investigated the expression of these arginine metabolic pathways over a 3-week period. Groups of 8–10 male Balb/C mice underwent a dorsal skin incision and subcutaneous polyvinyl alcohol sponge implantation. The animals were sacrificed at various times, and sponges were harvested to obtain wound fluid and wound cells. Cells or whole sponges were incubated withl-[2,3-3H]arginine, with or withoutNG-l-monomethyl-arginine (NMMA, a competitive inhibitor of nitric oxide synthase). Nitrite and nitrate (both stable end products of nitric oxide metabolism) and amino acids were measured in wound fluid and wound cell culture supernatants. Increasing concentrations of nitrite and nitrate were noted in wound fluid and in whole sponge cultures until the second week postwounding, indicating sustained wound nitric oxide synthesis. In wound fluid arginine levels were undetectable at all times, suggesting sustained utilization. Wound fluid citrulline levels showed an early peak and then a gradual decrease, suggesting that recycling for continued nitric oxide production may occur. Wound fluid ornithine levels increased until Day 10 and remained elevated, indicative of continued arginase activity.In vitroproduction of nitrite/nitrate and citrulline by cells and whole sponges was inhibitable by NMMA. Inducible nitric oxide synthase expression was confirmed by immunoblotting, while immunohistochemistry demonstrated that macrophages are a major source of wound nitric oxide. The data show that nitric oxide synthesis occurs for prolonged periods after injury and macrophages appear to be a major cellular source.

Tumour effect on arginine/ornithine metabolic relationship in hypertrophic mouse kidney.

The presence of a tumour significantly changes nitrogen metabolism, including that of amino acids and polyamines, in host animals. In this study, we examine whether developing tumours affect the metabolic relationship of arginine and ornithine, precursors of polyamines, in the testosterone-induced hypertrophic mouse kidney model. Androgen-induced changes in the activity of enzymes involved with ornithine biosynthesis (arginase), its consumption (ornithine aminotransferase, OAT and ornithine decarboxylase, ODC) and the hypertrophy of host mouse kidney were not affected by the presence of an ascitic tumour (EAC) and only slightly by a mammary carcinoma (MaCa). The HPLC determined renal level of arginine and ornithine showed a striking homeostasis and was disturbed neither by testosterone nor EAC. The effect of MaCa and testosterone on the levels of both amino acids, although significant, was not very pronounced. Developing tumours, especially ascitic, altered the renal activity of OAT and ODC, but not of arginase, in testosterone-untreated mice. All examined tumours, EAC, L 1210 and MaCa actively metabolized arginine and ornithine. the tumour content of arginine which coincided with the activity of arginase, resulted in a marked increase of the ornithine/arginine ratio in tumours, when compared with kidneys. These results indicate that the androgen-induced anabolic response in mouse kidney is preserved, in spite of tumour requirements for essential metabolites.

A profile of amino acid and catecholamine levels during endotoxin-induced acute lung injury in sheep: Searching for potential markers of the acute respiratory distress syndrome

The identification of plasma markers of the course of the acute respiratory distress syndrome (ARDS) is needed to improve its treatment and to further advance the development of new therapeutic agents. The status of markers of lung injury in ARDS is reviewed and some new potential markers are proposed. This study focused on plasma amino acids, related amino compounds, and catecholamine levels during the acute phase of endotoxin-induced lung injury in 8 sheep characterized by the onset of pulmonary edema caused by increased microvascular permeability. A number of significant changes from baseline values were found. During the sixth hour of a 12-hour period of endotoxin infusion, norepinephrine, epinephrine, and alanine levels increased whereas the isoleucine level decreased. During the sixth hour of the immediate postendotoxin period, the taurine level increased while the levels of arginine, citrulline, glycine, isoleucine, methionine, ornithine, serine, threonine, and tryptophan decreased. These findings are compared with prior studies in human subjects detailing the amino acid profile characteristic of advanced sepsis. We conclude that the present profile of catecholamine and amino acid changes during endotoxemia in sheep deserves further study in human subjects to determine its significance as a marker of the early stage of ARDS.

Arginase, Arginine Decarboxylase, Ornithine Decarboxylase, and Polyamines in Tomato Ovaries (Changes in Unpollinated Ovaries and Parthenocarpic Fruits Induced by Auxin or Gibberellin).

Arginase (EC 3.5.3.1) activity has been found in the ovaries and Young fruits of tomato (Lycopersicon esculentum Mill. cv Rutgers).Changes in arginase, arginine decarboxylase (EC 4.1.1.19), and ornithine decarboxylase activity (EC 4.1.1.17) and levels of free and conjugated putrescine, spermidine, and spermine were determined in unpollinated ovaries and in parthenocarpic fruits during the early stages of development induced by 2,4-dichlorophenoxyacetic acid (2,4-D) or gibberellic acid (GA3). Levels of arginase, free spermine, and conjugates of the three polyamines were constant in unpollinated ovaries and characteristic of a presenescent step. A marked decrease in arginase activity, free spermine, and polyamine conjugates was associated with the initiation of fruit growth due to cell division, and when cell expansion was initiated, the absence of arginase indicated a redirection of nitrogen metabolism to the synthesis of arginine. A transient increase in arginine decarboxylase and ornithine decarboxylase was also observed in 2,4-D-induced fruits. In general, 2,4-D treatments produced faster changes than GA3, and without treatment, unpollinated ovaries developed only slightly and senescence was hardly visible. Sensitivity to 2,4-D and GA3 treatment remained for at least 2 weeks postanthesis.

Plasma amino acids in four models of experimental liver injury in rats

We studied the plasma amino acid profiles in four models of hepatic injury in rats. In partially hepatectomized rats (65% of liver was removed) we observed significant increase of aromatic amino acids (AAA; i.e. tyrosine and phenylalanine), taurine, aspartate, threonine, serine, asparagine, methionine, ornithine and histidine. Branched-chain amino acids (BCAA; i.e. valine, leucine and isoleucine) concentrations were unchanged. In ischemic and carbon tetrachloride acute liver damage we observed extreme elevation of most of amino acids (BCAA included) and very low concentration of arginine. In carbon tetrachloride induced liver cirrhosis we observed increased levels of AAA, aspartate, asparagine, methionine, ornithine and histidine and decrease of BCAA, threonine and cystine. BCAA/AAA ratio decreased significantly in partially hepatectomized and cirrhotic rats and was unchanged in ischemic and acute carbon tetrachloride liver damage. We conclude that a high increase of most of amino acids is characteristic of fulminant hepatic necrosis; decreased BCAA/AAA ratio is characteristic of liver cirrhosis; and decrease of BCAA/AAA ratio may not be used as an indicator of the severity of hepatic parenchymal damage.

Early plasma amino acid pool alterations in patients with military gunshot/missile wounds.

Plasma amino acid profiles in patients during the early period (first 18 hours) following military gunshot/missile wounds were investigated. Patients (n = 29) were casualties from the war in the former Yugoslavia with injury severity scores ranging from 4 to 18. They were divided into three groups: soft tissue (muscle) damage, wounds with fractures, and vital structures injured. Controls were normal blood donors (n = 17). Free amino acids were analyzed in venous plasma. Increased concentrations of phenylalanine and glutamine associated with increased molar phenylalanine/tyrosine ratio in plasma indicated increased net protein catabolism in the peripheral tissues, regardless of the type of injured tissues. Decreased plasma arginine, ornithine and citrulline levels, accompanied with increased molar glutamine/valine ratio, suggested disturbance in urea cycle activity, although urea level was not altered. We concluded that early changes in plasma amino acid pool characteristics after wounds were of systemic origin, not related to the type of injured tissues.

Growth retardation in children receiving long-term total parenteral nutrition: effects of ornithine alpha-ketoglutarate.

The authors evaluated the effect of supplementing parenteral nutrition (PN) with ornithine‐α‐ketoglutarate (OAK) on linear growth and biochemical parameters in a small group of prepubertal children requiring long‐term PN because of short bowel syndrome. Six study patients (5 male, 1 female) were selected from a group of 62 children receiving long‐term PN followed at a pediatric hospital in Paris, France. All of the patients had demonstrated significant growth retardation at entry (1 to 4 standard deviations below expected 50th percentile for height), and were prepubertal as evidenced by Stage I Tanner scores and prepubertal blood levels of testosterone, estradiol, and insulin‐like growth factor‐I (IGF‐1). The patients were determined to be normally nourished, as they received adequate doses of energy and nitrogen in PN prior to the study and demonstrated appropriate weight‐for‐height ratios, skinfold measurements and normal serum protein concentrations. The subjects had received constant dietary energy and nitrogen intakes for at least 8 months prior to study (primarily via PN).The usual PN prescription was continued during the entire 10 month experimental period. PN provided mean (± SD) energy and nitrogen doses of 242 ± 33 kJ/kg/d (~ 50 kcal/kg/d) and 324 ± 87 mg N/kg/d (~ 2.0 g protein/kg/ day) respectively, during each of two consecutive 5 month study periods. During the first 5 months of study, 15 g OAK was added to the daily PN solution bag immediately before the weekly home delivery of PN. During the second 5 months of study (control period), no OAK was added to the PN solution. Linear growth (height) velocities, body weight and plasma concentrations of amino acids, transferrin, retinol‐binding protein, prealbumin, albumin, total IGF‐1, testosterone and estradiol were measured monthly.During the 5‐month period of OAK supplementation of PN, linear growth velocity significantly increased to a median of 156% (range 126 to 186%) of baseline in five of the six subjects. During the subsequent 5 month control period (when OAK was not administered), three of these subjects demonstrated decreased height velocity (60%, 64% and 94% of baseline). The remaining two OAK responders evidently entered puberty during the post‐OAK control period, as their height velocities accelerated to 219% and 238% of baseline, their Tanner scores increased to stage 11, and their plasma IGF‐I and testosterone levels markedly rose. Overall, during OAK treatment, height velocity increased from a median of 3.80 cm/y to 6.45 cm/y (p <.05) and decreased to a median of 3.65 cm/y in the subsequent OAK‐free period (p <.05). Plasma IGF‐I concentrations rose significantly from a median of 200 U/L to 945 U/ L during OAK (p <.05); IGF‐I levels fell after OAK in 3 of the 5 responders, but continued to rise in the two patients entering puberty.The change in IGF‐I level were positively correlated with the change in height velocity. No change in circulating proteins was observed. Although testosterone levels tended to rise in the 5 males studied during the OAK+ and OAK‐periods, levels remained prepubertal and no clear effect of OAK was discerned. No increase in plasma ornithine or other amino acid levels occurred during OAK, with the exception of plasma glutamine + glutamate, which rose by ~ 15% (from a mean of 621 to 715 mmol/L). The one subject who exhibited no increase in height response or IGF‐I levels during OAK had hepatic cirrhosis, and died of liver failure a few months after completion of study.

Protein metabolism in cirrhotic rats: effect of dietary restriction.

This paper evaluates the role of decreased food intake in protein metabolism in cirrhotic animals by comparing the changes with those observed in pair-fed controls. Rats were injected with [14C]leucine and then divided into 3 groups. Liver cirrhosis was induced in 1 group of rats by repeated intragastric administration of CCl4 in oil over a period of 8 weeks. Control animals were gavaged with oil and either pair-fed or given access to food ad libitum. Three days after the last intragastric dose, rats were injected with [3H]leucine and sacrificed 20 min later. The daily food intake of CCl4 rats declined to 60% of that of the ad libitum controls. Both the pair-fed control group and the cirrhotic group showed decreased body weight gain, and a decline in muscle and intestinal protein degradation. The pair-fed and the cirrhotic groups differed from one another in many metabolic abnormalities. In the cirrhotic group we observed higher levels of serine, asparagine, proline, methionine, tyrosine, phenylalanine, ornithine and histidine, and lower levels of valine, isoleucine and arginine. In these animals higher relative (per kilogram body weight) weights and protein content of the spleen, kidneys and heart were observed. Additionally higher liver weight despite lower protein concentration, as well as lower liver protein degradation and lower skeletal muscle protein synthesis were found.

Elevated ornithine decarboxylase activity and polyamine levels during early development in the brine shrimp Artemia franciscana

AbstractRehydrated Artemia cysts were assayed for ornithine decarboxylase (ODC) activity and levels of putrescine, spermidine, and spermine during pre‐emergent development, emergence and hatching. Low but detectable ODC activity levels increased significantly within 2 hr, suggesting de novo synthesis of ODC protein and representing one of the earliest enzymatic biochemical markers in post dormancy development. ODC activity increased 100‐fold during preemergent development (occurring in the absence of an increase in tissue polyamine content). This increase in enzyme activity occurs in the relative absence of DNA synthesis but may be related to an enhanced polyamine synthetic capacity necessary for other physiological processes such as early transcriptional and translational activity. A second, higher ODC activity peak (correlated with a significant increase in polyamines) prior to hatching may be related to DNA synthesis and other biochemical processes associated with hatching of stage 1 nauplii and is correlated with increasing ecdysteroid titres reported previously. Putrescine and spermidine levels were significantly higher than spermine levels (2.5, 2.65, and 0.13 μmoles/g dry weight) at the onset of rehydration. High endogenous polyamines levels in encysted embryos are most likely available for use in metabolic processes associated with early differentiation. Polyamine levels increased significantly just prior to emergence and continued increasing throughout hatching. Spermidine to spermine ratios (>18) should reflect high rates of overall biosynthetic processes throughout preemergence, emergence, and hatching. © Wiley‐Liss, Inc.

Free amino acid levels in serum and small intestine during the post-natal development of normal and sparse-fur mutant mice

Ornithine transcarbamylase (OTC) is a mitochondrial enzyme which catalyzes the conversion of ornithine into citrulline. In sparse-fur (spf) mutant mice, in which both hepatic and small intestinal OTC are deficient, only small amounts of citrulline are released into the blood. To evaluate the fate of ornithine as well as the levels of substrates and products of these metabolic pathways in normal and OTC-deficient mice, we measured the concentration of free amino acids in small intestinal mucosa and serum during post-natal development. In control animals, ornithine, alanine and citrulline concentrations in intestinal mucosa increased as a function of age, while glutamine, leucine, valine and methionine levels decreased around the weaning period. In contrast, the serum concentration of these amino acids remained fairly constant. Major changes were observed in spf mice: the ornithine level remained low in intestinal tissue, citrulline concentration was significantly decreased in both intestinal tissue and blood, circulating levels of arginine and essential amino acids were drastically reduced in sucklings while plasma glutamine increased after weaning. These data confirm the validity of spf mice as a model for the study of nutritional requirements in OTC-deficient animals.

Proline metabolic pathways in calli fromLycopersicon esculentum andL. pennellii under salt stress

The enzyme activities of the proline metabolic pathways were determined in control and satt-treated (140 M NaCl) calli derived from cotyledons of the domestic saltsensitive tomatoLycopersicon esculentum and the wild salt-tolerantL. pennellii. Glutamate, glutamine, asparagine, and aspartate levels increased in both genotypes under salt stress, while proline accumulation increased markedly only in the salt sensitive tomato. Activity of glutamine synthetase (GS) decreased in the salt-treated calli of the domestic species, whereas both NADH- and NADPH-glutamate synthase (GOGAT) activities increased; GS and NADPH-GOGAT decreased together in the salinized calli of the wild species. Decreasing ornithine levels were found due to NaCl in both tomato populations, while ornithine transaminase (OT) decreased in the wild type only. Increasing NADPH-Δ-pyrroline-5-carboxylate reductase (P5CR) and decreasing proline oxidase (Pro oxi) occurred in the salinized calli of the wild type. Conversely, Pro oxi and proline dehydrogenase (Pro dH) decreased highly in the salinized calli of the domestic population, while no significant changes in P5CR were found.

Hyperammonemia in Marasmic children.

The amino acids citrulline, ornithine and arginine, total serum proteins, serum enzymes glutamic oxalacetic and glutamic pyruvic transaminases, blood ammonia and urea were measured in 20 marasmic children with manifest psychomotor changes, before and after nutritional rehabilitation, as well as in 10 healthy age-matched children. Serum protein levels were significantly low and plasma ammonia concentrations were significantly elevated in marasmic children before refeeding (177 +/- 66 micrograms/dl). Plasma ammonia concentrations decreased significantly after 4 weeks of nutritional rehabilitation (38 +/- 18 micrograms/dl). The levels of blood urea, serum enzymes, citrulline arginine, and ornithine did not differ among the study groups. These findings denote that hyperammonemia in marasmic children is neither due to defective hepatic function nor due to enzymatic blockade in the urea cycle.

Early and late changes in fasting and absorptive plasma amino acids and ammonia after distal splenorenal shunt in cirrhosis

Levels of plasma amino acids, ammonia, glucagon and insulin and their 5-hr responses to a protein feeding were evaluated before and sequentially (3 mo and 1 yr) after distal splenorenal shunt in 10 patients with cirrhosis belonging to Child-Pugh's class A or B. An index of glucagon effectiveness (plasma glucose/glucagon) was also calculated. These parameters were related to liver test results, portal vein diameter and mental state, and they were compared with those found in seven patients undergoing sclerotherapy of esophageal varices with comparable liver function (control group). Liver test results and levels of plasma insulin did not change in either group. Shunt significantly increased levels of fasting tyrosine, methionine, ornithine, arginine, histidine, ammonia and glucagon with respect to the control group; it also significantly decreased levels of leucine, valine, glucagon effectiveness and portal vein diameter. The elevation of levels of tyrosine, ammonia and the sum of arginine and ornithine was correlated directly with the increase in glucagon and inversely with the decline in glucagon effectiveness. Tyrosine increase was also correlated with the reduction of portal vein diameter. One shunted patient showed mild hepatic encephalopathy. Protein feeding did not worsen the mental state of patients before and after the operation. Surgery significantly increased the 5-hr response to the meal of gluconeogenic amino acids; its rise was again correlated with the changes in glucagon plasma levels and effectiveness. Although the absorptive levels of plasma ammonia were significantly higher 1 yr after surgery, its 5-hr response barely rose. In cirrhotic patients with a relatively preserved liver function, distal splenorenal shunt progressively worsened the fasting plasma profile of nitrogen compounds and the response to protein ingestion of gluconeogenic amino acids. The decline of portal blood flow and glucagon effectiveness may be causal factors. Despite this, the "cerebral" tolerance to a moderate oral load of protein was not reduced by surgery.

Early and late changes in fasting and absorptive plasma amino acids and ammonia after distal splenorenal shunt in cirrhosis

Levels of plasma amino acids, ammonia, glucagon and insulin and their 5-hr responses to a protein feeding were evaluated before and sequentially (3 mo and 1 yr) after distal splenorenal shunt in 10 patients with cirrhosis belonging to Child-Pugh's class A or B. An index of glucagon effectiveness (plasma glucose/glucagon) was also calculated. These parameters were related to liver test results, portal vein diameter and mental state, and they were compared with those found in seven patients undergoing sclerotherapy of esophageal varices with comparable liver function (control group). Liver test results and levels of plasma insulin did not change in either group. Shunt significantly increased levels of fasting tyrosine, methionine, ornithine, arginine, histidine, ammonia and glucagon with respect to the control group; it also significantly decreased levels of leucine, valine, glucagon effectiveness and portal vein diameter. The elevation of levels of tyrosine, ammonia and the sum of arginine and ornithine was correlated directly with the increase in glucagon and inversely with the decline in glucagon effectiveness. Tyrosine increase was also correlated with the reduction of portal vein diameter. One shunted patient showed mild hepatic encephalopathy. Protein feeding did not worsen the mental state of patients before and after the operation. Surgery significantly increased the 5-hr response to the meal of gluconeogenic amino acids; its rise was again correlated with the changes in glucagon plasma levels and effectiveness. Although the absorptive levels of plasma ammonia were significantly higher 1 yr after surgery, its 5-hr response barely rose. In cirrhotic patients with a relatively preserved liver function, distal splenorenal shunt progressively worsened the fasting plasma profile of nitrogen compounds and the response to protein ingestion of gluconeogenic amino acids. The decline of portal blood flow and glucagon effectiveness may be causal factors. Despite this, the “cerebral” tolerance to a moderate oral load of protein was not reduced by surgery. (Hepatology 1994;19:329–338).

Glutamine force-feeding effect on plasma amino-acid concentrations in growing rats fed a cafeteria diet.

The effect of a glutamine force-feeding on plasma amino-acid levels in rats fed either a reference diet or a cafeteria diet was studied during weaning. The increases in plasma amino-acid levels shown by rats eating the cafeteria diet were related to the force-feeding and/or the age studied. The glutamine solution decreased the levels of proline, ornithine and tyrosine in the plasma of rats eating the cafeteria diet. In rats fed the reference diet, glutamine solution increased the plasma concentrations of threonine and cysteine. A major effect of diet over force-feeding was shown.

Lysinuric protein intolerance with chronic interstitial lung disease and pulmonary cholesterol granulomas at onset

Hyperammonemia and encephalopathy developed in an 11-year-old girl with chronic interstitial lung disease and cholesterol casts in her lung biopsy specimen. She had decreased plasma levels of ornithine, lysine, and arginine and excessive urinary excretion of lysine and arginine, consistent with the diagnosis of lysinuric protein intolerance. Analysis of plasma and urinary amino acids should be considered in the diagnostic evaluation of patients with interstitial lung disease of uncertain origin.

Trichomonas vaginalis: characterization of ornithine decarboxylase.

Ornithine decarboxylase (ODC), the lead enzyme in polyamine biosynthesis, was partially purified from Trichomonas vaginalis and its kinetic properties were studied. The enzyme appears to be of special significance in this anaerobic parasite, since the arginine dihydrolase pathway generates ATP as well as putrescine from arginine. ODC from T. vaginalis had a broad substrate specificity, decarboxylating ornithine (100%), lysine (1.0%) and arginine (0.1%). The enzyme had a pH optimum of 6.5, a temperature optimum of 37 degrees C and was pyridoxal 5'-phosphate-dependent. Attempts to separate ornithine- from lysine-decarboxylating activity by thermal-stability and pH-optima curves were not successful. Although Km values for ornithine and lysine were 109 and 91 microM respectively, and the Vmax values for these substrates were 1282 and 13 nmol/min per mg of protein respectively, the most important intracellular substrate is ornithine, since intracellular ornithine levels are 3.5 times those of lysine and extracellular putrescine levels are 7.5 times those of cadaverine. Ornithine was also an effective inhibitor of lysine-decarboxylating activity (Ki 150 microM), whereas lysine was relatively ineffective as inhibitor of ornithine-decarboxylating activity (Ki 14.5 mM). Crude ODC activity was localized (86%) in the 43,000 g supernatant and 3303-fold purification was obtained by (NH4)2SO4 salting and DEAE-Sephacel, agarose-gel and hydroxyapatite chromatography steps. The enzyme bound difluoro[3H]methylornithine ([3H]DFMO) with a ratio of drug bound to activity of 2500 fmol/unit, where 1 unit corresponds to 1 nmol of CO2 released from ornithine/min. The enzyme had a native M(r) of 210000 (gel filtration), with a subunit M(r) of 55,000 (by SDS/PAGE), suggesting that the trichomonad enzyme is a tetramer. From the subunit M(r) and binding ratio of DFMO, there is about 137 ng of ODC per mg of T. vaginalis protein (0.013%). The significant amount of ODC protein present supports the view that putrescine synthesis in T. vaginalis plays an important role in the metabolism of the parasite.

Substituting ornithine for arginine in total parenteral nutrition eliminates enhanced tumor growth.

Total parenteral nutrition (TPN) may enhance the growth of some tumors: this enhanced growth is associated with an increase in the erythrocyte polyamine levels. The effect of arginine in TPN on tumor growth was compared with ornithine using rats with a transplantable Ward colon tumor. The relationship of circulating arginine, ornithine, glutamine, and polyamines with tumor growth was investigated. For rats fed chow ad libitum, increasing tumor weights were associated with a linear decrease in the plasma arginine levels which was consistently lower than that of age-matched non-tumor bearing (NTB) rats; ornithine and lysine levels were not affected. Subsequent experiments suggest that plasma glutamine levels were also lower in tumor bearing rats. Pair-fed NTB rats had reduced arginine but not glutamine levels in plasma. TPN regimens with arginine or with ornithine substituted for arginine at two levels (equimolar [Orn-Em] or isonitrogenous [Orn-IN]) were given to colon tumor bearing rats for 8 days. The final tumor weight of rats which received the arginine-containing regimen (19.8 +/- 5.7 g, n = 4) (P less than 0.05) was significantly greater than the tumor weight of rats fed chow ad libitum (12.1 +/- 3.3 g, n = 6). The final tumor weights of Orn-EM (11.2 +/- 2.6 g, n = 4) or Orn-IN (11.6 +/- 0.8 g, n = 6) were similar to the chow-fed controls. The plasma arginine levels were elevated, compared with the control, when arginine was present in the regimen. The plasma arginine levels of rats which received Orn-EM or Orn-IN were lower than the controls. The plasma ornithine levels were not affected by arginine in the regimen but were elevated with increasing levels of ornithine in TPN. Plasma glutamine levels were decreased when arginine was present in the regimen but were elevated when ornithine was substituted for arginine. Erythrocyte putrescine was increased when either arginine or ornithine was included in the TPN regimens. These results demonstrate that while arginine in a parenteral regimen stimulates tumor growth, substituting ornithine for arginine in TPN does not enhance the growth of a transplantable colon tumor.

The metabolism and urinary excretion of orotic acid in hyperargininaemic sheep.

The synthesis, blood plasma turnover and urinary excretion of the orotic acid in normo- and hyperargininaemic sheep was investigated. The whole-body orotate formation was evaluated indirectly by the measurement of urinary orotate excretion after blockage of pyrimidine pathway with 6-azauridine (4 hour i.v. infusion of 0.2 mg.kg-1.min-1). Simultaneous infusion of L-arginine (2.5 mumols.kg-1.min-1) significantly elevated the blood plasma arginine, ornithine and urea level, however, it did not significantly influence urinary orotate excretion. In normoargininaemia blood plasma turnover of exogenous orotic acid amounted to 4.9 min and 67% of this compound was eliminated through the kidneys. The renal clearance of orotic acid amounted to 21.7 ml.min-1.kg-0.75. Hyperargininaemia elevated blood plasma turnover to 8.2 min, and diminished the renal clearance of this metabolite to 13.7 ml.min-1.kg-0.75. These results indicate that hyperargininaemia and hyperornithinaemia do not change the whole body synthesis of orotic acid in sheep but they can affect renal excretion of this metabolite, particularly at the rate of tubular secretion close to saturation.