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PubMed1994

Discrimination between citrulline and arginine transport in activated murine macrophages: inefficient synthesis of NO from recycling of citrulline to arginine.

1. The kinetics, specificity, pH- and Na(+)-dependency of L-citrulline transport were examined in unstimulated and lipopolysaccharide (LPS)-activated murine macrophage J774 cells. The dependency of nitric oxide production on extracellular arginine or citrulline was investigated in cells activated with LPS (1 microgram ml-1) for 24 h. 2. In unstimulated J774 cells, transport of citrulline was saturable (Kt = 0.16 mM and Vmax = 32 pmol micrograms-1 protein min-1), pH-insensitive and partially Na(+)-dependent. In contrast to arginine, transport of citrulline was unchanged in LPS-activated (1 microgram ml-1, 24 h) cells. 3. Kinetic inhibition experiments revealed that arginine was a relatively poor inhibitor of citrulline transport, whilst citrulline was a more potent inhibitor (Ki = 3.4 mM) of arginine transport but only in the presence of extracellular Na+. Neutral amino acids inhibited citrulline transport (Ki = 0.2-0.3 mM), but were poor inhibitors of arginine transport. 4. Activated J774 cells did not release nitrite in the absence of exogenous arginine. Addition of citrulline (0.01-10 mM), in the absence of exogenous arginine, could only partially restore the ability of cells to synthesize nitrite, which was abolished by 100 microM NG-nitro-L-arginine methyl ester or NG-iminoethyl-L-ornithine. 5. Intracellular metabolism of L-[14C]-citrulline to L-[14C]-arginine was detected in unstimulated J774 cells and was increased further in cells activated with LPS and interferon-gamma. 6. We conclude that J774 macrophage cells transport citrulline via a saturable but nonselective neutral carrier which is insensitive to induction by LPS. In contrast, transport of arginine via the cationic amino acid system y+ is induced in J774 cells activated with LPS.7. Our findings also confirm that citrulline can be recycled to arginine in activated J774 macrophage cells. Although this pathway provides a mechanism for enhanced arginine generation required for NO production under conditions of limited arginine availability, it cannot sustain maximal rates of NO synthesis.

Animals↗
PubMed1998

Inability of rat alveolar macrophages to recycle L-citrulline to L-arginine despite induction of argininosuccinate synthetase mRNA and protein, and inhibition of nitric oxide synthesis by exogenous L-citrulline.

In the present study it was tested whether rat alveolar macrophages (AMphi) convert L-citrulline to L-arginine to maintain nitric oxide (NO) synthesis under conditions of limited availability of L-arginine. Rat AMphi (0.5 x 10(6) cells/well, cultured for 20 h in the absence or presence of 1 microg/ml lipopolysaccharides, LPS), were incubated for 6 h in amino acid-free Krebs solution and nitrite accumulation was determined as a measure of NO synthesis. After culture in the absence of LPS, nitrite in the incubation media was at the detection limit, independent of the addition of L-arginine or L-citrulline. AMphi, cultured in the presence of LPS, produced about 4 nmol per 10(6) cells and 6 h nitrite, and L-arginine enhanced nitrite accumulation in a concentration-dependent manner, maximally about threefold (EC50: 55 microM). In LPS-treated AMphi L-citrulline (up to 10 mM) failed to enhance nitrite accumulation, but rather inhibited it by about 50% in the presence of 100 microM L-arginine, i.e. when NO synthesis was enhanced. L-Arginine in the culture medium was 3H-labelled and its metabolism analysed by HPLC. In medium of AMphi exposed to LPS [3H]-L-arginine was reduced by about 60% after a 20-h culture period and this was almost balanced by an almost equal increase in [3H]-L-citrulline and [3H]-L-ornithine, i.e. L-arginine was markedly consumed. When [14C]-L-citrulline was added to the culture medium of AMphi, no significant formation of [14C]-L-arginine could be detected. On the other hand, argininosuccinate synthetase mRNA (by RT-PCR) and protein (by Western blot) was marginally detectable in control AMphi, but clearly induced after exposure to LPS. Finally, L-citrulline was shown to inhibit L-arginine uptake in a concentration dependent manner, by about 50% at 10 mM. In conclusion, although the expression of argininosuccinate synthetase in rat AMphi can be induced by LPS, AMphi appear not to be able to recycle significant amounts of L-citrulline to L-arginine to maintain sustained NO synthesis. On the contrary, at high concentrations L-citrulline can reduce NO synthesis, and this effect appears to be caused by inhibitory effects on L-arginine uptake.

Animals↗
PubMed1994

Dietary citrulline but not ornithine counteracts dietary arginine deficiency in rats by increasing splanchnic release of citrulline.

Ornithine and citrulline have different arginine-sparing capabilities when provided in an arginine-deficient diet. Rats were fed arginine-deficient diets containing ornithine or citrulline to see the effect on net fluxes of free arginine, ornithine and citrulline across the portal-drained viscera (PDV) and liver. The diets contained either 10 g arginine/kg diet (+Arg) or no arginine: the -Arg/+Ala diet contained additional alanine and the -Arg/+Orn and -Arg/+Cit diets contained ornithine and citrulline, respectively, in amounts isomolar to the amount of arginine in the control (+Arg) diet. Blood arginine concentrations were 50% lower than control values (P < 0.001) in rats fed the -Arg/+Ala or the -Arg/+Orn diet. However, addition of citrulline to the arginine-deficient diet restored blood arginine concentrations. The source of the circulating arginine in the rats fed the -Arg/+Cit diet was neither the PDV nor the liver; net splanchnic uptake of arginine was 0.3 mumol/min. Net citrulline release was substantial from the PDV (0.65 mumol/min) as well as from the splanchnic bed (0.67 mumol/min) of rats fed the -Arg/+Cit diet, such that blood citrulline concentrations were more than double (P < 0.001) those in rats fed the +Arg or -Arg/+Orn diet. Splanchnic release of citrulline in rats fed the -Arg/+Cit diet but not in rats fed the -Arg/+Orn diet supported the production of arginine in non-splanchnic organs such as, presumably, the kidney.

Alanine↗
PubMed2026

Distinct HLA Associations for Antibody Multireactivity With Citrulline-Containing Type II Collagen Epitopes Versus More Limited Antibody Reactivity With Citrulline-Containing IgG Epitopes in Rheumatoid Arthritis.

OBJECTIVE: Anticitrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA) can be promiscuous, with cross-reactive binding to many antigens containing short motifs, or private with little cross-reactivity. Also, ACPA reactivity patterns differ among patients with RA, including for motif-containing epitopes in important self-antigens like collagen and IgG (bound by RA-associated rheumatoid factors [RFs]), with limited understanding of the underlying mechanism. The objective of this study was to determine if HLA alleles associate with ACPA reactivity patterns. METHODS: For 100 ACPA+RF+ participants with RA, serum IgG binding was quantified by enzyme-linked immunosorbent assay to 10 citrulline-containing peptides derived from Type II collagen and IgG1 (nine with motifs), and HLA loci were genotyped. Also, antibody and serum multireactivity were evaluated. HLA alleles present differentially in RA participants with high versus low IgG binding to specific peptides, as well as with multireactivity versus limited reactivity were identified by Fisher's exact test. RESULTS: Serum IgG multireactivity for citrulline-glycine motif-containing collagen peptides was high, at least partially due to promiscuous antibodies. HLA-DQA1*01:02 was present in more participants with anticitrullinated collagen antibodies and multireactive sera. In contrast, serum multireactivity was low for IgG1-derived peptides due at least in part to more private antibodies. Shared epitope-containing HLA-DRB1*04:01 was present more frequently in participants with RA-associated RFs irrespective of the citrulline-serine motif and less frequently in participants with anticitrullinated collagen antibodies. Several HLA alleles associated with specific antibody reactivities. CONCLUSION: Different HLA alleles may contribute to the different reactivity patterns of promiscuous anticitrullinated collagen antibodies and more private RA-associated RFs.

Humans↗
PubMed2000

Citrulline immunohistochemistry for demonstration of NOS activity in vivo and in vitro.

Nitric oxide (NO), a biomolecule with major cytotoxic potency, is generated by NO synthases (NOS) utilizing l-arginine as substrate and citrulline is formed as a "side product." In brain tissue, citrulline is considered to be produced exclusively by NOS, due to the incomplete urea cycle in the brain. We aimed to characterize NOS activity by citrulline immunostaining in different cell types of the brain under in situ conditions and in slice and culture experiments. NOS-positive neurons and activated microglial cells were the most prominent citrulline-positive structures. Lack of citrulline immunoreaction in neurons of nNOS knockout mice emphasizes the dependency of citrulline positivity on NOS activity, and likewise there was no citrulline staining after application of the NOS inhibitors 7-nitroindazole and NIL. Interestingly, only a portion of NOS-containing neurons costained for citrulline. The inhibition of argininosuccinate synthetase by alpha-methyl-dl-aspartate increased the number of citrulline-positive cells, apparently due to reduction of the turnover rate of citrulline. Cells positive for NOS but negative for citrulline may indicate that the enzyme is either not activated or inhibited by cellular control mechanisms. The fact that not all citrulline-positive cells were NOS positive may be explained by an insufficient detection sensitivity or by disparate sites of citrulline production and recycling. The present results show that citrulline immunocytochemistry offers a viable and convenient means for studying NOS activity at the single-cell level to elicit its posttranslational control under physiological and pathophysiological conditions.

Animals↗
PubMed1997

Regulation of citrulline recycling in nitric oxide-dependent neurotransmission in the murine proximal colon.

1. We investigated the contribution of nitric oxide (NO) to inhibitory neuromuscular transmission in murine proximal colon and the possibility that citrulline is recycled to arginine to maintain the supply of substrate for NO synthesis. 2. Intracellular microelectrode recordings were made from circular smooth muscle cells in the presence of nifedipine and atropine (both 1 microM). Electrical field stimulation (EFS, 0.3-20 Hz) produced inhibitory junction potentials (i.j.ps) composed of an initial transient hyperpolarization (fast component) followed by a slow recovery to resting potential (slow component). 3. L-Nitro-arginine-methyl ester (L-NAME, 100 microM) selectively abolished the slow component of i.j.ps. The effects of L-NAME were reversed by L-arginine (0.2-2 mM) but not by D-arginine (2 mM). Sodium nitroprusside (an NO donor, 1 microM) reversibly hyperpolarized muscle cells. This suggests that NO mediates the slow component of i.j.ps. 4. L-Citrulline (0.2 mM) also reversed the effects of L-NAME, and this action was maintained during sustained exposures to L-citrulline (0.2 mM). This may reflect intraneuronal recycling of L-citrulline to L-arginine. 5. Higher concentrations of L-citrulline (e.g. 2 mM) had time-dependent effects. Brief exposure (15 min) reversed the effects of L-NAME, but during longer exposures (30 min) the effects of L-NAME gradually returned. In the continued presence of L-citrulline, L-arginine (2 mM) readily restored nitrergic transmission, suggesting that during long exposures to high concentrations of L-citrulline, the ability to generate arginine from citrulline was reduced. 6. Aspartate (2 mM) had no effect on i.j.ps, the effects of L-NAME, or the actions of L-citrulline in the presence of L-NAME, L-Citrulline (0.2-2 mM) alone had no effect on i.j.ps under control conditions. 7. S-methyl-L-thiocitrulline (10 microM), a novel NOS inhibitor, blocked the slow component of i.j.ps. The effects of this inhibitor were reversed by L-arginine (2 mM), but not by L-citrulline (2 mM). 8. These results suggest that i.j.ps in the murine colon result from release of multiple inhibitory neurotransmitters. NO mediates a slow component of enteric inhibitory neurotransmission. Recycling of L-citrulline to L-arginine may sustain substrate concentrations in support of NO synthesis and this pathway may be inhibited when concentrations of L-citrulline are elevated.

Animals↗
PubMed1993

Regulation of L-arginine synthesis from L-citrulline by L-glutamine in endothelial cells.

L-Arginine synthesis from L-citrulline was studied in cultured bovine venular, bovine aortic, human microvascular, and cloned human microvascular endothelial cells (EC). L-Citrulline was actively recycled into L-arginine in all four EC lines, with similar rates between venular and aortic EC. L-Arginine synthesis from L-citrulline was very sensitive to extracellular L-citrulline concentrations in the range normally found in plasma (50-100 microM). L-Glutamine (0.5mM) decreased L-arginine synthesis from L-citrulline, whereas 0.5 mM L-arginine, L-alanine, L-glutamate, or L-lysine had no effect. In contrast to the findings in intact cells, 1 mM L-glutamine had no effect on L-arginine synthesis from L-citrulline in EC lysates. Similarly, L-glutamine (1 mM) had no effect on the conversion of argininosuccinate to arginine in EC lysates. L-Glutamine (0.5 and 1 mM), but not 0.5 mM L-arginine, L-alanine, L-glutamate, or L-lysine, inhibited L-citrulline transport by EC. The inhibition of L-citrulline transport by L-glutamine was dose dependent and competitive in nature. These results suggest that L-glutamine decreased L-arginine synthesis from extracellular L-citrulline by interfering with its transport. Inasmuch as nitric oxide (NO) and L-citrulline are constantly generated from L-arginine, with L-citrulline being actively converted into L-arginine in venular, microvascular, and aortic EC, our data indicate a functioning intracellular arginine-citrulline cycle in these cells. This cycle may function to efficiently scavenge the carbon and alpha-amino group of L-arginine and to maintain a sufficient cellular concentration of L-arginine during prolonged synthesis of NO in EC. (ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Stimulation-induced 3H-L-citrulline accumulation in isolated longitudinal muscle myenteric plexus preparations of rat small intestine: a measure to characterize nitrergic neurons.

Nitric oxide (NO) synthase activity in rat isolated longitudinal muscle myenteric plexus preparations of the small intestine was determine by measuring the accumulation of 3H-L-citrulline during 30 min incubation with 3H-L-arginine. In untreated preparations a significant amount of 3H-L-citrulline accumulated in the tissue, about 2000 dpm/30 mg per 30 min, accounting for about 1.7% of the tissue radioactivity. Intermittent electrical field stimulation (15 Hz, 10 s trains with 10 s intervals for total of 20 min) caused a threefold increase in 3H-L-citrulline accumulation. The NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) reduced the spontaneous accumulation of 3H-L-citrulline by 65% and prevented the electrically evoked increase. Removal of extracellular calcium or addition of tetrodotoxin blocked the electrically evoked increase in 3H-L-citrulline accumulation without affecting spontaneous accumulation. Application of the calcium ionophore A 23187 (10 mumol/l) or 45 mmol/l) or 45 mmol/l potassium caused a twofold increase in the accumulation of 3H-L-citrulline. The muscarine receptor agonist oxotremorine (1 mumol/l) had no effect on spontaneous accumulation of 3H-L-citrulline, but inhibited the electrically evoked increase by about 50%, and this effect was blocked by scopolamine. A substantial amount of 3H-L-citrulline (15000 dpm) accumulated also in the incubation media, and this was increased 1.7-fold by the presence of A 23187 and 2.7-fold by electrical stimulation. However, electrically evoked increase in 3H-L-citrulline was not prevented by tetrodotoxin, in contrast to observation on tissue levels. In conclusion, during incubation with 3H-L-arginine tissue levels of 3H-L-citrulline in rat isolated longitudinal muscle myenteric plexus preparations, but not accumulation in incubation media may be used as a biochemical marker of the activity of nitrergic intestinal neurons which appear to be inhibited via muscarine receptors.

Animals↗
PubMed1993

The activation of the arginine-citrulline cycle in macrophages from the spontaneously diabetic BB rat.

The activity of the arginine-citrulline cycle was investigated in macrophages from the spontaneous immunologically mediated diabetic BB rat. Peritoneal macrophages were prepared from male diabetes-prone (BBdp), diabetic (BBd) and age-matched non-diabetes-prone (BBn) rats. Cells were incubated at 37 degrees C for 2 h in Krebs-Henseleit bicarbonate buffer containing 0.5 mM L-arginine, 0.1 mM L-[ureido-14C]citrulline and 5 mM D-glucose to measure the activity of the arginine-citrulline cycle. The uptakes of citrulline and arginine by macrophages were measured during a 5 min incubation period with L-[ureido-14C]citrulline and L-[2,3-3H] arginine respectively. The production of NO3- (the major stable oxidation product of NO) increased (P < 0.01) by 112% and 151% in 75-day-old BBdp and 115-day-old BBd macrophages respectively, compared with age-matched BBn cells. The conversion of [14C]citrulline into [14C]arginine increased (P < 0.01) by 704%, 892% and 904% in 50- and 75-day-old BBdp and 115-day-old BBd macrophages respectively, compared with age-matched BBn cells. The enhanced NO synthesis in BBdp and BBd macrophages was associated with a 25-35% increase in the uptake of L-arginine. However, there were no differences in the uptake of citrulline between BBdp or BBd macrophages and age-matched BBn cells. Our results demonstrate for the first time the activation of the arginine-citrulline cycle in macrophages in an autoimmune condition. The inherent increase in the recycling of L-citrulline to L-arginine in BBdp and BBd macrophages may reflect an innate metabolic disorder in these cells. This increased L-arginine synthesis from L-citrulline may play a role in sustaining a sufficient intracellular L-arginine concentration for prolonged generation of NO in BBdp and BBd macrophages. A role for NO in the autoimmune destruction of pancreatic beta-cells in insulin-dependent diabetes mellitus warrants further investigation.

Animals↗
PubMed2001

Serum citrulline and rejection in small bowel transplantation: a preliminary report.

BACKGROUND: There is no known serum marker for intestinal rejection. Serum concentrations of the amino acid citrulline arise almost exclusively from the intestinal mucosa. We examined the impact of acute cellular rejection (ACR) of intestinal allografts on serum citrulline levels. METHODS: Citrulline concentrations were assayed in serum samples of healthy volunteers (n=6) and seven patients who underwent small bowel transplants (SBTx). Trends in mean citrulline concentrations versus degree of ACR were assessed by matching posttransplantation citrulline concentrations with patients' grade of ACR at time of serum collection. Rejection was confirmed by biopsy and graded by following standardized criteria. An additional patient had citrulline concentrations determined for 31 sequential specimens 3-60 days posttransplant. RESULTS: Mean citrulline concentrations in controls were significantly higher than posttransplantation samples at any rejection grade. Mean concentrations declined significantly as rejection severity increased. The overall downward trend was statistically significant (P<0.05). In sequential measurements, citrulline levels increased significantly over time with declining severity of rejection. The increase in mean citrulline concentration between posttransplant days 3-16 and 52-60 was significant (P<0.01). CONCLUSIONS: Serum citrulline levels decline with increasing grade of ACR and may be a useful serum marker for intestinal rejection.

Adult↗
PubMed1981

Source and fate of circulating citrulline.

Previous work has demonstrated a continuous release of citrulline from the small intestine into the circulation. To evaluate the physiologic significance of this process, we have now measured citrulline uptake and release by isolated, perfused livers and, through surgical means and arteriovenous difference measurements, by various organs of the rat in vivo. Intestinally derived citrulline, an end product of glutamine nitrogen metabolism, passes through the liver without appreciable uptake. No significant extraintestinal source of circulating citrulline was found. Contrary to earlier suggestions, the liver releases no citrulline normally, but only when supplied with unphysiological high levels of ornithine and ammonia. Renal citrulline uptake was equivalent to approximately 83% the rate of intestinal release; kidneys, in turn, released arginine equivalent to approximately 75% of the citrulline taken up. Acute experiments in which the intestine, intestine plus liver, or kidneys were excluded from the circulation indicate that additional organs may also participate in citrulline exchange, at least when the circulating citrulline level is abnormal. The intestinal-renal pathway seems to account for a large though still unmeasured portion of the citrulline turnover in the circulation.

Amino Acids↗
PubMed1999

L-Citrulline, the by-product of nitric oxide synthesis, decreases vascular smooth muscle cell proliferation.

Endothelium injury plays an important role in atherosclerosis. Damage to the endothelium results in vascular smooth muscle cell proliferation. Natriuretic peptides present a potent antimitogenic action, mediating their biological effects via the binding of guanylate cyclase-linked atrial natriuretic peptide (ANP) receptor and the production of cyclic GMP. In a previous study, we demonstrated that L-citrulline, the by-product of nitric oxide synthesis, could relax rabbit aortic rings by stimulating the guanylate cyclase-linked ANP receptor. In this work, we investigated the effect of L-citrulline on vascular smooth muscle cell proliferation. L-Citrulline (10(-8) M) significantly decreased rat aortic (A10 cell line) vascular smooth muscle proliferation. The percentage of inhibition exerted by L-citrulline on days 3, 5, and 7 of the proliferation curve was 20.0 +/- 0.5%, 37.5 +/- 8.3%, and 28. 5 +/- 7.2%, respectively. In addition, L-citrulline also inhibited serum-induced DNA synthesis, measured as 5-bromo-2'-deoxyuridine incorporation. 5-Bromo-2'-deoxyuridine incorporation into nuclei of vehicle-treated cells was 40.5 +/- 2.4%, whereas in L-citrulline-treated cells the percentage decreased to 36.0 +/- 4.1%, 29.1 +/- 2.0% (P <.01, n = 4), 30.5 +/- 2.4% (P <.05, n = 4), and 23.1 +/- 0.5% (P <.001, n = 4) for 10(-10), 10(-9), 10(-8), and 10(-7) M, respectively. Zaprinast, a phosphodiesterase type V inhibitor, enhanced 5-bromo-2'-deoxyuridine incorporation in serum-stimulated cells. Moreover, L-citrulline inhibition of serum-stimulated DNA synthesis was abolished by HS-142-1 (10(-5) M), an ANP receptor antagonist. In another group of experiments, L-citrulline was shown to increase intracellular cyclic GMP levels from 2.1 +/- 0.2 pmol of cGMP/mg protein to 4.1 +/- 0.1 for L-citrulline (10(-8) M) (P <.001, n = 3). These findings suggest that L-citrulline decreases vascular smooth muscle cell proliferation in the A10 cell line by acting on DNA synthesis by mechanisms that involve the ANP receptor.

Animals↗
PubMed2001

Specific presence of intracellular citrullinated proteins in rheumatoid arthritis synovium: relevance to antifilaggrin autoantibodies.

OBJECTIVE: To investigate the presence of citrullinated proteins in the synovial membrane of patients with rheumatoid arthritis (RA) and controls, and to analyze a possible relationship with antifilaggrin autoantibody (AFA) reactivity. METHODS: Synovial biopsy samples were obtained from 88 consecutive patients undergoing needle arthroscopy for knee synovitis associated with RA (n = 36), spondylarthropathy (n = 35), osteoarthritis (n = 9), or other diagnoses (n = 8). Tissue sections were stained with 2 different anticitrulline polyclonal antibodies and an antifilaggrin monoclonal antibody (mAb). The phenotype of citrulline-positive cells and the colocalization with affinity-purified AFA were investigated by double immunofluorescence on frozen sections. RESULTS: Studies with the first antibody showed that citrulline is expressed intracellularly in the lining and sublining layers of RA synovial tissue. Staining with the second antibody, monospecific for proteins containing modified citrulline, and with anti-inducible nitric oxide synthetase confirmed the presence of citrullinated proteins rather than free citrulline in the synovium. Citrulline-positive cells were detected in 50% of the RA patients (18 of 36) but in none of the controls (0 of 52). The anticitrulline reactivity colocalized with affinity-purified AFA reactivity, although stainings with the antifilaggrin mAb indicated the absence of filaggrin in the synovium. CONCLUSION: Intracellular citrullinated proteins, which are not recognized by an antifilaggrin mAb, are expressed in RA but not in control synovium. The high specificity of this finding and the colocalization with AFA reactivity boost the interest in citrullinated proteins as possible triggers of autoimmune responses in RA. Moreover, this is the first description of a specific histologic marker for RA synovium.

Adult↗
PubMed1997

L-citrulline recycling in opossum internal anal sphincter relaxation by nonadrenergic, noncholinergic nerve stimulation.

BACKGROUND & AIMS: L-citrulline formed stoichiometrically along with nitric oxide (1:1) from L-arginine may be enzymatically converted to L-arginine. The possibility of L-citrulline recycling in the maintenance of nitrergic neurotransmission in the opossum internal anal sphincter (IAS) smooth muscle strips was investigated. METHODS: Responses to nonadrenergic, noncholinergic (NANC) nerve stimulation by electrical field stimulation (EFS) (either short-train or continuous stimulation) on the basal IAS tension were recorded before and after the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA), L-NNA plus L-citrulline, or L-arginine. During continuous EFS, when the basal IAS tone after the initial relaxation had recovered to almost pre-EFS levels, the effects of L-citrulline or L-arginine were examined before and after L-glutamine, which is a putative blocker of L-citrulline uptake. RESULTS: Inhibition of NANC nerve-mediated IAS relaxation by L-NNA was reversed by L-citrulline as well as L-arginine. L-Citrulline and L-arginine caused concentration-dependent relaxation of the IAS tone recovered during the prolonged EFS. L-Glutamine blocked the responses of L-citrulline but not of L-arginine. Furthermore, L-glutamine increased the speed of recovery of IAS tone during continuous EFS. CONCLUSIONS: L-citrulline recycling may be responsible for the maintenance of IAS relaxation during frequent short-train and prolonged NANC nerve stimulation.

Anal Canal↗
PubMed1996

Quantitative aspects of interorgan relationships among arginine and citrulline metabolism.

The quantitative roles of the splanchnic region and the kidneys in whole body (WB) arginine and citrulline metabolism were assessed in postabsorptive mongrel dogs with primed constant intravenous infusions of [15N2-guanidino, 5,5-2H2]arginine and [13C-ureido]citrulline or [13C-guanidino]arginine and [15N]urea tracers. Isotope and metabolite concentration balances of arginine and citrulline were measured across the gut, liver, splanchnic region, and kidneys, together with WB arginine and citrulline fluxes and urea production rate. The WB citrulline flux and rate of citrulline to arginine (C-A) conversion were 16 and 9.4 mumol.kg-1.h-1, respectively. Concentration balance of citrulline across kidneys was +8.2 mumol.kg-1.h-1, and metabolism of citrulline by kidneys was 8.7 mumol.kg-1.h-1, which was derived about equally from intestine and liver. The appearance rate of citrulline-derived arginine in renal vein was 6.8 mumol.kg-1.h-1. These three separate estimates of C-A conversion within the kidneys were in good agreement, indicating 40% of blood C-A conversion occurring outside kidneys. These findings of interorgan metabolism are discussed in reference to the current knowledge derived largely from studies in laboratory rodents.

Animals↗
PubMed2000

Cardioprotective effects of citrulline in ischemia/reperfusion injury via a non-nitric oxide-mediated mechanism.

The effects of L-citrulline, the byproduct of nitric oxide (NO) synthesis, and its stereoisomer D-citrulline were studied in a polymorphonuclear leukocyte (PMN)-dependent isolated perfused rat heart model consisting of 20 min of global ischemia and 45 min of reperfusion. Ischemic hearts reperfused with either D- or L-citrulline (20 nM) exhibited a marked preservation of left ventricular developed pressure and of maximal rate of development of left ventricular developed pressure, compared to hearts perfused without either D- or L-citrulline (both p < 0.001). In addition, both D- and L-citrulline significantly attenuated PMN accumulation in the post-reperfused myocardium from 288 +/- 33 PMNs/mm2 in untreated hearts to 89 +/- 10 and 76 +/- 6 PMNs/mm2, respectively (both p < 0.001). In isolated rat aortic rings, neither D- or L-citrulline induced any vasodilation or release of nitric oxide from the vascular endothelium. However, expression of P-selectin on the coronary vascular endothelium was markedly attenuated in hearts perfused with either D- or L-citrulline compared to ischemic-reperfused hearts without citrulline (both p < 0.001). These results provide evidence that D- or L-citrulline significantly attenuates PMN-induced cardiac contractile dysfunction in the isolated perfused rat heart subjected to ischemia/reperfusion via a non-NO-mediated mechanism.

Animals↗
PubMed1982

Ammonia metabolism in Reye syndrome and the effect of citrulline.

Ammonia metabolism in Reye syndrome was studied by quantitative analysis of the time course of hyperammonemia and the urinary excretion of ammonia, urea, and total nitrogen. These measures were then utilized to assess the effect of citrulline administration in 8 patients compared to results in 22 patients managed without citrulline. Two indices of the severity and duration of hyperammonemia correlated strongly with mortality: the half-time for decline of hyperammonemia and the area under the hyperammonemia curve (an index of the total burden of ammonia presented to the brain). These results suggest that the total amount of ammonia delivered to brain may be important to the pathogenesis of encephalopathy. Citrulline-treated patients had more severe disease at admission and greater abnormalities in indices of nitrogen and ammonia metabolism, though the latter did not reach significance. The urine ammonia/urea nitrogen excretion ratio, an index of the efficiency of ammonia conversion to urea, normalized more rapidly in the citrulline-treated group, evidence that citrulline may have improved urea cycle function. Overall mortality did not differ in the two groups. The deaths of 2 citrulline-treated patients in this small group were attributable to factors unrelated to treatment, however, so the possible effect of citrulline on mortality was not definitively tested. No indication was found that citrulline was harmful, nor that it increased ammonia levels.

Ammonia↗