1Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta; 2The Research Institute, The Hospital for Sick Children; and the Departments of 3Paediatrics and 4Nutritional Science, University of Toronto, Toronto, Ontario, Canada
Submitted 2 November 2004 ; accepted in final form 10 January 2005
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ABSTRACT |
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proline; arginine biosynthesis; first-pass metabolism
The neonatal porcine liver has detectable activity of the two enzymes necessary to convert proline to ornithine, proline oxidase (EC no. not assigned) and OAT (18, 29). Because the piglet liver also has complete urea cycle enzymatic activity (8, 15, 16), the piglet liver has all the enzymes necessary to synthesize arginine from proline; however, whether this actually occurs and can release measurable quantities of arginine to the rest of the body has not been quantified. We hypothesized that first-pass hepatic metabolism in enterally fed neonatal piglets could account for the difference between whole body arginine synthesis and first-pass intestinal arginine synthesis. In the present study, our first goal was to examine arginine synthesis under dietary conditions previously shown to result in both basal and maximal rates of endogenous arginine synthesis (31).
Arginine synthesis in adult men (10) and rats (14) appears to be independent of arginine intake, and in men the metabolic response to an arginine-free diet is a decrease in the rate of ornithine oxidation (12). Neonatal piglets are able to increase arginine synthesis in response to arginine deficiency (31), although their ability to decrease arginine hydrolysis during arginine deficiency has not been examined. The portion of the plasma urea that is derived from dietary arginine is five times higher in piglets fed a generous arginine diet than in piglets fed a deficient arginine diet (31), suggesting that the hydrolysis of dietary arginine is decreased, as a conservation mechanism, during times of inadequate arginine intake. We hypothesized that, if piglets are able to conserve arginine during times of deficiency, this will result in a lower relative conversion of arginine to other urea cycle intermediates, such as ornithine and citrulline, compared with piglets fed a generous amount of arginine.
The conversion of arginine to either citrulline or ornithine can only be measured with a label that is not removed during urea formation, such as [4,5-3H]arginine. Because the label remains in the urea cycle, this results in an accumulation of the label in arginine as well as the other urea cycle intermediates. We hypothesized that the label recycling of the [4,5-3H]arginine isotope would result in an underestimation of arginine flux and an overestimation of the conversion of arginine to urea cycle intermediates.
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MATERIALS AND METHODS |
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Before surgery (day 0), piglets were given an intramuscular (im) injection of ampicillin sodium (20 mg/kg Novopharm, Toronto, ON, Canada) and then preanesthetized with an im injection of acepromazine maleate (0.22 mg/kg Atravet; Wyeth Laboratories, Guelph, ON, Canada) and atropine sulfate (0.05 mg/kg; MTC Pharmaceuticals, Cambridge, ON, Canada). Piglets were then intubated, and anesthesia was maintained throughout surgery using 1% halothane. Each piglet was implanted with gastric, jugular vein, femoral vein (TiCell Bioservices, Thornhill, ON, Canada), and umbilical vein (0.040 in. ID x 0.085 in. OD Silastic tubing; Dow Corning, Midland, MI) catheters using previously described aseptic techniques (37). A Stamm gastrostomy (28) was performed to implant the gastric feeding catheter. The femoral catheter used for blood sampling was inserted into the left femoral vein and then advanced to the inferior vena cava just caudal to the heart. The jugular catheter used for isotope infusion was inserted into the left jugular vein and then advanced to the superior vena cava just cranial to the heart (37). The portal catheter used for isotope infusion was implanted by introducing the catheter transperitoneally into the umbilical vein and then advancing it to the portal-hepatic junction (4). To ensure the patency of the umbilical vein catheter, a 0.9% saline solution was infused into this catheter at a rate of 1.2 ml/h throughout the entire trial.
After surgery, piglets were given an im injection of the analgesic buprenorphine hydrochloride (0.03 mg/kg Buprenex; Rekitt and Colman Pharmaceutical, Richmond, VA). Piglets were given additional im injections of buprenorphine hydrochloride 8 and 16 h later. Ampicillin sodium was given iv into the jugular vein catheter (10 mg/kg) every 12 h on days 1 and 2, and gentamicin sulfate (2.5 mg/kg Garasol; Schering-Plough Animal Health, Pointe-Claire, PQ, Canada) was given im on the mornings of days 1 and 2. A topical antibacterial and antifungal creme (Hibitaine Veterinary Ointment, Wyeth Laboratories) was used on all incision sites.
Piglets were housed individually in circular wire mesh cages, 75 cm in diameter. These cages allowed for visual and audio contact between the piglets, and toys were provided for additional environmental enrichment. Lighting was on a 12:12-h light-dark schedule, and the room temperature was maintained between 21 and 27°C, with localized supplemental heat provided by heat lamps.
Diets. A complete elemental diet, designed to meet the nutrient requirements of neonatal piglets (37), was continuously infused enterally via the gastric catheter throughout the experiment by means of pressure-sensitive infusion pumps (IVAC 560; IVAC, San Diego, CA). Piglets were fitted into cotton jackets that allowed them to be secured to a tether. The tether is part of a swivel-tether system (Alice King Chatham Medical Arts, Hawthorne, CA) that allows piglets to move freely while they are receiving a constant diet infusion, without the risk of catheters becoming tangled or occluded. The targeted nutrient intakes were 15 g amino acid·kg1·day1 and 1.1 MJ metabolizable energy·kg1·day1, with glucose and lipid (Intralipid 20%; Fresenius Kabi, Bad Homburg, Germany) each providing 50% of the nonprotein energy intake. The amino acid composition of the complete diet was similar to that of an elemental total parenteral nutrition solution that is based on human milk protein (Vaminolact, Fresenius Kabi). The amino acid composition of the complete diet was similar to that provided in Shoveller et al. (30), with the following exceptions: L-arginine (4.41 g/l), glycine (1.36 g/l), L-phenylalanine (2.24 g/l), L-serine (1.78 g/l), and L-tyrosine (0.43 g/l). The base solution (amino acid mixture + 90 g/l glucose) was prepared and stored using previously described procedures (37). Just before diet infusion, a mixture of fat- and water-soluble vitamins (Multi-12/K1 Pediatric; Sabex, Boucherville, PQ, Canada), minerals [supplied at 200% of the NRC (26) requirement], iron dextran (Ferroforte; Bimeda-MTC, Cambridge, ON, Canada), and lipid was added to the base solution. The ratio of lipid to base solution was 1:5.
Immediately following surgery, the complete diet was infused parenterally via the jugular catheter at 50% of targeted intake until the morning of day 1. Diet infusion was then continued via the gastric catheter at 50% of targeted intake for 12 h, 75% of targeted rate for 12 h, and then at a full target rate (13.5 ml·kg1·h1) for the remainder of the trial. On the morning of day 3, piglets were randomly assigned to receive a diet containing either a generous (1.80 g·kg1·day1 or 6.62 g/l in base solution; n = 8) or deficient (0.20 g·kg1·day1 or 0.74 g/l in base solution; n = 8) concentration of arginine. These diets were chosen to represent diets that would result in minimum and maximum rates of arginine synthesis (31) without creating adverse metabolic effects (7). To ensure that the diets were isonitrogenous, the concentrations of alanine (generous arginine diet: 1.37 g/l; deficient arginine diet: 9.64 g/l) and glycine (generous arginine diet: 0.44 g/l; deficient arginine diet: 3.61 g/l) in the base solution were adjusted.
Blood sampling. Beginning on the morning of day 3, before the allocation to test diets, blood samples (2 ml) were collected every 24 h until the end of the trial on the evening of day 7. The daily blood samples were used for the determination of plasma ammonia and urea nitrogen levels, and the blood sample taken on the morning of day 7 was also used for the determination of plasma amino acid concentrations. As described under Constant tracer infusions, additional blood samples were taken during tracer infusions on days 5, 6, and 7.
Constant tracer infusions. On the morning of day 5, proline kinetics were determined by a primed [740 kBq (20 µCi)/kg], constant [370 kBq (10 µCi)·kg1·h1] infusion of L-[U-14C]proline (8.58 GBq/mmol; Amersham Biosciences, Baie d'Urfe, PQ, Canada). One-half of the piglets in each dietary treatment were given an iv infusion of the isotope via the jugular vein catheter, and the other piglets received an intraportal (ip) infusion via the umbilical vein catheter. The routes of infusion were crossed over on day 7, and piglets were infused with L-[U-14C]proline via the route of infusion that they did not receive on day 5. The isotope was infused over a 7-h period, and blood (1 ml) was sampled at 0, 60, 120, 180, 240, 270, 300, 330, 360, 390, and 420 min. On day 7, an additional sample was taken 1 h (60 min) before the start of isotope infusion to correct for the background specific radioactivity (SRA) of arginine, citrulline, glutamate, glutamine, hydroxyproline, ornithine, and proline in the blood. During the ip infusions, the 1.2 ml/h infusion of 0.9% saline was discontinued.
On day 6, whole body arginine kinetics were determined using a primed [111 kBq (3 µCi)/kg], constant [185 kBq (5 µCi)·kg1·h1] infusion of either L-[guanido-14C]arginine (n = 4 per treatment group; 1.9 GBq/mmol; NEN Life Science Products, Boston MA) or L-[4,5-3H]arginine (n = 4 per treatment group; 1,480 GBq/mmol; American Radiolabeled Chemicals, St. Louis MO). Isotope was infused iv into the jugular catheter for 6.5 h. Blood (1 ml) was sampled at 60, 0, 60, 120, 180, 240, 270, 300, 330, 360, and 390 min. The infusion doses and lengths for all infusions were based on previous experiments (4, 31).
After the isotope infusion on day 7, piglets were anesthetized with halothane and killed by the injection of 1,000 mg of pentobarbital sodium into the jugular vein catheter.
Analytic procedures. Plasma amino acid concentrations and the SRAs of arginine, citrulline, glutamate, glutamine, hydroxyproline, proline, and ornithine were measured by reverse-phase HPLC using phenylisothiocyanate derivatives as previously described (6, 23). The internal standards norleucine and L-[4,5-3H]leucine (1,920 GBq/mmol; Amersham Pharmacia Biotech, St. Louis MO) were added to each 300-µl plasma sample. Postcolumn radioactive derivatives were collected in 2-ml fractions, 14 ml of scintillant (Biodegradable Counting Scintillant; Amersham Canada, Oakville, ON, Canada) was added, and samples were counted on a scintillation counter. The determination of the urea concentration and radioactivity was as previously described (4).
Plasma ammonia (Reference 20002; Diagnostic Chemical, Charlottetown, PEI, Canada) and urea nitrogen (Sigma Procedure no. 640; Sigma Diagnostics, St. Louis MO) concentrations were determined every 24 h during test diet infusion (day 3 to day 7) using spectrophotometric assays.
Calculations. The formulas and procedures that were used to calculate the plasma SRAs of the postcolumn radioactive derivatives, the fractional net conversions of the precursor (either proline or arginine) to the product amino acids, the whole body fluxes of the infused amino acids (proline and arginine), and the absolute conversions of proline to arginine (Qproline to arginine) were as previously reported (31). The calculated flux values included the amino acids entering the plasma pool through all sources: dietary, de novo synthesis, and protein breakdown. The first-pass hepatic contributions were calculated within piglet by subtracting the iv value from the ip value for both the proline fractional net conversions and the Qproline to arginine. A similar approach has been previously used to isolate the effects of first-pass intestinal metabolism (4, 31).
Statistical analyses. All data were analyzed using the mixed model of SAS version 8.3 (SAS Institute, Cary, NC), and data were considered statistically significant if P < 0.05.
The dependent variables plasma ammonia and plasma urea nitrogen were analyzed using repeated-measures analysis, where the fixed effect was diet (generous or deficient arginine diet) and the random variables were piglet nested in diet and day. The Kenward-Roger option was used to estimate the denominator degrees of freedom. The variance-covariance matrix was chosen for each analysis on the basis of Schwarz's Bayesian Criterion. When the effects were significant (P < 0.05), least square means were separated using the pdiff option. We expected the plasma ammonia and urea nitrogen levels to be greater in piglets fed the deficient arginine diet (33); therefore a one-tailed t-test was used to compare values between treatment groups.
The results from the iv and ip proline infusions and the iv and ip Qproline to arginine were analyzed using a 2 x 2 factorial design with the diet, route of infusion, and interaction between diet and route of infusion as the fixed effects. Day of isotope infusion was tested as a covariate for the proline infusion data and was included in the model only when the effect was significant (P < 0.05). When there were no significant differences within a diet between the iv and ip values, the first-pass hepatic contribution was considered to be not significantly different from zero. 2 x 2 Factorial analysis was also used to analyze the arginine flux data with the diet, isotope infused, and interaction between diet and isotope infused as the fixed effects. All other data were analyzed using diet as the fixed effect. For all statistical analyses, piglet nested in diet was used as the random term, and when the model P value was <0.05, least square means were separated using the pdiff option, and the two-tailed P values were used to assess significance.
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RESULTS |
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There were no differences between the two treatment groups for piglet weight at initiation of test diet infusion (pooled mean = 2.08 kg, SE = 0.08 kg), rate of weight gain on test diet (pooled mean = 91 g·kg1·day1, SE = 10 g·kg1·day1), and final piglet weight (pooled mean = 2.91 kg, SE = 0.16 kg).
Both diet (P = 0.0004) and the interaction between day and diet (P = 0.004) had a significant effect on plasma ammonia concentrations (Fig. 1). Piglets fed the deficient arginine diet had higher plasma ammonia concentrations (P < 0.05) than those piglets fed the generous arginine diet from the morning of day 4 onward (Fig. 1). Diet (P < 0.0001) and the interaction between day and diet (P = 0.05) also significantly impacted plasma urea nitrogen concentrations (Fig. 1). From the morning of day 5 onward, piglets fed the deficient arginine diet had higher plasma urea nitrogen concentrations (P < 0.02) than the piglets fed the generous arginine diet (Fig. 1).
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DISCUSSION |
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Although the neonatal piglet intestine contains all of the enzymes necessary to convert both glutamine and proline to arginine (18, 35, 36), and in vitro studies have shown that, in week-old piglet enterocytes, the net production of arginine from proline is less than that from glutamine (33), whole body studies in week-old piglets have clearly shown that it is proline that is the major precursor for arginine in vivo (7, 25, 31). A potential reason for the discrepancy between the in vitro and in vivo data is that glutamine is a source of the nitrogen moieties incorporated into arginine (24, 33). These uses of glutamine/glutamate in arginine synthesis would not have been accounted for with the [14C]glutamate used in the in vivo studies (25, 31). Furthermore, Wilkinson et al. (31) found that, when piglets are fed an arginine-deficient diet, proline contributes to 27% of whole body arginine flux whereas glutamate makes no contribution. Because the in vivo data suggest that in week-old piglets proline is the major source of the carbon backbone for arginine synthesis (25, 31), the [U-14C]proline used in the present study was a valid choice for a tracer to measure endogenous arginine synthesis.
Our finding that the liver does not release arginine to the rest of the body is in agreement with the adult mammalian data. Although urea cycle enzymes are abundant in the liver, hepatic release of arginine is low or absent in adult and growing rats (17, 20, 32), mice (19), and humans (3), even when fed an arginine-free diet (20, 21). Adult mammalian hepatocytes have high arginase (EC 3.5.3.1 [EC] ) activity (15, 16, 22), and there is tight channeling of urea cycle between the cytoplasmic urea cycle enzymes (13), presumably resulting in efficient ammonia detoxification to urea. On the basis of the present results, it appears that the metabolic priority of the urea cycle enzymes in the neonatal piglet liver is ammonia detoxification and not endogenous arginine synthesis.
We have previously used the same generous and deficient arginine diets to examine both whole body and first-pass intestinal arginine synthesis (31). On the basis of the similar plasma ammonia (Fig. 1), urea nitrogen (Fig. 1), and plasma amino acid (Table 1) concentrations and the ip fractional net conversions of proline to arginine (Table 3; Ref. 31) between the two studies, the metabolic status of these piglets was similar between the present and previous (31) studies, and therefore the results will be considered together to gain a more complete understanding of the sites of endogenous arginine synthesis in neonatal piglets.
Our previous study calculated Qproline to arginine using an intragastrically (ig) infused arginine isotope to determine arginine flux (31), whereas the present study used an iv infused arginine isotope. Both approaches are valid as long as the distinction is made as to what the Qproline to arginine value represents. Flux calculated with the ig-infused isotope includes the effects of first-pass splanchnic metabolism of the isotope; therefore, the resulting Qproline to arginine is the total endogenous arginine synthesis. Qproline to arginine calculated with the iv-infused arginine isotope excludes the arginine that is synthesized and subsequently extracted by the splanchnic tissues during first-pass metabolism and thus represents net arginine synthesis. Arginine synthesis calculated using both the iv (Table 2) and the ig (31) arginine flux values is presented in Table 6. First-pass intestinal metabolism is necessary for 60 and 40% of whole body arginine synthesis when piglets are fed a generous or deficient diet, respectively (31). However, first-pass hepatic metabolism does not contribute to whole body arginine synthesis (Tables 3 and 5). Therefore, the remainder of whole body arginine synthesis must require sites not associated with first-pass splanchnic metabolism. In the present study, the synthesis of arginine from proline during peripheral metabolism was threefold higher in the piglets fed the deficient vs. the generous arginine diet (Table 5), suggesting that these are potential sites for the increased arginine synthesis during arginine deficiency.
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On the basis of the results from the present study and of previous studies by our group (4, 5, 7, 31), we hypothesize that second-pass intestinal metabolism is the site of increased arginine synthesis during arginine deficiency. The intestine has the enzymatic capability to convert proline to arginine (33), and the findings of Brunton et al. (7) suggest that intact first-pass splanchnic metabolism is necessary for the conversion of proline to arginine. However, the results from the present experiment and that by Wilkinson et al. (31) eliminate first-pass metabolism by both gut and liver as potential sites of increased arginine synthesis during arginine deficiency. The discrepancy in these observations may be explained by the importance of the enteral intake of nutrients in maintaining gut morphology (4) and splanchnic blood flow (27), both of which are negatively affected by parenteral feeding. The absence of healthy gut morphology and lower blood flow may have reduced the ability of the parenterally fed gut to extract proline from arterial circulation to use in second-pass arginine synthesis (7). Although an arterial-venous difference study, in 2-wk-old fasted piglets, concluded that there was no uptake of arterial proline by the jejunum (34), it is still possible that arterial proline may be extracted by the gut of the fully fed week-old piglets used in the present study. The activities of the enzymes involved in endogenous arginine synthesis and the interconversions between arginine precursors and urea cycle intermediates both undergo changes between 1 and 2 wk of age in neonatal porcine enterocytes (33, 35, 36). Furthermore, week-old piglet enterocytes synthesize a greater amount of arginine from proline than those from 2-wk-old piglets (33), and thus arterial proline extraction may be necessary to sustain this synthesis. Research directly examining at the importance of second-pass intestinal metabolism in arginine synthesis is necessary.
The lower iv whole body arginine fluxes observed in piglets fed the arginine-deficient diet were expected (10, 31) and were primarily due to the differences in arginine intake, which has also been observed in humans fed arginine-free vs. arginine-supplemented diets (9, 10, 12). Approximately 8095% of the difference in arginine fluxes between the two diets was accounted for by arginine intake, when arginine intake was corrected for first-pass splanchnic extraction by use of the approach of Castillo et al. (11). By use of the iv arginine fluxes from the present study, in combination with the ig arginine fluxes of Wilkinson et al. (31) (arginine deficient: 590 µmol·kg1·h1; arginine generous: 1,011 µmol·kg1·h1), 57 and 51% of the dietary arginine from the arginine-deficient and -generous diets, respectively, was extracted during first-pass splanchnic metabolism. First-pass intestinal extraction of dietary arginine in piglets is 40% (4); therefore, first-pass intestinal metabolism makes a larger contribution than first-pass hepatic extraction (1117%) to total splanchnic extraction of dietary arginine. The conversions of arginine to urea during the iv infusion (Table 4) were similar to the results obtained from an ig infusion (generous: 68%; deficient: 14%; pooled SE = 3) (31), indicating that first-pass splanchnic metabolism is not a major site of dietary arginine hydrolysis in week-old piglets. Why piglet intestinal tissue extracts a substantial amount of arginine during first-pass metabolism is unknown. Other possible fates of the arginine extracted by the intestine include protein synthesis or the synthesis of metabolically active compounds such as polyamines or nitric oxide.
Arginine fractional conversion to urea, ornithine, and citrulline was 4.5-, 2-, and 11-fold greater, respectively, in piglets fed the generous vs. deficient arginine diet (Table 4); therefore, arginine makes a smaller contribution to the fluxes of these metabolites in times of arginine deficiency. Although arginine is the immediate precursor to urea, circulating arginine accounted for only 16 and 73% of the whole body urea flux (Table 4), when measured using the guanido-labeled arginine, for the deficient and generous arginine diets, respectively. The remainder of the urea may be synthesized from intracellularly derived arginine, especially during arginine deficiency. Urea derived from arginine produced intracellularly would not contain the label on the guanido carbon and therefore would not be accounted for in our conversion calculation. Studies in isolated rat hepatocytes have found that arginine synthesized in the hepatocytes was the major source of arginine used for urea synthesis, due to a tight channeling between the cytoplasmic urea cycle enzymes (13). Furthermore, whole body isotopic studies in adult men have shown that urea flux is substantially (1.56 times) greater than arginine flux, which would not be the case if circulating arginine were the sole precursor for urea synthesis (2). The present results and those of others who have measured arginine conversion to urea by using plasma kinetics (2) indicate that there may be intracellularly derived arginine that does not equilibrate with the extracellular pool; therefore, these methods underestimate the whole body arginine-to-urea conversion. Nevertheless, the results from the present study, using guanido-labeled arginine, clearly indicate that circulating arginine is a less important urea precursor when piglets are fed a deficient vs. a generous arginine diet (Table 4). This response is probably a conservation mechanism in response to the lower amount of circulating arginine (Table 1).
Neither ornithine nor citrulline is found in protein, nor was either provided in the diet; thus the only source of these amino acids in the extracellular pool was through endogenous formation. The present study demonstrates that, during arginine deficiency, less citrulline and ornithine are derived from arginine than when a generous amount of arginine is provided (Table 4). The lower conversion rates of arginine to both citrulline and ornithine suggest that an important metabolic response to arginine deficiency in piglets is decreased arginine hydrolysis. Compared with men fed a normal intake of arginine, men fed a deficient arginine diet had decreased arginine-to-ornithine conversion as well as a decline in ornithine oxidation (12), whereas those consuming a therapeutic level of arginine had greater conversion of arginine to ornithine and a higher rate of ornithine oxidation (2). Therefore, when arginine-deficient diets are eaten, both adult humans and neonatal piglets conserve arginine by reducing its degradation.
In piglets fed the arginine-deficient diet, there was a greater discrepancy between the two arginine flux values than in the piglets fed the generous arginine diet (35 vs. 20% lower for the [4,5-3H]arginine vs. the [guanido-14C]arginine; Table 2). This indicates that arginine deficiency results in a greater amount of arginine recycling in piglets. This response agrees with our previous conclusion that arginine is conserved when it is limiting in the diet. The fractional net conversion of arginine to ornithine, calculated using the [4,5-3H]arginine tracer, in the piglets fed the generous arginine diet was greater than 100% (Table 4), which further supports our hypothesis of label recycling. In a study in men fed an arginine-enriched diet, and using an arginine isotope that was recycled, the portion of plasma ornithine flux derived from the arginine was determined to be 150% (2). Those authors proposed that plasma arginine might be sequestered in a distinct intracellular pool where ornithine is synthesized and then released back into the plasma, resulting in an overestimation of whole body arginine to ornithine conversion (2). Our data do not allow us to comment on their proposal of a distinct intracellular pool that sequesters ornithine; however, our data clearly indicate that recycling probably accounts for a substantial portion of the ornithine flux that they observed.
In conclusion, the neonatal porcine liver in vivo is not capable of synthesizing arginine from proline during first-pass metabolism, even when fed a limiting arginine diet. Whole body arginine synthesis is upregulated when a deficient arginine diet is fed; however, because first-pass intestinal arginine synthesis was not affected by arginine intake (31), extrasplanchnic tissues or second-pass intestinal metabolism are likely responsible for this additional synthesis. In addition, piglets fed a deficient arginine diet also appear able to conserve circulating arginine by decreasing its conversion to other urea cycle intermediates. This study clearly demonstrates that, in neonatal piglets, whole body arginine synthesis is upregulated when arginine is deficient but not by first-pass intestinal or hepatic metabolism. The site of increased arginine synthesis during arginine deficiency requires further investigation.
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GRANTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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