1 Department of Agricultural, The indispensability of arginine has not been
conclusively established in newborns. Because parenteral feeding
bypasses the gut (where de novo synthesis of arginine occurs from
proline), a dietary supply of arginine that is sufficient to maintain
urea cycle function may be of greater importance during intravenous compared with enteral feeding. Two-day-old piglets
(n = 12) were fed nutritionally
complete diets for 5 days via either a central vein catheter (IV pigs,
n = 6) or a gastric catheter (IG pigs, n = 6). Subsequently, each piglet
received three incomplete test diets [arginine free
(
hyperammonemia; total parenteral nutrition; newborn; urea cycle
IN VIVO EVIDENCE of net arginine release from the small
intestine of young piglets (22, 27) and in vitro evidence from harvested enterocytes (5, 28) have demonstrated that the gut is an
important site of endogenous arginine synthesis. Conditions of gut
atrophy or dysfunction, such as malnutrition, intestinal disease, or
parenteral feeding, will result in a lack of luminally derived
metabolic precursors of arginine that could impair the biosynthetic
capabilities of the neonate. This deficit in arginine synthesis must be
met by higher dietary intake, but the quantity required is not known.
Endogenous arginine synthesis may be very important to the newborn,
because arginine intake from milk is low relative to requirements for
growth (26). The pathway for de novo synthesis of both arginine and
proline is from glutamate via the intermediate conversion to
L- Proline is one of the most abundant amino acids in porcine and human
milk (7). Proline oxidase (no EC number assigned), responsible for the
conversion of proline to P-5-C, and OAT have been identified in
intestinal tissue and cultured enterocytes from suckling pigs (26).
Conversion of gastrically infused
[14C]proline to
[14C]arginine has been
reported in 10-day-old piglets fed a proline-deficient diet (16).
Additional in vivo evidence is necessary to determine whether dietary
proline contributes to whole body arginine requirements such that it
could ameliorate dietary arginine deficiency.
A critical biological role of arginine is the disposal of ammonia via
urea synthesis. Hyperammonemia was observed in term and preterm
neonates fed early total parenteral nutrition (TPN) solutions with low
(or zero) arginine concentrations (11, 20). The hyperammonemia was
resolved by an infusion of
L-arginine in most infants (11,
19), suggesting that arginine is indispensable. Preterm infants
frequently demonstrate elevated plasma ammonia concentrations, perhaps
due to immature hepatic amino acid metabolism or a subclinical arginine
deficiency (2). As the precursor for nitric oxide, inadequate arginine
availability has been implicated in the onset of, or delayed recovery
from, neonatal diseases such as sepsis (23), persistent pulmonary
hypertension (6, 24), and necrotizing enterocolitis (9). Improvement in
our understanding of arginine metabolism during the neonatal period and
of the enteral and parenteral dietary arginine requirements is critical
for the optimal care of this compromised population.
We conducted a study in two groups of newborn piglets, which were
either 1) subjected to gut atrophy
induced by parenteral feeding (using a previously established protocol)
(3, 30) or 2) enterally fed via
gastrostomy. The primary objectives were 1) to evaluate the indispensability
of arginine during parenteral and enteral feeding,
2) to determine the impact of an
atrophied gut on de novo arginine synthesis by feeding identical
arginine-free diets parenterally or enterally,
3) to determine whether proline is a
major precursor for arginine in piglets fed enterally or parenterally,
and 4) to determine whether proline
is indispensable in piglets fed enterally or parenterally.
Animals and surgical procedures.
Twelve intact male Yorkshire piglets were obtained from a specific
pathogen-free herd (Arkell Swine Research Station, University of
Guelph, Guelph, ON, Canada). Piglets were left with the sow for
2-4 days after birth and then were transferred to the laboratory for immediate surgical implantation of catheters under aseptic conditions. Anesthesia was induced with an intramuscular injection of
acepromazine (0.5 mg/kg, Atravet; Ayerst Laboratories, Montreal, PQ,
Canada) and ketamine hydrochloride (10 mg/kg, Rogarsetic; Rogar STB,
Montreal, PQ, Canada) and was maintained during surgery with a mixture
of oxygen and halothane (Fluothane, Ayerst Laboratories, Montreal, PQ,
Canada) delivered by mask. Each piglet was implanted with a Silastic
venous sampling catheter (Ed-Art, Toronto, ON, Canada), which was
inserted into the left femoral vein and advanced to the inferior vena
cava immediately caudal to the heart. Piglets in the intravenously fed
(IV) group (n = 6) also received an
infusion catheter that was inserted into the left external jugular vein and advanced to the superior vena cava immediately cranial to the
heart. In the intragastrically fed (IG) group
(n = 6), a Stamm gastrostomy was
performed (16) to provide continuous enteral feeding.
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
ARG/+PRO), proline free (
PRO/+ARG), or arginine and
proline free (
ARG/
PRO)] in a randomized crossover design. Plasma ammonia was assayed every 30 min for 8 h or until hyperammonemia was observed. Ammonia increased rapidly in IV pigs receiving
ARG/+PRO and
ARG/
PRO (84 ± 36 and 74 ± 37 µmol · l
1 · h
1,
respectively), requiring early diet cessation. A rapid increase was
also exhibited by IG pigs receiving the
ARG/
PRO, but not the
ARG/+PRO diet (31 ± 15 vs. 11 ± 7 µmol · l
1 · h
1,
respectively, P < 0.05). Plasma
arginine and proline were indicative of deficiency (IG and IV groups)
when deplete diets were infused. Arginine is indispensable in
parenteral and enteral nutrition, independent of dietary proline.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
1-pyrroline-5-carboxylate
(P-5-C) by P-5-C synthase. Subsequently, P-5-C is converted into either
proline by P-5-C reductase (EC 1.5.1.2) or ornithine by ornithine
aminotransferase (OAT; EC 2.6.1.13), and then from ornithine to
citrulline and arginine in the urea cycle. In the young animal, the
conversion of glutamate to P-5-C is believed to be limited to the small
intestine and thymus because P-5-C synthase is found exclusively in
these tissues (13). Also, low P-5-C synthase activity during the
suckling period (28) dictates that an alternate precursor for arginine synthesis must be responsible for meeting requirements.
METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
Diets.
The diets were based on an elemental parenteral TPN solution and were
manufactured by the Parenteral Service Pharmacy (The Hospital for Sick
Children, Toronto, ON, Canada) to the investigators' specifications
(12). The TPN base solution was free of arginine, proline, and serine.
For a complete amino acid diet, the three crystalline amino acids were
dissolved in water, and the solution was injected into sterile bags of
TPN through a 0.22-µm filter to provide final concentrations of 3.36 g arginine/liter, 4.58 g proline/liter, and 3.09 g serine/liter. For
the three test diets, arginine (ARG/+PRO), proline
(
PRO/+ARG), or arginine and proline (
ARG/
PRO) were
removed; serine was added to ensure that all diets were isonitrogenous.
Just before feeding, vitamins (MVI Paediatric, Rhone-Poulenc Rorer,
Montreal, PQ, Canada), minerals (Micro +6 Concentrate, Sabex,
Boucherville, PQ, Canada), and lipid (Intralipid 20%, Pharmacia,
Mississauga, ON, Canada) were added to the TPN solution. The diets were
infused continuously (24 h) either intravenously or intragastrically,
via pressure-sensitive peristaltic pumps, through a swivel-tether
system (Alice King Chatham Medical Arts, Los Angeles, CA). The complete
diet was designed to supply all nutrients required by piglets (30),
including 15 g of amino
acids · kg
1 · day
1
and 1.1 MJ metabolizable
energy · kg
1 · day
1.
Experimental design. Beginning on the morning of day 6, each piglet was subjected to the three dietary treatments on three consecutive days in a randomized, crossover design. Immediately after blood sampling for baseline data (time 0), the test diet was initiated. Venous blood was sampled every 30 min for 9 h, with a final sample taken at 10 h.
A preliminary study to test the response of piglets (n = 2) to arginine-free TPN demonstrated that the onset of hyperammonemia was much more rapid and extreme than anticipated; plasma ammonia concentration exceeded 1,000 µmol/l during an overnight infusion, and symptoms of ammonia toxicity were observed. For this reason, during the main experiment, the test diets were ceased if hyperammonemia was detected in excess of the predetermined critical value (CrV) of 270 µmol/l. This CrV was established in our laboratory by sampling plasma from eight healthy sow-fed piglets; it represents the group mean ± SD (58 ± 32 µmol/l) times 3. Diets were infused for a maximum of 8 h if the CrV was not exceeded. At diet cessation, all piglets were "rehabilitated" with a bolus of amino acid(s) equal to the deficiency accrued during the test period. The amino acids were infused in a saline solution for 1 h into either the femoral (IV piglets) or gastric (IG piglets) catheters. Plasma ammonia concentration was determined every 30 min during treatment infusion by a colorimetric assay based on the amination of 2-oxoglutarate to glutamate, with simultaneous oxidation of NADPH (procedure no. 171-UV, Sigma Diagnostics, St. Louis, MO). Whole blood pH, bicarbonate, electrolytes, CO2 and O2 pressures (PCO2, PO2, respectively), and osmolality were determined every 90 min (Nova Statprofile 9+, Nova Biomedical, Waltham, MA). Plasma urea was determined in hourly samples by use of a colorimetric assay in which ammonia was liberated from urea by enzymatic hydrolysis. Subsequently,Statistics. The slope of the change in plasma ammonia concentration from 2 h after initiation of the test diet until cessation was calculated for each piglet and then compared by analysis of covariance, with diet order and previous treatment included as covariates (BMDP Student Version, BMDP Statistical Software, Los Angeles, CA). Only slopes that were significantly different from zero (P < 0.05) were included. Two hours was chosen as the first point for the regression analysis, because after the treatments were started, plasma ammonia initially declined in all piglets. Changes in plasma urea were similarly compared by use of values from baseline to cessation. Growth performance and ammonia concentration, plasma amino acids, bicarbonate, and pH at diet cessation (8 h or CrV) were compared between IG and IV groups by one-way ANOVA (Minitab Statistical Software, Minitab, State College, PA).
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RESULTS |
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The IG- and IV-fed piglets were similar in age and body weight at the
time of surgery. Rate of weight gain after adaptation (day 2 to day
5) to the nutritionally complete diet also was not different between IG and IV piglets (Table
1) and was similar to that of sow-fed
piglets (30). During the 3-day period (day 6 to day 9) when IG
and IV piglets received the same test diets, the IG piglets gained
weight at a greater rate than IV piglets (Table 1), indicating that the
effect of the deficient diets was more severe in the IV piglets.
|
The initiation of the ARG/+PRO and
ARG/
PRO diets
for both the IV and IG piglets resulted in a significant decline in
plasma ammonia compared with baseline during the 1st h of treatment
(P < 0.05; Fig.
1, A and
B). Subsequently, the IV piglets fed
ARG/+PRO or
ARG/
PRO had a rapid rise in plasma
ammonia (Table 2), with all but one IV
piglet reaching the CrV before 8 h for both treatments (Fig. 1,
A and
B). Time to CrV and peak plasma
ammonia concentrations were not different in IV piglets fed
ARG/+PRO compared with
ARG/
PRO diets (Table 2). A
significant difference was observed in the peak ammonia concentrations
of IV vs. IG piglets fed either
ARG/+PRO or
ARG/
PRO diets (Table 2); IV-fed piglets demonstrated a
more rapid rise and a greater peak concentration at time of CrV or diet
cessation (Table 2). During the
PRO/+ARG diet infusions to both
IG and IV groups, plasma ammonia declined during the 1st h, with no
subsequent significant changes (Fig.
1C).
|
|
The inclusion of proline in the IG-fed ARG/+PRO diet prevented
hyperammonemia. None of the piglets attained the CrV during the IG
ARG/+PRO feeding (Fig.
1A). The plasma ammonia
concentration at diet cessation for IG piglets was significantly higher
after the
ARG/
PRO treatment than after the
ARG/+PRO diet (Table 2). The exclusion of proline
(
PRO/+ARG) from the IV and IG diets containing
arginine did not result in a rise in plasma ammonia (Table 2).
The bolus infusion of arginine or arginine and proline at cessation of
the test diets resulted in an immediate decline in plasma ammonia
concentration in hyperammonemic piglets. Most piglets returned to
baseline levels within 2 h of being fed a replete diet (Fig.
2).
|
Plasma urea concentration declined significantly
(P < 0.05) during all diet
treatments, with no significant difference in rates of decline between
IG and IV pigs (Table 2). Blood pH was similar between IV and IG pigs
before the initiation of the test diets (all piglets: 7.428, pooled SD:
0.033), and pH did not change during any of the treatments (data not
shown). Blood bicarbonate concentration was significantly less in the
IV compared with the IG pigs at cessation of the ARG/+PRO (27.2 vs. 32.2 mmol/l, pooled SD: 3.7, P < 0.05) and
ARG/
PRO (26.3 vs. 33.0 mmol/l, pooled SD: 2.2, P < 0.001) treatments. At
diet cessation, the bicarbonate concentration as a percentage of
baseline was higher in the IG vs. IV pigs (
ARG/+PRO, 106 vs.
93%, pooled SD: 9%, P < 0.05;
ARG/
PRO, 96 vs. 109%, pooled SD: 10%,
P < 0.05).
Plasma concentrations of arginine and ornithine at baseline were
significantly higher in the IG compared with the IV piglets (Table
3). During the infusions of ARG/+PRO
and
ARG/
PRO diets, plasma arginine fell to >2 SD below
a reference mean (31) within 1 h of initiation in the IV piglets, and
within 2 h in the IG piglets; subsequently, arginine remained low in
all animals until cessation of treatment (Fig.
3, A and
B). The
PRO/+ARG diet induced a fall in plasma proline in both IV and IG piglets, also to levels indicative of a deficiency state (Fig.
3C). At cessation of the
ARG/+PRO and
ARG/
PRO diets, IG piglets had higher
concentrations of arginine and ornithine compared with IV piglets
(Table 3). IG piglets fed
PRO/+ARG also maintained greater
plasma proline and ornithine concentrations than IV piglets receiving
identical intakes (Table 3). IV vs. IG feeding resulted in higher
plasma concentrations of glutamine, glutamate, and aspartate at the
cessation of the
ARG/+PRO and
ARG/
PRO diets (Table
3).
|
|
Mode of feeding also resulted in the IV piglets having significantly
greater plasma concentrations of the branched-chain amino acids,
histidine, phenylalanine, and lysine in response to the ARG/+PRO
and
ARG/
PRO diets
(P < 0.05, data not shown). No
differences in branched-chain amino acid concentrations were observed
between IG- and IV-fed piglets receiving the
PRO/+ARG diet.
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DISCUSSION |
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---|
In this study, severe hyperammonemia developed within hours of feeding arginine-free diets to intravenously fed neonatal piglets, clearly demonstrating the indispensability of arginine during parenteral nutrition. In enterally fed piglets, moderate hyperammonemia developed after 8 h of being fed arginine-free diets; combined with lower plasma concentrations of arginine and urea, this indicates that even orally fed piglets could not synthesize sufficient arginine to maintain urea synthesis. By employing identical diets and using plasma ammonia as an indicator of arginine deficiency, we also conclude that the arginine requirement is clearly higher for neonatal piglets fed parenterally vs. enterally.
Parenteral feeding involves a lower metabolic capacity due to gut
atrophy and a nutrient supply that is exclusively systemic. Because the
neonatal small intestine is an important site for arginine synthesis
(5, 22), these factors could explain the present observations that,
when both IV and IG groups were provided with identical arginine-free
(ARG/+PRO) diets, the rapid development of hyperammonemia was
observed only in intravenously fed piglets. Alternately, there are
complex metabolic changes that occur with parenteral (vs. enteral)
feeding, such as the hormonal responses evoked by intraluminal
nutrients (1), which could cause alterations in arginine synthesis or
catabolism. We previously showed no conversion of intravenously infused
[14C]proline or
[14C]glutamate into
ornithine, citrulline, or arginine in piglets fed orally, although
these conversion products were detected when the tracers were infused
intragastrically (16). Because those piglets were all orally fed and
had healthy intestines, our results (16) and those of others (27) have
demonstrated that arterial proline and glutamate were minimally
available to the small intestine. Thus luminally derived precursors
and/or a healthy small intestine may be necessary for de novo arginine
synthesis in the neonate. Our current study confirmed that plasma
proline was not available to the enterocyte for arginine synthesis,
because hyperammonemia occurred equally as quickly in the IV piglets
fed
ARG/+PRO and
ARG/
PRO.
Glutamine is also a potential precursor for arginine via the same
pathways as glutamate (27). In vitro research suggested that
enterocytes require a source of glutamine for arginine synthesis from
proline (26). During the catabolism of glutamine, an ammonia group is
donated to the intramitochondrial synthesis of carbamoyl phosphate,
which is necessary for the conversion of proline-derived ornithine to
citrulline in the urea cycle (26). Our diets did not contain glutamine;
however, in vivo research shows that glutamine is readily taken up by
the enterocyte across the basolateral membrane (22, 25). During the IV
infusions of ARG/+PRO and
ARG/
PRO treatments,
plasma glutamine increased at a rate of ~200
µmol · l
1 · h
1
(Table 3). Therefore, glutamine was available as a nitrogen donor and
as a potential precursor and was not likely a limiting factor in the
synthesis of arginine in IV-fed piglets. Regardless of the mechanisms,
during parenteral nutrition, endogenous arginine synthesis from
potential precursors cannot meet even the basic arginine requirement
for urea synthesis, let alone for growth.
Synthesis and release of significant amounts of arginine by the intestine for use by the liver and periphery appear to occur only in the young animal; mature animals appear to synthesize arginine in the kidney from intestinally derived citrulline that bypasses the liver (8, 27). Low arginase (EC 3.5.3.1) activity has been demonstrated in enterocytes cultured from preweaning pigs (5), which would account for the release of arginine as opposed to ornithine or citrulline. These important differences in arginine metabolism between young and mature animals make it essential that arginine requirements be quantified for the neonate as opposed to being extrapolated from adult requirements.
The intragastrically infused ARG/+PRO and
ARG/
PRO
diets evoked very different metabolic responses, in contrast to the IV infusions. The inclusion of proline in the diet of the IG-fed piglets
sustained sufficient urea cycle function to avoid hyperammonemia. The
IG piglets fed
ARG/
PRO experienced a rise in plasma
ammonia that was rapid compared with the IG
ARG/+PRO treatment.
Interestingly, the rise in plasma ammonia during the
ARG/
PRO infusions was not as severe in the IG compared
with the IV-fed piglets. Because there was no dietary proline
available, it is likely that some conversion of dietary glutamate to
arginine was occurring in the healthy gut. Although excess glutamate
was provided in all of our diets, our observation of a slow rise in
plasma ammonia during the IG
ARG/
PRO diet infusion
demonstrates that its use as a precursor for arginine is limited,
likely due to low P-5-C synthase activity in the neonate (29). Murphy
et al. (16) demonstrated in young pigs fed orally that a greater amount
of arginine was synthesized from labeled proline than could be detected
from a similar intragastric infusion of labeled glutamate. It is
important to note that the increases in plasma ammonia in IG piglets
fed arginine-free diets were significant (11 and 31 µmol · l
1 · h
1
for
ARG/+PRO and
ARG/
PRO diets, respectively),
although not as rapid as in the IV-fed piglets (Table 2). Even in
orally fed pigs, the removal of dietary arginine would eventually have
resulted in critical hyperammonemia. Thus proline and arginine should
be considered "coindispensable"; however, proline can only
ameliorate arginine deficiency during enteral feeding.
The indispensability of arginine was also demonstrated by plasma
arginine concentrations, based on levels indicative of a deficiency
state during the infusion of either of the arginine-free test diets in
both IV and IG piglets (Fig. 3). In IG piglets fed ARG/+PRO, a
portion of the dietary proline must have been converted to arginine to
avert hyperammonemia; however, plasma proline concentration did not
decline. Therefore, the decline in plasma arginine in the IG piglets
was not due to inadequate dietary proline but rather to insufficient de
novo synthetic capabilities that could not fulfill whole body arginine
requirements. The indispensability of arginine was further demonstrated
by the rapid recovery from hyperammonemia with the addition of arginine
to the diet. All piglets recovered within 2 h of repletion, as
determined by biochemical indexes such as plasma ammonia, bicarbonate,
urea, and amino acids.
Plasma proline concentrations during the
PRO/+ARG diets were also indicative of
deficiency for both IG- and IV-fed piglets. Proline concentrations were
<20% of the baseline values after 8 h of infusion of the
proline-free diet. Final plasma proline concentration was twofold
greater in the IG- compared with the IV-fed piglets, but both groups
were >2 SD below the mean reference value for sow-fed piglets (31).
The difference may be attributed to the conversion of intragastrically,
but not intravenously, infused glutamate as a precursor for proline
(16). Arginine can also act as a precursor for proline synthesis when
provided intravenously or enterally. Approximately 40% of the proline
deposited in proteins during growth in neonatal pigs adapted to a
low-proline diet could have been synthesized from arginine (15). The
piglets fed
PRO/+ARG in this study were likely not receiving
enough dietary arginine to support adequate proline synthesis.
Furthermore, we observed a decline in plasma urea concentration over
time in both IG- and IV-fed piglets receiving the
PRO/+ARG
diets, which suggests that at our concentration of dietary arginine,
ureagenesis was impeded. Further quantification of the
coindispensability of arginine and proline is essential to
establish the safe, minimal dietary requirement for both amino acids.
P-5-C is central to the interconversion of glutamate to urea cycle metabolites (ornithine, citrulline, and arginine) or to proline. P-5-C reductase (P-5-C to proline) is present in most tissues, but P-5-C synthase (glutamate to P-5-C) is found only in the intestine and thymus (13). Neonates with reduced enteric mucosal mass (secondary to TPN feeding) would therefore have limited conversion of glutamine and glutamate to proline or ornithine during TPN feeding and during reinitiation of oral feeding. In vivo evidence of limited conversion of glutamate to proline was recently reported in premature infants receiving TPN (14). The label recovered in proline from an infusion of [13C]glucose was only ~10% of that in glutamate (14). Enrichment of urea cycle metabolites was not reported. Therefore, neonates have greater dietary requirements for both proline and arginine during TPN feeding. Additional arginine and proline should also be supplied during the reintroduction of enteral feeding after parenteral feeding due to limited de novo synthetic capacity.
The plasma concentrations of ornithine at baseline differed between IV-
and IG-fed piglets, demonstrating that the mode of feeding
significantly affects the metabolism of this amino acid as well. The
difference was not due to a dilution effect, because baseline blood
osmolarity was not lower in the parenterally fed piglets. Plasma
ornithine concentration declined in the IG pigs during the
PRO/+ARG infusion; in the IV pigs, plasma ornithine was
significantly lower than in IG pigs at baseline and remained constant.
This decline in the IG piglets may reflect the conversion of ornithine
to proline by OAT and P-5-C reductase in the liver or gastrointestinal
tract. This mechanism appears to be limited in its capability to
maintain plasma proline concentration. The P-5-C reductase activity in
tissues of piglets adapted for 11 days to a low-proline diet was
similar to that in control piglets (18). Therefore, upregulation of
endogenous synthesis of proline from ornithine and arginine does not
appear to be a mechanism that can compensate for a dietary deficiency.
Glutamine synthesis is considered to be an important pathway for nitrogen disposal in response to ammonia toxicity secondary to arginine deficiency. This mechanism was not clearly exhibited in 20- to 50-kg pigs fed arginine-deficient diets, even when challenged with 60-min infusion of ammonium into the portal vein to induce hyperammonemia (17). Prior and Gross (17) speculated that glutamine synthesis may not be as important for ammonia disposal in pigs as previously demonstrated in rats. The rapid rise in plasma glutamine and glutamate concentrations in the IV-fed piglets in this study indicates that endogenous glutamine synthesis is an important mechanism for nitrogen disposal; the discrepancy in results between our study and that of Prior and Gross could be due to differences in amino acid metabolism in neonatal pigs vs. older pigs (20-50 kg).
There was an effect of diet order on the rate of rise in ammonia concentration in the IV-fed piglets that was not seen in IG-fed piglets. The randomized crossover design allowed for unbiased analyses, which eliminated effects that might have been introduced by diet order. However, the significance of the diet order covariate indicates that the IV piglets did not fully recover, during the 16 h between studies, from the metabolic aberrations induced by the treatments. Although none of the other biochemical parameters that we measured at baseline indicated that diet order was a confounding variable, the IV-fed piglets did not grow as rapidly as IG-fed piglets during the 3 days of test diets.
By employing piglet models fed identical diets either intravenously or intragastrically, we have clearly demonstrated that arginine and proline are indispensable amino acids for both parenterally and enterally fed neonates. Furthermore, we established that the gut acts as an important mediator of whole body arginine supply by using proline as a major substrate for arginine synthesis; however, dietary proline or glutamate cannot fully spare the whole body requirement for arginine. Hence, dietary requirements for arginine and proline appear to be "codependent" and are altered by the mode of feeding. Clearly, the dietary arginine requirement is greater for parenterally than for enterally fed neonates. Low plasma arginine concentrations have been observed in preterm infants on TPN, particularly during stress or surgical trauma, suggesting that the commercial formulas currently available do not contain enough arginine.
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ACKNOWLEDGEMENTS |
---|
The amino acids were donated by Pharmacia-Upjohn, Stockholm.
![]() |
FOOTNOTES |
---|
This study was supported by grants from the Natural Sciences and Engineering Council of Canada, The Alberta Pork Producers Development Corporation, and Alberta Agricultural Research Institute.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: R. O. Ball, Dept. of Agricultural, Food, and Nutritional Science, Univ. of Alberta, Edmonton, AB, Canada T6G 2P5 (E-mail: RBALL{at}AFNS.UALBERTA.CA).
Received 5 October 1998; accepted in final form 15 April 1999.
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